Family History Of Hematologic Malignancy Research Articles

Lymphoid Malignancy Risk with Rare Inherited Variants in Known Cancer Predisposition Genes

Introduction Lymphoid malignancy (LM) is a heterogenous neoplasm with respect to biology, aggressiveness, and treatment with over 100 subtypes, including Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM). Genome-wide association studies have identified common variants associated with risk of specific LM subtypes, but less is known about the contribution of rare inherited pathogenic variants (PV) in the genetic architecture of LM risk. Rare PV have been shown to contribute to the genetic architecture of solid tumor cancer risk, many of which have been found in genes that are important to the DNA-damage repair (DDR) pathway (e.g., BRCA1, BRCA1, ATM). Here, we investigated the prevalence of PV in cancer predisposition genes regularly included on multi-gene panel testing based on NCCN guidelines and correlated with risk of LM overall and by common subtypes. Methods In this association study, cases were newly diagnosed lymphomas (excluding chronic lymphocytic leukemia) from Mayo Clinic who were enrolled between 2002 and 2015 in the Lymphoma SPORE Molecular Epidemiology Resource (MER) and MM from Mayo Clinic enrolled primarily between 1998 and 2022 in a clinical registry. Controls were from the Mayo Clinic Biobank who were enrolled between 2009 and 2016, from which we excluded individuals with a history of hematologic malignancy. All participants provided a blood sample for whole exome sequencing, performed by Regeneron on an Illumina NovaSeq panel (mean coverage of 48X). Variants were called using GATK v4 and variant annotation was performed using BioR. All loss-of-function variants (i.e., nonsense, frameshift, and consensus splice sites) and pathogenic missense in 19 cancer predisposition genes with a minor allele frequency < 0.5% were included in the analyses. Logistic regression was used to estimate odds ratio (OR) and 95% confidence intervals (CI) for the association between mutation status by gene (burden test) and risk of LM overall, and by subtype that had more than 5 mutation carriers. All analyses were adjusted for age (at diagnosis for cases and at enrollment for controls) and sex. Results A total of 6990 cases and 42432 controls were included. Median age was 63 years for both cases and controls (case range 18-94 years, control range 18-99 years). Males accounted for 58.5% (n=4090) of the cases and 41.7% (n=17762) of the controls. MM accounted for 31% (n=2138) of the cases, followed by diffuse large B-cell lymphoma (DLBCL, n=1146) and follicular lymphoma (FL, n=1132) each accounting for 16% of cases. CHEK2 (1.0%), ATM (0.4%), BRCA2 (0.4%), and BRCA1 (0.3%) had the most PV carriers in controls; these frequencies are in the range of published control populations. A total of 1816 (3.7%) individuals had a PV across the 19 genes, with 4.7% of cases and 3.5% of controls carrying any PV (OR=1.34, 95% CI: 1.18-1.51). ATM (OR=1.86, 95% CI: 1.36-2.49), CHEK2 (OR=1.74, 95% CI: 1.42-2.13) and TP53 (OR=9.07, 95% CI: 4.51-18.87) were all significantly associated with increased risk of LM overall (Figure 1). When investigating subtypes (Table 1), CHEK2 (OR=1.93, 95% CI: 1.23-2.89) and TP53(OR=10.97, 95% CI: 3.06-31.43) were significantly associated with DLBCL. ATM (OR=2.22, 95% CI: 1.13-3.90) was significantly associated with FL. ATM (OR=1.97, 95% CI: 1.16-3.12), CHEK2 (OR=1.75, 95% CI: 1.24-2.41) and TP53 (OR=7.67, 95% CI: 2.43-20.72) were significantly associated with MM and ATM (OR=8.62, 95% CI: 4.47-15.12), NBN (OR=6.94, 95% CI: 2.41-15.76) and TP53 (OR=38.30, 95% CI: 10.27-116.69) were significantly associated with mantle cell lymphoma (MCL). When subset to LM cases overall, there was no evidence of enrichment for young onset (age <60 years), male sex, or family history of hematologic malignancy between PV carriers and non-PV carriers. However, FL cases with an ATM PV tended to be less than 60 years (OR=3.21, P=0.09) compared to non- ATM PV carriers. Similarly, MM cases with a TP53 PV tended to be less than 60 years of age (OR=7.39, P=0.07) compared non-carriers. Discussion In this large case-control study, PV in established cancer predisposition genes were associated with increased risk of LM overall, demonstrating that rare inherited variants may play an important etiologic role. This study also suggests that PV in cancer predisposition genes may be subtype specific. These results will help inform LM risk for individuals who undergo genetic testing of cancer predisposition genes.

Persistence of Monoclonal Gammopathies in Serial Samples from a US Population-Based Screening Study

Background: The prevalence of monoclonal gammopathy of undetermined significance (MGUS) in a population at high risk of developing multiple myeloma (MM) was recently described in a US screening study. In a high-risk population, MGUS prevalence was measured as 6% by serum protein electrophoresis with immunofixation (SPEP/IFX) and 13% by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Screening by MALDI-TOF MS allowed for the detection of monoclonal proteins (M-proteins) below the threshold of detection of gel-based assays, that was referred to as Monoclonal Gammopathy of Indeterminate Potential (MGIP). MGIP was found in 25% of the screened cohort and was significantly associated with aging. Other studies indicated that MGUS and MGIP detected by MS may be transient and their detection may not be critical for long term outcomes. Therefore, we aimed to determine the fate of M-proteins detected by MS in a US population-based study. Methods: High-risk individuals enrolled in the study include those who self-identify as Black or have a family history of hematologic malignancies or a precursor condition to MM. Samples that tested positive for MGUS (M-protein >= 0.2 g/L) by MALDI-TOF MS were confirmed using clinically approved assays and results were returned to participants. All participants who had an M-protein detected at baseline by MALDI-TOF MS were invited to submit follow-up samples to investigate the fate of the M-proteins detected at the MGIP and MGUS levels. Serum was analyzed using the Binding Site Group's EXENT® assay based on MALDI-TOF MS for the identification and quantification of M-proteins. Persistence of the M-protein detected at baseline was defined as the presence of the same isotype M-protein on a serial sample and within +/-5 mass to charge ratio on mass spectra. All serial samples where the M-protein was not detected by MALDI-TOF MS were reflex tested to liquid chromatography (LC) MS. Results: We analyzed 262 multi-timepoint samples collected from 102 participants who tested positive for an M-protein, with a median follow-up of 336 days (Range 36 - 1,240; IQR 141 - 737). The median age at screening was 60.8 years, 65 (64%) participants were female, 9 (9%) self-identified as Black, and 93 (91%) were non-Black and reported a family history of hematologic malignancy. At baseline, 66 (65%) participants had MGIP (M-protein <0.2g/L) and 36 (35%) had MGUS (M-protein >=0.2/L) measured by MALDI-TOF MS. All participants with MGIP were negative at baseline by SPEP/IFX, while among those with MGUS at baseline, 25/36 (69%) participants had an M-protein detected by SPEP/IFX. At baseline, the distribution of isotypes was 21% IgG, 17% IgA, and 62% IgM for MGIP and 69% IgG, 17% IgA, and 14% IgM for MGUS. For all 102 cases, their most recent serial samples were tested by MALDI-TOF MS or LC-MS. 60/66 (91%) of the MGIP cases were re-confirmed on serial sampling, with a median follow-up time of 504 days (Range 41 - 1,240; IQR 149 - 888). As for MGUS, 36/36 (100%) of cases detected at baseline persisted on serial sampling, with a median follow-up time of 239 days (Range 36 - 1105; IQR 103 - 628) (Figure 1). Time from baseline to serial sampling was not associated with persistence. In 12 participants so far, M-proteins detected by MS were seen to persist for more than 3 years after baseline testing. In 5 of the MGIP cases, M-protein concentration measured by MALDI-TOF MS increased from MGIP level to above the MGUS threshold. These participants had a median baseline M-protein concentration of 0.14 g/L (Range 0.13 - 0.17 g/L; IQR 0.13 - 0.14), which was in the upper MGIP concentration level, and had a median follow-up time of 532 days (Range 171 - 1,127; IQR 302 - 570). Of these, 3 persisted as IgG, 1 IgA, and 1 IgM isotypes. Conclusion: We present the first longitudinal analysis of M-proteins detected by MS, including those below the threshold of detection of gel-based assays, in a US population-based screening study. Results confirm the persistence of 91% of MGIP and 100% of MGUS cases detected by MS. Some cases showed increasing M-protein concentration, crossing the threshold of detection by gel-based assays. Additional studies are underway to further validate our findings in a larger cohort with longer follow-up time. Testing serial samples with increasing M-protein concentration by gel-based assays will help better understand the significance of early detection of MGIP cases by MS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Assessment of Concurrent Personal and Family History of Hematologic Malignancies in Patients Referred for Genetic Counseling at Thomas Jefferson University Hospital (TJUH), Sidney Kimmel Cancer Center (SKCC) from 2014-2021

