Family History Of Leukemia Research Articles

Assessing the current situation and the influencing factors affecting perceived stigma among older patients after leukemia diagnosis

BACKGROUND Psychological problems are becoming increasingly prominent among older patients with leukemia, with patients potentially facing stigmatization after diagnosis. However, there is limited research on the stigma experienced by these patients and the factors that may contribute to it. AIM To investigate the stigma faced by older patients after being diagnosed with leukemia and to analyze the potential influencing factors. METHODS A retrospective analysis was conducted using clinical data obtained from questionnaire surveys, interviews, and the medical records of older patients with leukemia admitted to the Hengyang Medical School from June 2020 to June 2023. The data obtained included participants’ basic demographic information, medical history, leukemia type, family history of leukemia, average monthly family income, pension, and tendency to conceal illness. The Chinese versions of the Social Impact Scale (SIS), Perceived Social Support Scale (PSSS), Self-Rating Anxiety Scale (SAS), and Self-Rating Depression Scale (SDS) were used to assess indicators related to stigma, social support, and mental health status. We used Pearson’s correlation coefficient to analyze the strength and direction of the relationship between the scores of each scale, and regression analysis to explore the factors related to the stigma of older patients with leukemia after diagnosis. RESULTS Data from 120 patients with leukemia aged 65-80 years were analyzed. The total score on the SIS and PSSS was 43.60 ± 4.07 and 37.06 ± 2.87, respectively. The SAS score was 58.35 ± 8.32 and the SDS score was 60.58 ± 5.97. The stigma experienced by older leukemia patients was negatively correlated with social support (r = -0.691, P < 0.05) and positively correlated with anxiety and depression (r = 0.506, 0.382, P < 0.05). Age, education level, smoking status, average monthly family income, pension, and tendency to conceal illness were significantly associated with the participants’ level of stigma (P < 0.05). Age, smoking status, social support, anxiety, and depression were predictive factors of stigmatization among older leukemia patients after diagnosis (all P < 0.05), with a coefficient of determination (R2) of 0.644 and an adjusted R2 of 0.607. CONCLUSION Older patients commonly experience stigmatization after being diagnosed with leukemia. Factors such as age, smoking status, social support, and psychological well-being may influence older patients’ reported experience of stigma.

Dietary patterns and the risk of hematological malignancy in the California Teachers study cohort.

10545 Background: Many studies show a correlation between diet and the risk of developing cancer, but most of these studies pertain to solid tumors and data linking certain diets to hematologic malignancies is scarce. This study aims to elucidate the effect of dietary patterns on the risk of developing hematologic malignancy. This study aims to elucidate dietary patterns and correlation with the risk of developing a hematologic malignancy. Methods: Data from 106,029 women in the California Teachers Study (CTS) cohort was analyzed, 476 participants were diagnosed with lymphocytic, monocytic, or other leukemia, 895 with Hodgkin’s or non-Hodgkin’s lymphoma, and 227 with multiple myeloma between 1995-2020. Results: Five major dietary patterns were identified as: 1) plant-based diet, characterized by a high consumption of fruit and vegetables, 2) high-protein, high-fat diet characterized by a high consumption of animal proteins animal protein (e.g., meat and eggs) and added fats (e.g., butter and mayonnaise), 3) high-carbohydrate diet characterized by a high consumption of convenience foods, pasta, and bread, 4) ethnic diet characterized by a high consumption of legumes, soy-based foods, rick and dark-green leafy vegetables and 5) the salad and wine diet characterized by high consumption of salad and low-fat dressing, fish, wine, coffee and tea, using principal factors analysis (PCFA). Relative risk and confidence intervals were analyzed for each dietary pattern and their correlation to a diagnosis of a hematologic malignancy. Models were adjusted for race-ethnicity/birthplace, living/working half a mile from a chemical plan, living/working half a mile from a powerplant, cigarette use, family history of leukemia and/or lymphoma, BMI (kg/m2), daily caloric intake (kcal/day), socioeconomic status, and moderate physical activity (h/wk). Overall, the high-carbohydrate diet was shown to be protective against hematologic malignancy risk with the lowest RR in all quintiles, but lowest in the 5th quintile (RR: 0.73; 95% CI: 0.59, 0.99, p=0.004). A high-carbohydrate diet was also shown to be associated with a reduction in multiple myeloma risk specifically with the lowest RR in all quintiles, but lowest in the 5th quintile (RR: 0.79; 95% CI: 0.63, 0.98, p=0.03). The ethnic diet was associated with a higher risk of multiple myeloma with the highest RR in all quintiles but highest in the 2nd quintile (RR:1.21; 95% CI 1.06, 1.39, p=0.006). Conclusions: The finding that the high-carbohydrate diet is associated with a reduced risk of a hematologic malignancy warrants further research to characterize the degree of risk reduction, what specific foods, if any, in the category offer protective effects, and if it is a potential approach for prevention.