Introduction: Studies have suggested that 5% of adult patients with MDS and AML have inherited mutant alleles that predispose to disease development. More than 50 hereditary cancer syndromes have been defined-many specifically associated with myeloid and lymphoid malignancies. Yet hereditary hematologic malignancies (HHMs) continue to go unrecognized. The implications for patients, especially regarding family donor selection for allogeneic stem cell transplant, necessitate greater awareness. Referrals for genetic counseling at SKCC have been triggered primarily by a personal or family history of solid tumors. The aim of this study was to assess the frequency of hematologic malignancies in the setting of concurrent solid tumor diagnosis or significant family history of cancer. Methods: In order to gain preliminary insight into the unmet need for genetic counseling for HHMs at our institution, we queried our Cancer Genetics REDCap database (IRB-approved #16D.743) for all patients who had a cancer diagnosis, a family history of cancer, and a hematologic malignancy (HM). Cancer diagnoses and family history were collected at time of genetic counseling by a genetic counselor and were primarily patient reported. After identifying patients with self-reported HMs, HM diagnoses were confirmed by medical history and pathology report, if available, in our electronic medical record system. Results: The database included 5073 patients who were evaluated at SKCC's Cancer Genetics Program between 2014 and 2021. 3150 patients had a known cancer diagnosis including: breast (1812), prostate (349), ovarian (219), colon/rectal (218), pancreatic (157), melanoma (123), kidney (83), lung (18), and other (708). 4734 patients had a family history of cancer. 2913 patients had both a personal cancer diagnosis and a family history of cancer. Overall, 58 (2%) of these patients had a hematologic malignancy. Among patients with a HM, average age at HM diagnosis was 47 years (median 50, range 5-80) and average age at time of genetics counseling was 60 years (median 63.5, range 35-83). 48 of the patients were female. 51 were White/Caucasian, 6 were Black/African American, and 1 was Asian. 1 patient was Hispanic and 8 patients were Ashkenazi Jewish. There was a wide range of HM diagnoses (Table 1). 39 (67%) patients had a concurrent solid malignancy. The 58 patients with a HM and family history of cancer had on average 5.2 family members with a malignancy (median 4, range 1-14). 53 (91.4%) of the patients had at least 1 first degree relative with a malignancy (Table 2). 17 (29%) patients had a family member with a known HM, including 11 (19%) with a first degree relative. HMs identified among first and second degree relatives included: CLL (N=5) Non-Hodgkin lymphoma (N=3), Hodgkin lymphoma (N=3), Waldenstrom macroglobulinemia (N=2), lymphoma not otherwise specified (N=3), AML (N=1), leukemia NOS (N=3), multiple myeloma (N=2), and polycythemia transformed to myelofibrosis (N=1). Of the 40 HM patients who had germline genetic testing performed, alterations were identified in 22. 10 of the patients had 11 pathogenic or likely pathogenic variants in CHEK2, ATM, FANCC, NBN, MSH2, MSH6, BRCA2, and/or FH. 6 (60%) of these patients had alterations in genes known to be associated with HHMs. 21 variants of unknown significance were identified in 14 patients, including in 2 patients with pathogenic variants. Conclusions: Approximately 2% of patients referred for genetic counseling for a personal malignancy and family history of cancer had a concurrent diagnosis of a HM. This likely under-represents the number of patients with HHMs, particularly since 6 of the 10 patients identified to have pathogenic or likely pathogenic variants had alterations in genes associated with HHMs. The findings that 67% of the HM patients had a second malignancy and that HM patients had on average 5 family members with cancer highlight the importance of identifying high risk patients to guide surveillance for earlier detection. Earlier recognition is crucial, as the average age of genetics counseling was 60. Despite striking family cancer histories, germline variants were not identified in several patients, suggesting that there may be germline variants that have yet to be identified. Efforts to expand genetic screening that focus on earlier identification, standardized germline testing for high risk patients, and appropriate surveillance will be important. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Dead and Deah-Box Helicases Other Than DDX41 Are Mutated in Myeloid Neoplasia

DEAD (DDX)/ DEAH (DHX)-box family of putative RNA helicases are enzymes belonging to the SF2 helicase superfamily. These enzymes are essential for RNA metabolism and integrity of RNA machinery by conserving the helicase cores while unwinding RNA helices. Mutations of several DDX/DHX-family members have been associated with a variety of conditions such as X-linked neurodevelopmental disorders (DDX3X and DDX54) and early-onset autosomal recessive retinitis pigmentosa (DHX38). To date, the only family member involved in the pathogenesis of myeloid neoplasia (MN) is DDX41, which was identified as a causative gene for late onset familial myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). In light of the correlation between gene paralog and human diseases, we explored whether variants in members of the DDX and DHX-box helicases other than DDX41 may also been observed in MN. To that end, we compiled the most comprehensive phylogenetic analysis of 52 RNA helicases genes in MN, describing variants ontogeny (somatic-SOM vs. germline-GL), molecular associations and exploiting informative cases. A total of 1,843 patients (including public sources as TCGA and Beat AML) with MN were analyzed by WES/WGS1,2 and targeted sequencing. We have identified 112 variants belonging to the DDX and 15 to the DHX family of genes in 131 patients. (Fig.1) As in our original report on DDX41 mutations3, the majority (68%) of the variants were GL with DDX41 being the most recurrently mutated gene accounting for up to 75% of cases, of which 15% displaying a biallelic GL plus SOM configuration. We then tested whether GL or SOM hits in other helicases may substitute for the DDX41 GL or SOM mutations carriers, respectively. We did not find any GL variants of other helicases to form compound heterozygous configuration with SOM DDX41 mutations. However, there were two patients who harbored DDX54SOM/DDX41SOM, one patient carried DHX29SOM/DDX41SOM/DDX54SOM and one displayed somatic mosaicism with DDX6SOM/DHX29SOM configuration. The second most commonly mutated DDXs gene in our cohort was DDX54 (n=8; GL/SOM=3/5) while the most common DHX mutated gene was DHX29 (n=10; GL/SOM=1/9). In analogy to DDX41, 3/5 with DDX54 mutations and 1/9 DHX20 showed biallelic GL/SOM configuration. Furthermore, we have also found 11 variants in DDX4/DHX29 located as DDX41 on 5q. Consistent with the topography of DDX41, which was recapitulated in our cohort (60% of the DDX41 variants mapped within the DEAD/Helicase ATP binding and Helicase C-terminal functional domains), half of the DDX54 variants also were located in the DEAD/Helicase ATP binding domains. In terms of MN diagnosis, MDS phenotype was the most frequent (50%), followed by AML (41%) and MPN (9%). Overall, median age of patients was 69 (range, 28-90) and did not differ between carriers of GL or SOM variants. Male gender was predominant in both cases with GL or SOM hits (M/FGL=2.1; M/FSOM=5.5). Abnormal karyotype (mostly including +8, del5q and del20q) was found in 40% of our cohort without differences between patients with GL or SOM. Of note, no family history of hematologic malignancies was noted in cases with DDX54 or DHX29 variants. Phenotypically, one male patient with DDX54GL presented with pancytopenia at 30 years of age, one had a 20-year long-standing history of anemia while the only patient with a DXH29GL variant developed MDS at 48 years of age. A Medline search led us to associate two GL stopgains in DDX11 (R558* and R829*), a gene belonging to other human helicases (e.g.,XPD, FANCJ, RTEL1) implicated in MN, to Warsaw breakage syndrome. Noteworthy is that we detected a DDX11R558* (previously reported in consanguineous with such disorder) in a patient with RTEL1 and RAD51 variants and a somatic NRASG12D. Finally, with regards to additional myeloid driver lesions, TET2 and DNMT3A were among the most frequently mutated genes in all 3 cohorts of DDX41, DDX54 and DHX29-mutants. Our study represents the first in-depth analysis of DDX and DHX helicases in MN. One could speculate that paralogs DDX-DHX genes in MN exhibit a redundant function justifying why deleterious variants in more than one gene of the SF2 family do not propagate in the population. Beside the established role of DDX41 in inherited familiar cases, the rare occurrence of mutations in other helicases and their contribution to MN pathogenesis deserves attention and further studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinicopathological Features of Isolated Thrombocytopenia Associated with SRSF2 Mutations: A Case Series

Introduction: Mutations of SRSF2, a gene involved in RNA splicing, are identified across a heterogenous group of myeloid neoplasms including MDS, CMML, and MPN. SRSF2 mutations have been associated with thrombocytopenia in MDS, but not in the case of MDS/MPN overlap conditions. When co-mutated with TET2, SRSF2 is associated with monocytosis and a myeloproliferative phenotype. SRSF2 mutations are also identified in normal individuals and in those with clonal cytopenias of undetermined significance (CCUS). Studies have examined genotype-phenotype correlations in myeloid malignancies, but similar analysis of the heterogeneity amongst patients with CCUS are lacking. Although dysplasia is not a defining feature of CCUS, sub-diagnostic dysplasia can be seen in CCUS and this subset notably had a higher proportion of spliceosome mutations. Here we describe the clinical and pathological features of a series of CCUS patients with prolonged, isolated thrombocytopenia and a SRSF2 mutation. Methods: We conducted a retrospective review of the electronic medical records of patients seen in the outpatient Hematology Clinic at the University of Southern California Norris Comprehensive Center between May 2014 and December 2021. Patients with persistent (> 6 months) isolated thrombocytopenia, a SRSF2 pathogenic mutation identified on a myeloid molecular panel, and absence of WHO-defined dysplasia or hematologic neoplasm on initial bone marrow biopsy were included. A work-up for alternative etiologies of thrombocytopenia was completed based on the clinical judgment of the treating physician. Bone marrow biopsies were reviewed by 2 independent hematopathologists. This study was approved by the Institutional Review Board of the University of Southern California. All patients signed informed consent. Results: Five patients met criteria for inclusion. All patients were male. Median age at diagnosis of thrombocytopenia was 61 years (56-74). Two patients were Asian and 3 were Caucasian. The median time from diagnosis of thrombocytopenia to the identification of a mutation on a myeloid molecular panel was 4 years (3-12). No patients had a family history of hematologic malignancy. Initial bone marrow biopsies did not meet WHO-defined thresholds for morphologic dysplasia. However, all patients had megakaryocytic hyperplasia and megakaryocytes with hyperchromasia and high nuclear-cytoplasmic ratio in 20% of megakaryocytes (Figure 1). Two patients who had CD34 staining showed positive staining in 30% of megakaryocytes. Four patients had normal cytogenetics and 1 patient had monosomy 7. Median bone marrow cellularity was 65% (30-80%). Two patients had intermittent peripheral monocytosis but did not meet the diagnostic criteria for CMML. No monocyte proliferation or immature monocytes were seen on bone marrow. SRSF2 mutations were P95H in 3 patients and P95L in 2 patients. Average variant allele frequency was 37.3% (range 28 - 50.2). Four patients had a co-occurring TET2 mutation; other co-mutated genes included RUNX1 (3 pts.), ASXL1 (1 pt.), DNMT3A (1 pt.), and NF1 (1 pt.). Median number of co-occurring mutations was 2 (0-3). Three patients were treated empirically for immune thrombocytopenia and had no response to IVIG and/or steroids. Three patients were treated with thrombopoietin receptor agonists (2 eltrombopag, 1 romiplostim) and had minimal transient platelet count increases not meeting the IWG MDS criteria for response. One patient was treated with hypomethylating agents for 4 months before progressing to MDS or AML. Four patients required as-needed platelet transfusions. To date, 4 have progressed to MDS or AML with a median time from diagnosis to progression of 6.3 years (range 5-10). Three patients have received allogeneic hematopoietic stem cell transplant. Conclusion: This series describes a subset of CCUS patients with isolated thrombocytopenia associated with SRSF2 mutations. We also describe atypical megakaryocytic findings which do not meet current WHO diagnostic criteria for dysmegakaryopoiesis; however, the uniform presence of these findings in this cohort suggests an association with thrombocytopenia and CCUS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Family History of Hematologic Malignancies and Risk of Multiple Myeloma in Black Americans

Introduction: Multiple Myeloma (MM) is the most common hematologic malignancy in Black Americans. Standardized incidence rates are increasing, consistent with an aging population, and are 2- to 3- fold higher among Black Americans compared to White Americans for reasons that remain unclear. Methods: Using participants enrolled in the Integrative Molecular And Genetic Epidemiology (IMAGE) study of myeloma (955 MM cases; 1,316 sex-, race-, age-, geography- matched controls), we investigated the risk of MM associated with family history of cancer and differences by race. We estimated risk using odds ratios and corresponding 95% confidence intervals adjusted for confounders calculated from logistic regression. Results: Overall, MM risk in cases with a first degree relative affected with any hematologic malignancy was significantly elevated compared to controls (OR=1.36, 95% CI 1.02-1.82; P=0.038). Myeloma risk associated with a family history of MM was higher than the risk associated with any hematologic malignancy (OR=2.13, 95% CI 1.20-3.79; P=0.001), and the magnitude of this effect was greater for Black Americans (OR=4.88, 95% CI 1.90-12.51; P=0.001) than White Americans (OR=1.03, 95% CI 0.45-2.32; P=0.951) with similar relationships observed among first degree relatives with any plasma cell proliferative disorder (ORBlack=5.34, 95% CI 2.11-13.54; P=0.0004 and ORWhite=1.18, 95% CI 0.59-2.37;P=0.642) and with increasing numbers of affected relatives (P-trend=0.001). Conclusions: Findings confirm our previous report that the excess risk of MM observed in Black Americans may be attributed to shared germline and environmental susceptibility. Studies, which include family history of plasma cell proliferative disorders, to determine screening effectiveness in high-risk populations are warranted.