Systematic evaluation of clinical efficacy of CYP1B1 gene polymorphism in EGFR mutant non-small cell lung cancer observed by medical image.

Lung cancer is the cancer with the highest mortality rate and the highest incidence in the world at this stage. Among them, non-small lung cancer is the most common type of lung cancer, and most small cancers have disappeared, which is the optimal time for surgery at the time of diagnosis. To explore and systematically evaluate the clinical efficacy of CYP1B1 gene polymorphism in the treatment of epidermal growth factor receptor (EGFR) Mutant non-small cell lung cancer, this article proposes the principles of lung cancer screening based on CYP1B1 gene polymorphism and polarization imaging and explores the diagnosis and treatment of non-EGFR mutant lung cancer. Based on a large number of medical image data, imageomics can directly reflect the correlation between tumor molecular phenotype and image characteristics by deeply mining some imaging features of the image, which has important value in the early diagnosis of disease, the formulation of personalized treatment plan, and efficacy evaluation and prognosis prediction. A total of 141 NSCLC patients with sensitive EGFR mutation were included in this study, including 101 patients with EGFR single-gene mutation and 40 patients with EGFR multigene mutation coexisting mutation. Both groups of patients were female, aged ≥60 years, no smoking history, no family history of leukemia, adenocarcinoma, lung cancer, stage IV, lymph node metastasis, living, far from metastasis, and ECOG score of 0-2. This study examined the relative number of gene expression and PFS in EGFR multigene co-existing mutations. When the number of mixed genes is 1, 2, and higher, the PFS is 9 months, 8 months, and 6 months, respectively. The PFS time of this group of patients gradually shortened. Therefore, this study examined the benefit of polygenic mutation in estimation by comparing the clinical characteristics of patients with EGFR single-gene mutation and polygenic mutation, to provide measurement of EGFR-TKI and to provide suggestions for future drug selection.

Prevalence and significance of DDX41 gene variants in the general population

AbstractGerm line variants in the DDX41 gene have been linked to myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) development. However, the risks associated with different variants remain unknown, as do the basis of their leukemogenic properties, impact on steady-state hematopoiesis, and links to other cancers. Here, we investigate the frequency and significance of DDX41 variants in 454 792 United Kingdom Biobank (UKB) participants and identify 452 unique nonsynonymous DNA variants in 3538 (1/129) individuals. Many were novel, and the prevalence of most varied markedly by ancestry. Among the 1059 individuals with germ line pathogenic variants (DDX41-GPV) 34 developed MDS/AML (odds ratio, 12.3 vs noncarriers). Of these, 7 of 218 had start-lost, 22 of 584 had truncating, and 5 of 257 had missense (odds ratios: 12.9, 15.1, and 7.5, respectively). Using multivariate logistic regression, we found significant associations of DDX41-GPV with MDS, AML, and family history of leukemia but not lymphoma, myeloproliferative neoplasms, or other cancers. We also report that DDX41-GPV carriers do not have an increased prevalence of clonal hematopoiesis (CH). In fact, CH was significantly more common before sporadic vs DDX41-mutant MDS/AML, revealing distinct evolutionary paths. Furthermore, somatic mutation rates did not differ between sporadic and DDX41-mutant AML genomes, ruling out genomic instability as a driver of the latter. Finally, we found that higher mean red cell volume (MCV) and somatic DDX41 mutations in blood DNA identify DDX41-GPV carriers at increased MDS/AML risk. Collectively, our findings give new insights into the prevalence and cognate risks associated with DDX41 variants, as well as the clonal evolution and early detection of DDX41-mutant MDS/AML.