P876: INCIDENTAL DISCOVERY OF PROBABLE PATHOGENIC GERMLINE VARIANTS IN MULTIPLE MYELOMA PATIENTS UNDERGOING SOMATIC GENOMIC PROFILING

Background: Next-generation sequencing (NGS) is increasingly used to characterize the somatic mutational landscape of patients with multiple myeloma (MM) and guide precision medicine approaches. Somatic genomic profiling (SGP) in cancer patients can lead to the incidental discovery of pathogenic or likely-pathogenic germline variants (PGVs) in ~4% of cases (PMID 26787237). Our previous analysis of whole exome germline data from 895 MM patients in the MMRF CoMMpass dataset showed ~8% of MM patients carry a PGV in a hereditary cancer gene (HCG), and identified shared characteristics among PGV carriers including younger age at diagnosis, higher likelihood of having family history of hematologic malignancy, higher likelihood of t(11;14) MM, and favorable outcomes (Thibaud et al, ASH 2021). Aims: The present study aims to assess the rate of detection of probable PGVs (PPGVs) in MM patients undergoing targeted SGP. Methods: We retrospectively reviewed results of 1,614 commercial NGS panels performed by a single genetic testing laboratory on bone marrow aspirates of 1,095 MM patients treated at our institution since 2015 who were not enrolled in the MMRF CoMMpass study. We considered individual variants to be PPGVs when all of the following criteria were met: 1) variant found in a panel of 106 well-established HCGs (same panel used in our prior study, but excluding TP53 given high rate of somatic mutations in MM); 2) variant unambiguously listed as pathogenic or likely pathogenic (P/LP) in ClinVar, or variant classified as “conflicting interpretations of pathogenicity” but reported by ≥2 CLIA-certified labs as P/LP; 3) variant allele frequency (VAF) >30% (per PMID 33236764); 4) variant detected in all available test reports for a given patient (and VAF >30% in all available test reports). Well known founder variants (FV) in specific populations were labeled as PPGV-FVs. Results: 95 MM patients (8.7%) had a genetic variant meeting criteria to be classified as a PPGV. Two patients had 2 distinct PPGV. PPGV were most commonly detected in the following HCGs (Table 1): APC (n=22), CHEK2 (n=20), ATM (n=7), BRCA1 (n=6), MUTYH (n=6). Of all PPGV carriers, 47 (49%) carried a PPGV-FV. Median VAF for PPGVs was 48.2% (range 30-85%). 34 PPGV carriers had serial NGS tests available (range 2-5 reports); in these patients, VAF standard deviation across serial measurements was <5% in 89% of cases. Taken together, these findings indicate a high likelihood that PPGV detected in these MM patients while undergoing tumor sequencing are indeed incidentally-discovered PGV warranting referral to a genetic counselor for consideration of confirmatory testing. Image:Summary/Conclusion: SGP of bone marrow aspirate in MM patients incidentally detected PPGV in well-established HCG in 8.7% of cases. These findings are consistent with those of our prior study, which found an 8.6% prevalence of PGV in newly-diagnosed MM patients. In MM patients undergoing SGP, detection of a mutation involving a HCG and with a VAF >30% should prompt referral to genetic counseling for confirmatory testing, as PGV detection can have clear implications for patients and their families.

Abstract 741: Evaluation of etiologic heterogeneity for risk of diffuse large B-cell lymphoma (DLBCL) subtype defined by cell-of-origin

Abstract Background: DLBCL is the most common non-Hodgkin lymphoma subtype in western countries and is clinically heterogeneous. Gene expression profiling has identified two major biologically distinctive DLBCL subtypes defined by their cell-of-origin (COO): germinal center B-cell (GCB) - characterized by BCL2 rearrangement and C-REL amplification, and activated B-cell (ABC) - characterized by constitutive activation of the NF-kB pathway. We evaluated putative DLBCL risk factors for etiologic heterogeneity as defined by COO. Methods: We used a clinic-based study of newly diagnosed NHL cases and frequency matched controls, enrolled from 2002-2014, with a total of 687 DLBCL cases and 2253 controls for this analysis. Using formalin-fixed, paraffin-embedded tumor tissue, we determined COO by either digital expression profiling (NanoString; classified as GCB, ABC, undetermined) or clinically using the Hans algorithm (immunohistochemical markers; classified as GCB, non-GCB, undetermined). Integrating these two sources of COO data, there were 271 GCB, 170 non-GCB, and 246 undetermined/missing (mainly due to lack of tissue) cases. Risk factor data were collected from self-administered questionnaires and included family history of hematologic malignancy; history of atopy, allergy, asthma, eczema, or autoimmune disease; blood transfusion; vaccination history; regular low-dose aspirin use; body mass index (BMI) 2 years prior diagnosis/enrollment; smoking history; alcohol consumption (never/current/former); leisure-time physical activity; and recreational sun exposure. Polytomous logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals for COO subtypes, adjusted for age, sex and residence. Results: The median age of cases was 64 years with 55% male; the median age of controls was 64 years and 53% male. The association with BMI (30+ vs. 18.5-24.9 kg/m2) was stronger for non-GCB (OR=2.21; 1.40-3.49) than for GCB (OR=1.70; 1.21-2.40) DLBCL (P-heterogeneity 0.02), while a family history of hematologic malignancy was associated with non-GCB (OR=2.27; 1.47-3.50) but not GCB (OR=1.30; 0.86-1.96) DLBCL, although the P-heterogeneity was not significant (P=0.13). For GCB, there was an inverse association with former (vs. never) alcohol use for GCB (OR=0.57; 0.39-0.83) but not for non-GCB (OR=0.98; 0.61-1.57) DLBCL (P-heterogeneity 0.007), and an inverse association with regular use of low-dose aspirin for GCB (OR=0.64; 0.47-0.87) but not for non-GCB (OR=0.88; 0.61-1.25) DLBCL (P-heterogeneity 0.05). No other risk factors evaluated showed important heterogeneity by COO. Conclusions: These initial results suggest most DLBCL risk factors do not show etiologic heterogeneity by DLBCL COO, although associations with BMI and family history with non-GCB DLBCL and alcohol and low-dose aspirin use with GCB DLBCL warrant follow-up. Citation Format: Geffen Kleinstern, Dennis P. Robinson, Lisa M. Rimsza, Melissa C. Larson, Rebecca L. King, Grzegorz S. Nowakowski, Carrie A. Thompson, Stephen M. Ansell, Matthew J. Maurer, Andrew L. Feldman, Susan L. Slager, Anne J. Novak, Thomas M. Habermann, James R. Cerhan. Evaluation of etiologic heterogeneity for risk of diffuse large B-cell lymphoma (DLBCL) subtype defined by cell-of-origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 741.