Evaluation of Risk Factors for Pediatric Cancers in the West of Iran

Background: Occurrence of pediatric cancers is affected by maternal, environmental, and hereditary/genetic factors. Objectives: The purpose of this study was to evaluate the correlation between background radiation, ultrasound and other possible risk factors for pediatric cancers incidence indicators. Methods: In a cross-sectional study during 2 years, 103 patients under 14 years were studied. A total of 13 environmental, maternal and hereditary/genetic risk factors were studied, and the study was performed by using a questionnaire, measurement of background radiation, and statistical data. Incidence in the studied sample size at city (ISSSC) and incidence in the studied sample size at area (ISSSA) indicators were defined. Results: The mean age of patients was (6.31 ± 3.22) including 54 (52.4%) males and 49 (47.6%) females. History of repeated ultrasound before gender determination (RUBGD) and repeated ultrasound during pregnancy (RUDP) were statistically higher in solid tumors group. Toxic substances (TS) and pediatric medical ionizing radiation (PMIR) was higher in hematologic malignancies. Statistically significant association were found between of cancer types and Family history of leukemia (FHL), Family history of solid tumors (FHST), Abortion history (AH), Maternal smoking during pregnancy (MSDP), Children’s residence place (CRP), and background radiation (BR) variables. No statistically significant association was found between cancer types and maternal pregnancy age (MPA), IVF baby, and maternal ionizing radiation exposure (MIRE) variables. Conclusions: Pediatric cancers are multifactorial diseases. Increased background radiation is correlated with an increased incidence of all pediatric malignancies. It seems that increasing ultrasound scans might increase the risk of solid tumors in children.

Association of Parental, Child, and Environmental Factors with the Occurrence of Childhood Leukemia in Upper Egypt

Background: Leukemia is the most common malignant tumor in children, responsible for nearly one-third of all childhood cancers. However, the exact risk factors of childhood leukemia are unknown. Objective(s): The aim of this study was to identify risk factors of leukemia among Upper Egyptian children. Methods: We conducted a case-control study in 2019. Cases included 170 children aged ≤18 years with a confirmed leukemia diagnosis at the South Egypt Cancer Institute. The controls included 170 children matched for age and sex, free from hematological problems, and diagnosed with a mild illness in a pediatric outpatient clinic. Data were collected from children’s parents using an interview questionnaire. Results: The significant predictors for childhood leukemia were abnormal birth weight (4 kg) (OR = 2.89, 95% CI: 1.46–5.71) and childhood exposure to previous diagnostic radiation (OR = 3.95, 95% CI: 1.37–11.31). The risk increased if the father’s occupation was farming (OR = 2.14, 95% CI: 1.04–4.40), household monthly income Conclusion: Abnormal birth weight, father’s occupation is farming, exposure to diagnostic radiation and pesticides, family history of leukemia or other cancers, and low income are risk factors for leukemia in Egyptian children.

Role of CTLA4-49A polymorphism in the pathogenesis of acute leukemia

Background Acute leukemia is a clonal disorder of both myeloid and lymphoid progenitors with distinctive morphologic, immunophenotypic, and genotypic features and represents the most frequent malignancy of childhood. Acute leukemia is associated with several humoral and cellular immune abnormalities that could lead to an inadequate antitumor response. One of the co-stimulators that regulates immune response is CTLA-4 which has been well established as a negative regulator of T-cell function. Objective The aim of this study was to investigate the association of an Single-Nucleotide Polymorphism (SNP) in CTLA4 49-A with genetic susceptibility to acute leukemia. Participants and methods This is a case–control study that included 65 Egyptian patients with acute lymphoblastic leukemia (ALL) and 25 patients with acute myeloid leukemia (AML). The control group comprised 60 healthy unrelated participants with no family history of leukemia or autoimmune disease. Using the PCR-restriction fragment length polymorphism methodology, CTLA4 49 A/G was analyzed in 150 samples representing 90 patients (65 patients with ALL, and 25 patients with AML) and 60 controls. Results There was no significant differences that were encountered between the different groups with regard to CTLA4 +49 A/G genotype or allele frequencies in ALL and AML cases. Neither was there a relation between the various genotypes and age of onset or the mode of presentation. Conclusions CTLA4 49 A/G polymorphism was not recognized as a risk susceptibility factor in our case–control study. To our knowledge, this is the first study involving acute leukemia. The authors recommend that additional studies with larger sample sizes and different populations are required to confirm the findings of the present study

Prevalence of Inherited Cancer Predisposition Mutations in a Cohort of Older AML Patients Enrolled on the Beat AML Master Trial

Prevalence of Inherited Cancer Predisposition Mutations in a Cohort of Older AML Patients Enrolled on the Beat AML Master Trial

Classification of acute myeloid leukemia by the revised fourth edition World Health Organization criteria: a retrospective single-institution study with appraisal of the new entities of acute myeloid leukemia with gene mutations in NPM1 and biallelic CEBPA

The 2016/2017 World Health Organization (WHO2016/2017) classification for acute myeloid leukemia (AML) includes new entities with gene mutations in NPM1 (AML-NPM1mut) and biallelic CEBPA (AML-biCEBPAmut). To retrospectively identify and study these new molecularly defined WHO2016/2017entities, we reviewed clinicopathologic data and pretherapy archived pathologic materials at diagnosis for 143 consecutive AML cases (55.2% male, median age 62 [range 18-89] years) and classified all cases by the 2008 WHO (WHO2008) and revised WHO2016/2017 criteria. By WHO2008, cases included 21 (15%) with recurrent genetic abnormalities (52.3% male, median age 54 [range 18-82] years), 54 (38%) with myelodysplasia-related changes (57.4% male, median age 65 [range 32-84] years), 3 (2%) therapy related (100% male, median age 66 [range 32-84] years), and 65 (45%) not otherwise specified (52.3% male, median age 61 [range 19-89] years). Twenty-two (15.4%) cases (21 AML, not otherwise specified; 1 AML with myelodysplasia-related changes by WHO2008) reclassified by WHO2016/2017 as AML-NPM1mut showed female predominance (54.5%), and median (range) values were as follows: age 60.5 (23-84) years, hemoglobin 8.6 (5.6-12.9) g/dL, total leucocytes 30.1 (2.58-241.84) × 109/L, monocytes 1.65 (0-49.34) × 109/L, neutrophils 1.96 (0-29.79) × 109/L, platelets 55 (11-320) × 109/L, blasts (peripheral blood 41% [2%-98%], bone marrow 66% [17%-97%]), with myeloblastsCD34neg (17 [77%]/21), cytogeneticsnormal (20 [91%]/22), FLT3-ITDpos (9 [41%]/22), FLT3-ITDnegFLT3-TKDpos (5 [23%]/22), FLT3-ITDnegFLT3-TKDneg (8 [36%]/22), and extramedullary involvement (6 [27%]/22), including 1 novel cutaneous presentation. Notably, presenting features among AML-NPM1mut included those of anemia (22 [100%]) and thrombocytopenia (20 [91%]/22). This is also the first report of 4 [18%]/22 AML-NPM1mut (including 3 [75%]/4 nonsmokers) with a family history of leukemia and one 74-year-old with familial AML-biCEBPAmut. This study validates the application of the WHO2016/2017 classification criteria by retrospectively identifying AML-NPM1mut and AML-biCEBPAmut cases using single-gene molecular analyses. Additional studies are needed to characterize the complete spectrum of WHO2016/2017-defined AML-biCEBPAmut and for familial AML including AML-NPM1mut.

Heterozygous CTC1 Variants in Acquired Bone Marrow Failure

Germ line (GL) alterations of telomerase machinery genes may lead to inherited telomeropathies, but recent analysis of large control populations revealed that some of the previously assumed pathologic variants are present in comparable frequencies in healthy individuals. Pathogenic telomerase gene variants can be found, but are rare in idiopathic aplastic anemia (AA) and are associated with excessive telomere attrition. Previously, in a cohort of patients with MDS, pathogenic germ line variants of telomerase genes were very extremely rare.Recently a patient with bone marrow failure and liver cirrhosis presented with a biallelic CTC1 gene mutation. CTC1 is a member of the CTC complex, located on Chr 17p13.1, and critical for telomere replication. GL alterations of this gene were found to cause inherited disease, including Coats plus (CP), dyskeratosis congenital (DC) and cerebroretinal microangiopathy with calcifications and cysts (CRMCC) in a compound heterozygous manner. Our patient (age 28) had compound heterozygous CTC1 germline mutations (p.Lys242Leufs*41 and p.Cys985del) resulting in early childhood presentation of DC, subsequent severe AA at the age of 19, and a significant shortening of telomeres. Both parents as confirmed CTC1 variant carriers showed normal blood counts.Based on this index case and literature reports, manifest CTC1 diseases follow a recessive trait, however, but it is possible that heterozygous carriers may indeed have also an increased, albeit attenuated risk of BMF leading to a later manifestation or incomplete penetrance. To test this possible scenario we screened a cohort of acquired BMF (n=538) with AA/PNH (172), MDS/AML (n=366), with deep NGS of all coding regions of CTC1. In total, we identified 10 heterozygous CTC1 variants in 10 unrelated patients (8 AA/PNH and 2 MDS); 4/10 variants (1 stop gain R1202X and 3 frameshift deletions D405fs, P999fs, E454fs) were fulfilled the criteria of Tier-1 lesions and were found in AA/PNH patients (4/172, 2.3%), The remaining 6 missense variants were of uncertain significance or likely benign(Tier-2), 2 of which (H1092G and E1136K) were found in a compound heterozygous configuration in a AA/PNH patient. K438N, as a novel missense variant, was recurrently present in 2 MDS pts. Given the expected frequency of the CTC1 variants found in controls (104/33370, 0.3%), CTC1 variants appear to be enriched in AA/PNH subgroup (p<0.001). Of note is that none of the carriers of pathogenic CTC1 mutations showed any physical signs of inherited congenital BMF syndromes or any family history of leukemia, BMF and any other cancers. Interestingly, patients with sAA/PNH syndrome and biallelic CTC1 variant eventually evolved to MDS, while the other monoallelic CTC1 carriers showed stable disease and responsed to immunosuppression. Flow cytometric telomere length measurement (adjusted for age) showed a markedly shortened telomere in the index case, as well as 1 SAA case carrying biallelic CTC1 variants and 1 AA case with co-concurrent POT1 and CTC1 variants when compared with age matched controls. A significant difference was seen when comparing telomere length between CTC1 variants carriers and age-matched normal controls, while no difference was seen among CTC1 variants carriers, AA/PNH group without any variants.Because of the curious co-incidence of heterozygous CTC1 variants and AA/PNH, we further analyzed this subgroup for the presence of other telomerase gene mutations, 11/172 Tier-1 variants, while 6 Tier-1 GLVs detected in MDS. Most frequent SNVs were found in POT1 with 5/172 (3%) in AA/PNH and 3/366 (0.8%) in MDS/AML. Notably, in one AA/PNH patient POT1 stop gain variant (Q364X) was co-concurrent with CTC1 heterozygous frame shift deletion (P999fs). The enrichment of variants in TELO-related genes in AA/PNH subgroup was found in comparison to MDS/AML (p<.01) and ExAC database controls (p<.01). Further clinical phenotype analysis indicated that 3 AA/PNH cases harboring POT1, TINF2 and TERT Tier-1 variants had family history of cancer. Family history of cancer was also found in a MDS patient with a TINF2 variant.In sum, our results indicate that heterozygous CTC1 variants were associated with otherwise typical AA with clonal outgrowth of PNH clone and the presence of this variant does not seem to preclude response to immunosuppression. DisclosuresMaciejewski:Ra Pharmaceuticals, Inc: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract PR03: Association of environmental risk factors, family history, and polygenic risk scores with chronic lymphocytic leukemia