Pathogenic Germline Variants in Multiple Myeloma

BACKGROUND: There is growing evidence supporting inherited predisposition to multiple myeloma (MM). Epidemiologic studies have shown that 1st-degree relatives of MM patients (pts) have a 2-4 fold increase in risk of developing MGUS or MM. Genome-wide association studies (GWAS) have identified common SNPs as well as rare high-penetrance variants that collectively explain ~16% of the estimated heritability of multiple myeloma (PMID 30213928). Pathogenic/likely-pathogenic germline variants (PGV) in hereditary cancer genes (HCG) are common in adult cancer patients (~8%, PMID 29625052), but prevalence in MM is not known. The aim of our study is to investigate the occurrence of PGV in newly-diagnosed MM (NDMM), and to describe clinical characteristics & outcomes of carriers.METHODS: We analyzed MMRF CoMMpass data (version IA16) and identified 895 NDMM pts for whom whole-exome sequencing of germline DNA was available. We used the clinical annotation pipeline from Sema4, a CLIA/CAP certified genetic testing laboratory, to identify pts with PGV according to ACMG variant classification guidelines. We compared clinical characteristics & disease phenotypes of PGV carriers vs non-carriers. We used Chi-Square and Fisher's Exact tests to assess statistical significance, which we defined as a two-sided p value < 0.05. Logistic regression models were used for multivariate analyses. Kaplan-Meier method and Cox proportional-hazards models were used for uni- and multivariate survival analysis, respectively. Bonferroni method was used to account for multiple testing.RESULTS: We identified 83 PGV in 31 distinct HCG in 79 (8.8%) of 895 NDMM pts (83% European ancestry) [Figure 1A]. Most PGV involved DNA damage repair (DDR) genes (78%), and homologous recombination (HR) genes were the most commonly mutated (34%). PGV in CHEK2 were the most common (n=10, 1.1% of all MM pts). 2 pts carried PGV in TP53 and reported extensive family history of Li-Fraumeni-associated cancers (breast, sarcoma, gastric & melanoma). 6 pts had germline mismatch repair (MMR) gene defects (1:149, considerably higher than the estimated prevalence of Lynch syndrome in Western populations). 4 pts carried PGV in BRCA2 (previously identified in a family study as a potential MM predisposition gene, PMID 11904319). MM pts with a family history of hematologic malignancy (leukemia, lymphoma or MM) in a 1st or 2nd-degree relative were significantly more likely to carry PGV (22 vs 7.6%, OR=3.3, p<0.001), an association that remained significant in MVA (OR=4.1, p<0.001). CHEK2 variants emerged as leading drivers of this correlation (OR 18.2, 95% CI 4.1-75, adjusted p<0.01), & especially protein-truncating founder variant c.1100delC. Likelihood of being diagnosed w/ MM before age 40 was significantly higher in PGV carriers (6.3 vs 1.8%, OR=3.7, p=0.025). 25% of those younger than 40 y/o carried PGV, but none of these were in DDR-HR genes, a notable difference with other age groups (0 vs 41%, p=0.02). 2/6 MMR PGV were detected in pts diagnosed before age 40. In univariate survival analysis, DDR-PGV carriers had a significant PFS1 advantage over non-carriers (median 52 vs 35 months, p=0.008), as well as a non-significant OS advantage (p=0.08). PFS1 difference remained significant in MVA after adjusting for age, ISS stage, high-risk cytogenetics, treatment type & transplant status (OR 0.65, 95% CI 0.44-0.97, p=0.03) [Figure 1B].CONCLUSIONS: PGV in HCG were common (8.8%) in this large cohort of NDMM pts of predominantly European ancestry, especially in those with a family history of hematologic malignancy (1:4, with high prevalence of CHEK2 variants & particularly protein-truncating founder variant c.1100delC), and in those diagnosed before age 40 (1:4). Routine screening in high-prevalence subgroups might be warranted, as carriers may benefit from counseling and enrollment in early cancer detection programs. We observed a clinically and statistically significant PFS1 advantage in carriers of PGV in DDR genes, possibly due to increased sensitivity to MM therapies, a well-described phenomenon in other cancer types (PMID 33158305). Prospective validation of these findings is needed to better understand prognostic & therapeutic implications of PGV in MM. [Display omitted] DisclosuresChari: Karyopharm: Consultancy; Takeda Pharmaceutical Company: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Oncopeptides: Consultancy; Antegene: Consultancy; Glaxosmithkline: Consultancy; Secura Bio: Consultancy. Richard: Karyopharm, Janssen: Honoraria. Richter: Sanofi: Consultancy; Antengene: Consultancy; Karyopharm: Consultancy; BMS: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Adaptive Biotechnologies: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; X4 Pharmaceuticals: Consultancy; Oncopeptides: Consultancy; Adaptive Biotechnologies: Consultancy; Secura Bio: Consultancy; Astra Zeneca: Consultancy. Parekh: Foundation Medicine Inc: Consultancy; Amgen: Research Funding; PFIZER: Research Funding; CELGENE: Research Funding; Karyopharm Inv: Research Funding.

P-063: Pathogenic germline variants in hereditary cancer genes in patients with Multiple Myeloma

<h3>Background</h3> GWAS have identified common SNPs & rare high-penetrance variants that explain ~16% of the estimated heritability of multiple myeloma (MM)(PMID 30213928). Pathogenic/likely-pathogenic germline variants (PGV) in hereditary cancer genes (HCG) are common in adult cancer pts (~8%), but prevalence in MM is not known. The aim of our study is to investigate the occurrence of PGV in newly-diagnosed MM (NDMM) and describe clinical characteristics & outcomes of carriers. <h3>Methods</h3> We analyzed MMRF CoMMpass data & identified 895 NDMM pts with whole-exome sequencing of germline DNA. We used the clinical annotation pipeline from Sema4, a CLIA/CAP certified genetic testing laboratory, to identify pts with PGV according to ACMG variant classification guidelines. We compared clinical characteristics & disease phenotypes of PGV carriers vs non-carriers. We used Chi-Square and Fisher's Exact tests to assess statistical significance. <h3>Results</h3> We identified 83 PGV in 31 distinct HCG in 79 (8.8%) of 895 NDMM pts (83% European ancestry). Most PGV involved DNA damage repair (DDR) genes (78%), & homologous recombination (HR) genes were the most commonly mutated (34%). PGV in CHEK2 were most common (n=10,1.1% of all MM pts). 2 pts carried PGV in TP53, & 6 pts had mismatch repair (MMR) gene defects (1:149). MM pts with family history (FH) of hematologic malignancy (HM) in a 1st or 2nd-degree relative were more likely to carry PGV (22 vs 7.6%,OR=3.3,p<0.001), an association that remained significant in multivariate analysis (MVA) (OR=4.1,p<0.001). CHEK2 variants were leading drivers of this correlation (OR 18,adjusted p<0.01), & especially protein-truncating founder variant c.1100delC. Likelihood of MM dx before age 40 was significantly higher in PGV carriers (6.3 vs 1.8%,OR=3.7,p=0.025). 25% of those <40y/o carried PGV, but none of these were in DDR-HR genes, a notable difference with other age groups (0 vs 41%,p=0.02). 2/6 MMR PGV were detected in pts <40y/o. In univariate analysis, DDR-PGV carriers had a significant PFS1 advantage (median 52 vs 35 months,p=0.008) & a non-significant OS advantage (p=0.08). PFS1 difference remained significant in MVA adjusting for age, ISS stage, high-risk cytogenetics, treatment type & transplant status (OR 0.65,95% CI 0.44-0.97,p=0.03). <h3>Conclusions</h3> PGV in HCG were common (8.8%) in this large cohort of NDMM pts of predominantly European ancestry, especially in those with FH of HM (1:4, with high prevalence of CHEK2 variants), and in those <40y/o (1:4). Routine screening in high-prevalence subgroups may be warranted, as carriers can benefit from counseling & enrollment in early cancer detection programs. We observed a clinically & statistically significant PFS1 advantage in PGV carriers, possibly due to increased sensitivity to MM therapies, a well-described phenomenon in other cancers (PMID 33158305). Prospective validation of these findings is needed to better understand prognostic & therapeutic implications of PGV in MM.

Epi-P-03 - Association between primary cutaneous lymphomas and other primary malignancies in patients’ personal or family history in Greek population; a retrospective single-center study

<h3>Background:</h3> Primary cutaneous lymphomas (PCLs) consist of an heterogenous group of rare malignancies. Cutaneous T-cell lymphomas are the most common among them, with mycosis fungoides being the main representative. The etiology of PCLs is rather unknown; however, there are indications that genetic factors may play a role in CTCL developments [1]. Several studies have examined the incidence of second malignancies in patients with PCLs, as well as their family history of malignancies [2–4]. In our study we examine the association between PCLs and other primary malignancies in patients' personal or family history in Greek population. <h3>Methods:</h3> This retrospective study included 144 patients with histopathologically confirmed diagnosis of PCL and 130 controls matched by gender and age (±4 years). All patients and controls completed a detailed questionnaire regarding sun exposure habits-including personal history of sunburns, use of photo-protective measures, use of sunbeds- exposure to ionizing radiation, smoking and alcohol consumption habits, detailed medical personal history (diseases, medication, other chronic skin conditions, personal history of malignancies, etc.) and family history (chronic skin conditions, malignancies). Statistical analysis of the data was performed using PASW Statistics v25 software. <h3>Results:</h3> Of the 144 patients included, 78 (54.2%) were males and 66 (45.8%) females (median age 57 years old) and among the 130 control subjects, 70 (53.8%) were males and 60 (46.2%) females (median age 61 years old). Analysis showed that family history of solid organ cancer is related to higher relative risk (OR 1.815) of CL development (p<0.05, 95% CI 1.11–2.95). The two types of solid organ tumors more highlighted were liver cancer (p=0.046) and stomach cancer (p=0.002). Family history of skin cancer as well as hematologic malignancies doesn't seem to affect the risk of CL in statistically significant way (p=0.247 and p=0.093 relatively) in our group. As far as the personal history of other primary malignancies is concerned, statistical analysis showed that there might be a correlation between other malignancies and primary cutaneous lymphomas (p<0.05). At this point we should notice the limitation that the number of patients and controls having a personal history of any type of cancer was small, but it consists a predictor. <h3>Conclusion:</h3> There are several studies analyzing the correlation of PCLs and second primary cancers. The results of our study showed an association of personal history of cancer with PCLs, as well as a correlation of family history of solid organ malignancy with a higher relative risk of cutaneous lymphoma development. No higher relative risk was detected in subjects with family history of hematologic malignancies. We believe that it is important to be aware of the personal and the family history of patients with PCL, as far as the malignancies are concerned, and try to early recognize possible second malignancies in these patients.

26508 Blastic plasmacytoid dendritic cell neoplasm

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic neoplasm that arises from precursors of plasmacytoid dendritic cells. Clinical findings of BPDCN may be nondescript, making histologic evaluation, with the aid of immunohistochemical stains, essential. We present a case of a 76-year-old male with no known medical history who presented with chief complaint of a lesion on his chest. He previously thought the lesion was a bruise; however, when it failed to resolve, he sought medical evaluation. The patient denied personal or family history of hematologic malignancy. Thorough review of systems was negative with the exception of recent onset fatigue. Physical examination revealed a solitary, well-defined erythematous-to-violaceous plaque with a central nodular component on the patient’s chest. A 4-mm punch biopsy was obtained from the nodular component. Hematoxylin–eosin evaluation demonstrated dermal nodules of tumor cells extending into the fat with sparing of the overlying epidermis. Individual cells were oval in shape with dispersed nuclear chromatin and eccentric pink plasmacytoid-like cytoplasm. Immunohistochemistry staining was positive for CD123, CD56, and CD4, but negative for CD3, supporting a diagnosis of BPDCN. Subsequently, the patient was referred to hematology and oncology for systemic evaluation and treatment. Our case highlights a rare entity as well as underscores the importance of immunohistochemical stains in accurately diagnosing hematologic neoplasms with cutaneous manifestations. While rare, BPDCN represents an important diagnostic consideration for dermatologists as it most commonly presents in the integumentary system and early identification may impact treatment course and outcome.

Association of Clinical Epidemiologic Exposures and Overall Survival with Genome-Wide DNA Methylation Profiles in Acute Myeloid Leukemia: Analysis of the Mayo Clinic AML Epidemiology Cohort

Background: We previously demonstrated that putative clinical epidemiologic exposures associated with leukemia risk are prevalent among AML patients, and some are associated with unique cytogenetic risk group and with clinical phenotype (Finn, Cancer Epidemiol, 2015). Herein, we studied genome-wide DNA methylation in a cohort of AML patients to evaluate the association of individual hyper- and hypo-methylated CpG sites with epidemiologic exposures and overall survival.Methods: The Mayo Clinic AML Epidemiology Cohort is a highly annotated retrospective case series of 295 consecutive patients (pts) with AML diagnosed and treated at Mayo Clinic Florida and Arizona, with central cytogenetics performed in all cases. The prevalence of clinical epidemiologic exposures, past medical and family history as well as medication use and lifestyle was systematically obtained. After IRB approval, we interrogated the cytogenetic database and successfully obtained leukemia DNA from available remnant diagnostic cytogenetic cell pellets in a cohort of 148 AML patients in the Mayo epidemiology case series and performed an assessment of genome-wide DNA methylation using the Infinium HumanMethylation450K BeadChip. Samples were processed using the R Bioconductor package ‘minfi’ using Subset Within Array Quantile Normalization (PMID: 22703947). Individual CpGs that did not reach a detection p-value of <0.05 were filtered out. An internal control was included on each array to control for significant batch effects. To determine differential methylation status of 473,864 individual CpG sites (after exclusion of 11,648 that did not pass detection p-value QC), CpG sites with low interpatient variability, a standard deviation <0.05 of methylation values, and an interquartile range <0.05 of methylation values and X/Y chromosome probes were excluded from analysis. Epidemiologic and important clinical variables occurring in at least 10 pts or previously-identified as of unique interest but in fewer than 10 pts were evaluated, including sex, BMI, performance status and comorbidities, tobacco and alcohol use, family history of hematologic malignancy, medications of interest, history of toxin exposure, and history of immunosuppression and/or solid organ transplant or of secondary and therapy-related AML (t-AML).Associations of differential hypo or hypermethylation at 281,259 CpG sites with epidemiologic exposures/clinical variables were evaluated using Spearman's test of correlation (continuous or ordinal exposures), a Wilcoxon rank sum test (dichotomous exposures), or a Kruskal-Wallis rank sum test (multi-category exposures). A Bonferroni correction was applied for multiple testing, after which p <1.8 x 10-7 was considered as significant. To reduce the likelihood of false-negative findings, we additionally considered p <5 x 10-6 as indicating suggestive evidence of an association. CpG sites and associated gene and function was determined using Illumina manifest file & www.ncbi.nlm.nih.gov/gene.Results: Statistically significant associations (p <1.8 x 10-7) with individual epidemiologic and clinical exposures were identified for 109 unique CpG sites, corresponding to differential methylation in the genes listed in Table. Specifically, obesity (predominantly hypomethylation), specific cytogenetic lesions and risk group, and gender were highly significantly associated with unique CpG methylation status, but not smoking, toxin exposure, family history, comorbidity or performance status, secondary or t-AML, immunosuppression, medication use, of family history in the analysis. A further 353 unique CpG sites had defined suggestive associations (ongoing analysis). We also identified 8 additional CpG sites where differential methylation was associated with overall survival (p <5 x 10-6, Table).Conclusion: Obesity, cytogenetic lesions, and sex are associated with differential methylation of unique CpG sites at AML diagnosis, using stringent univariate statistical criteria. Significant CpG sites were identified in genes previously linked to AML biology and prognosis (DOCK6, HOXB3, MIR10A, FOXN3/CHES1, GPX1, MYST2/KAT7, PTPRD), but some represent novel findings in AML. These preliminary results suggest an association of some AML risk factors and clinical variables with unique gene methylation and will undergo validation in a prospective AML epidemiology dataset. [Display omitted] DisclosuresCerhan:Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding; Celgene: Research Funding. Foran:Agios: Research Funding; Xencor, Inc.: Research Funding.

Polygenic Risk Score in Follicular Lymphoma Risk and Prognosis in a Population-Based Case-Control Study in Los Angeles County

Background: Although several prognostic factors are regularly utilized for follicular lymphoma (FL) - e.g., extent of disease, presence of B-symptoms, and the FL international prognostic index (IPI) - they do not fully account for the heterogeneity in patient outcomes. Etiologic risk factors may influence the heterogeneity of prognostic outcomes, but relatively few risk factors for FL have been identified and subsequently confirmed. Recent epidemiologic studies have uncovered genetic risk loci associated with FL risk. To date, the association between these risk alleles with FL prognosis remains unknown. We therefore sought to evaluate whether identified genetic risk loci specific to FL also play a role in FL prognosis.Methods: We previously conducted a population-based case-control study of primary, incident Non-Hodgkin Lymphoma (NHL) among women in Los Angeles County diagnosed from 2006 to 2009. A total of 230 FL cases were enrolled in the study along with 246 age- and race- matched controls. To ascertain treatment and follow-up information, medical records were retrieved and abstracted, and data linkages to the California hospitalization discharge records and SEER-Medicare were conducted. Based on abstracted data, we constructed a surrogate to the FL IPI. Genotyping for FL genetic risk alleles identified in the National Human Genome Research Institute-European Bioinformatics Institute genome wide association study catalog (rs12195582, rs13254990, rs17749561, rs4245081, and rs4938573) was conducted and used to construct a polygenic risk score (PRS). The PRS was computed by taking a weighted average of the five alleles and the log of their reported odds ratio and creating tertiles based on the values of our control. To confirm the risk association, we first evaluated the association between our PRS and FL risk, adjusted for demographic characteristics and potential confounders (e.g., smoking status, BMI, and family history of hematologic malignancies). We subsequently confirmed the prognostic performance of our reconstructed IPI and then evaluated the association between the PRS and FL outcomes, including overall survival (OS), defined as date of initial diagnosis to date of death or last known follow-up; and event-free survival at 12 months (EFS12) and 24 months (EFS24), where events consisted of progression, refractory disease, or death.Results: In case-control analysis, we confirmed an increased FL risk associated with the third tertile PRS (OR=2.19, 95% CI=1.22-3.94), compared to the first tertile. The median follow-up time among FL cases was 8.5 years (IQR: 7.1-10.1) after initial diagnosis: 50 (22%) FL cases had died, 198 (86%) achieved EFS12 and 186 (81%) achieved EFS24. The re-constructed FL-IPI in our case population was statistically significantly associated with overall survival (HR=4.00, 95% CI=1.32-12.16). In our multivariate model that included the PRS, we observed a marginally significant risk for longer overall survival (HR=0.39, 95% CI=0.15, 1.01), but no association with EFS12 or EFS24. No statistically significant associations of individual risk alleles and prognostic outcomes were observed. Race-specific results and evaluation of demographic and other risk factors on risk and survival will also be presented in relation to the PRS.Conclusion: In our population sample of FL cases identified from the Los Angeles County Cancer Registry and initially recruited for a case-control study, we confirmed the association between a PRS and FL risk. We further report a potential association between the PRS and improved overall survival, suggesting an opposite effect for the PRS on risk versus survival. Larger studies on FL with genetic data and prognostic outcomes are warranted to replicate this finding. DisclosuresChao:Seattle Genetics: Research Funding.

Adherence to the Western, Prudent, and Mediterranean dietary patterns and chronic lymphocytic leukemia in the MCC-Spain study.

Diet is a modifiable risk factor for several neoplasms but evidence for chronic lymphocytic leukemia (CLL) is sparse. Previous studies examining the association between single-food items and CLL risk have yielded mixed results, while few studies have been conducted on overall diet, reporting inconclusive findings. This study aimed to evaluate the association between adherence to three dietary patterns and CLL in the multicase-control study (MCC-Spain) study. Anthropometric, sociodemographic, medical and dietary information was collected for 369 CLL cases and 1605 controls. Three validated dietary patterns, Western, Prudent and Mediterranean, were reconstructed in the MCC-Spain data. The association between adherence to each dietary pattern and CLL was assessed, overall and by Rai stage, using mixed logistic regression models adjusted for potential confounders. High adherence to a Western dietary pattern (i.e. high intake of high-fat dairy products, processed meat, refined grains, sweets, caloric drinks, and convenience food) was associated with CLL [ORQ4 vs. Q1=1.63 (95%CI 1.11; 2.39); P-trend=0.02; OR 1-SD increase=1.19 (95%CI: 1.03; 1.37)], independently of Rai stages. No differences in the association were observed according to sex, Body Mass Index, energy intake, tobacco, physical activity, working on a farm, or family history of hematologic malignancies. No associations were observed for Mediterranean and Prudent dietary patterns and CLL. This study provides the first evidence for an association between a Western dietary pattern and CLL, suggesting that a proportion of CLL cases could be prevented by modifying dietary habits. Further research, especially with a prospective design, is warranted to confirm these findings.

Occupational, dietary, and other risk factors for myelodysplastic syndromes in Western Greece

ABSTRACTPurpose: We have observed an increasing incidence of myelodysplastic syndromes (MDS) in the geographic area of Western Greece during the past two decades. The objective of this study was to investigate potential risk factors for the manifestation of MDS in this area of Greece.Methods: A hospital-based case–control study was conducted in the public hospitals of the region. Participants were interviewed based on a questionnaire regarding demographics, occupational exposures, smoking, alcohol consumption, dietary, and domestic factors.Results: A total of 228 individuals (126 cases, 102 controls) were recruited in this study. Univariate analysis showed that risk of MDS was associated with a family history of hematologic malignancy or solid tumor, exposure to pesticides, insecticides, herbicides, increased weekly intake of meat and eggs, and increased alcohol intake, whereas fruit intake had a protective effect. Analysis by pesticide ingredient showed a weak association of exposure to paraquat and glyphosate with the occurrence of MDS. Multivariate analysis showed that independent risk factors for the manifestation of MDS were family history of solid tumor (OR 2.47, 95% CI 1.32–4.65), meat intake for ≥5 days/week (OR 2.67, 95% CI 1.05–6.80) and exposure to pesticides (OR 3.25, 95% CI 1.73–6.11).Conclusions: Exposure to pesticides is a major risk factor of MDS in Western Greece. Family history of solid tumor and increased meat intake also appear to play a role in the pathogenesis of MDS. Public health authorities should implement policies to advise and protect farmers from the harmful effects of agrochemicals. Emphasis should also be given to health promotion advice including healthy eating.

Abstract 1762: Body mass index shows etiologic heterogeneity for risk of diffuse large B-cell lymphoma (DLBCL) subtype defined by cell-of-origin

Abstract Background. DLBCL is the most common non-Hodgkin lymphoma (NHL) subtype in western countries and is known to be clinically heterogeneous. Gene expression profiling has identified two major, biologically distinctive DLBCL subtypes on the basis of their cell-of-origin (COO): the germinal center B-cell (GCB) - characterized by BCL2 rearrangement and C-REL amplification, and activated B-cell (ABC) - characterized by constitutive activation of the NF-kB pathway. Recently, the InterLymph Subtypes Project identified medical history, lifestyle, and family history risk factors for DLBCL using a large pooled analysis of case-control studies. In this study we evaluated these same risk factors for etiologic heterogeneity as defined by DLBCL COO. Methods. For this analysis we used a clinic-based study of newly diagnosed NHL cases and frequency matched controls, enrolled from 2002-2012, with 474 DLBCL cases and 2203 controls. COO was determined clinically using the Hans algorithm, which is based on immunohistochemistry markers using formalin-fixed, paraffin-embedded tumor tissue. Amongst DLBCL cases 107 were ABC, 207 were GCB, and 160 were missing subtype (tissue unavailable). Risk factor data, including body mass index (BMI), smoking, alcohol use, any allergy, asthma, blood transfusion, diabetes, rheumatoid arthritis, sun exposure, lived on a farm and family history of hematologic malignancy, were collected from self-administered questionnaires. Polytomous logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals for ABC and GCB subtypes, adjusted for age and sex. Results. The mean age of cases was 60.4 years with 53% male; the mean age of controls was 61.6 years and 53% male. We identified a strong positive association for BMI with risk of ABC but not GBC DLBCL (p-heterogeneity 0.025). Compared to BMI 18.5-24.9 kg/m2, those with a BMI of 25.0-29.9 (OR = 1.65; 0.93-2.93) or 30+ (OR = 2.61; 1.48-4.62) were at increased risk of ABC DLBCL. There was no association for a BMI of 25.0-29.9 (OR = 0.91; 0.63-1.31) or 30+ (OR = 1.21; 0.83-1.76) with GCB DLBCL. There was no evidence of significant heterogeneity between ABC and GCB DLBCL for the other risk factors that we evaluated. Further adjustment of the BMI association for educational level, smoking, and alcohol only slightly attenuated these findings. Conclusions. We observed a strong positive association of BMI with ABC but not GCB DLBCL. In contrast, other evaluated risk factors showed no heterogeneity by COO. While BMI has not been clearly associated with NHL overall, there has been evidence for an association with DLBCL. The etiologic heterogeneity we observed for ABC DLBCL is notable as BMI is also a strong risk factor for multiple myeloma, another post-germinal center B-cell malignancy. While requiring replication, our findings suggest BMI may influence B-cell neoplasia through effect on post-germinal center pathways. Citation Format: Matthew K. Breitenstein, Megan M. O’Byrne, Andrew L. Feldman, Carrie A. Thompson, William R. Macon, Grzegorz S. Nowakowski, Stephen M. Ansell, Susan L. Slager, Thomas M. Habermann, James R. Cerhan. Body mass index shows etiologic heterogeneity for risk of diffuse large B-cell lymphoma (DLBCL) subtype defined by cell-of-origin. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1762.

Family history of hematologic malignancies and risk of multiple myeloma: differences by race and clinical features.

PurposeMultiple myeloma (MM) is the most common hematologic malignancy affecting Blacks in the USA, with standardized incidence rates that are twofold to threefold higher than Whites. The rationale for the disparity is unclear.MethodsUsing participants enrolled in the Molecular And Genetic Epidemiology study of myeloma (259 MM cases; 461 controls), we examined the risk of MM associated with family history of cancer, differences by race and among cases, defining clinical features. Risk estimates were calculated using odds ratios and corresponding 95% confidence intervals from logistic regression adjusted for confounders.ResultsOverall, MM risk in cases with relatives affected with any hematologic malignancy was significantly elevated compared to controls (OR 1.89, 95% CI 1.25–2.86). Myeloma risk associated with a family history of MM was higher than the risk associated with any hematologic malignancy (OR 3.75, 95% CI 1.75–8.05), and the effect was greater for Blacks (OR 20.9, 95% CI 2.59–168) than Whites (OR 2.04, 95% 0.83–5.04), among cases with early onset (≤60 years; OR 4.58, 95% CI 1.21–17.3) and with increasing numbers of affected relatives (p trend = 0.001). Overall, frequencies of end organ damage differed in cases with relatives affected with any hematologic malignancy and significantly more cases exhibited κ light chain restriction (OR 3.23, 95% CI 1.13–9.26).ConclusionsThe excess risk of MM observed in Blacks and the variation in clinical features observed in MM patients according to family history of hematologic malignancy may be attributed to a shared germline and environmental susceptibility.Electronic supplementary materialThe online version of this article (doi:10.1007/s10552-015-0685-2) contains supplementary material, which is available to authorized users.

Medical history, lifestyle, family history, and occupational risk factors for lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.

Lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (LPL/WM), a rare non-Hodgkin lymphoma subtype, shows strong familial aggregation and a positive association with chronic immune stimulation, but evidence regarding other risk factors is very limited. The International Lymphoma Epidemiology Consortium (InterLymph) pooled data from 11 predominantly population-based case-control studies from North America, Europe, and Australia to examine medical history, lifestyle, family history, and occupational risk factors for LPL/WM. Age-, sex-, race/ethnicity-, and study-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression for a total of 374 LPL/WM cases and 23 096 controls. In multivariate analysis including all putative risk factors, LPL/WM risk was associated with history of Sjögren's syndrome (OR = 14.0, 95% CI = 3.60 to 54.6), systemic lupus erythematosus (OR = 8.23, 95% CI = 2.69 to 25.2), hay fever (OR = 0.73, 95% CI = 0.54 to 0.99), positive hepatitis C serology (OR = 2.51, 95% CI = 1.03 to 6.17), hematologic malignancy in a first-degree relative (OR = 1.64, 95% CI = 1.02 to 2.64), adult weight (OR = 0.61, 95% CI = 0.44 to 0.85 for highest vs. lowest quartile), duration of cigarette smoking (OR = 1.46, 95% CI = 1.04 to 2.05 for ≥ 40 years vs. nonsmokers), and occupation as a medical doctor (OR = 5.54, 95% CI = 2.19 to 14.0). There was no association with other medical conditions, lifestyle factors, or occupations. This pooled analysis confirmed associations with immune conditions and family history of hematologic malignancy, and identified new associations with hay fever, weight, smoking, and occupation, and no association with other lifestyle factors. These findings offer clues to LPL/WM biology and prevention.

Etiologic heterogeneity among non-Hodgkin lymphoma subtypes: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.

Non-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes. We pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case-control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE). Risks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10(-4)), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10(-4)). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Using a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.