Abstract Background: Chronic lymphocytic leukemia (CLL) is a lymphoid malignancy with a strong genetic component. There are over 30 common single nucleotide polymorphisms (SNPs) associated with the risk of CLL. Moreover, in the InterLymph Subtypes Project a number of non-genetic exposures have been found to be associated with CLL, including family history (FH), height, history of atopic conditions, UV radiation, and farming exposures. However there has not been a study evaluating the joint effects among these genetic and non-genetic factors with CLL risk. Methods: Using the Mayo Clinic CLL case-control study of 587 newly diagnosed CLL cases and 790 controls, we performed analyses evaluating joint effects of genetic and non-genetic factors. For genetic effects, we computed a polygenetic risk score (PRS), a weighted averaged of the number of risk alleles across 34 SNPs, with the weights being the log of the odds ratio for each SNP. Exposure data was available for 65% of the cases and 79% of the controls. We evaluated individual and joint associations of FH of any hematological malignancy, total sun exposure categorized by quartiles based on the controls, ever living or working on a farm, any atopy, any allergies, asthma, height, and PRSs categorized by quintiles based on the controls. Multivariate logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: In our preliminary results, the frequency of CLL cases in the upper PRS quintile was 49% while in the lowest quintile only 5%. The PRS has a strong evidence of association with CLL (OR= 3.04, CI =2.20-4.20 for highest versus the middle quintile). When adjusting for PRS, we still found a positive association with FH for any hematological malignancy (OR = 1.90, CI = 1.25-2.88), FH of non-Hodgkin lymphoma (OR = 2.02, CI = 1.08-3.79), and FH of leukemia (OR = 1.73, CI = 0.98-3.07). When stratifying by FH, the upper quintile of the PRS had a 5.85-fold (CI = 1.69-20.3) increased risk of CLL relative to those in the middle quintile in the FH strata, and a 2.65-fold (CI = 1.75-4.01) increased risk in the non-FH strata. After adjusting for PRS, FH and age, there remained an inverse association with sun exposure in the highest quartile (hours per week) (OR = 0.49, CI = 0.31-0.79) and a positive association with height (per 10 cm change) (OR = 1.37, CI = 1.17-1.62), but there were no associations with atopy, any allergies, history of asthma, or farming. No statistical evidence of an interaction among the variables was observed. Conclusions: We found evidence of independent effects among the genetic and non-genetic factors with risk of CLL. Among these factors, the PRS had the largest effect size. Although we did not observe any statistical interactions, larger sample sizes are warranted to fully evaluate these effects on risk of CLL. We are currently increasing our sample size through collaboration with other research groups. Final results will be presented in the meeting. This abstract is also being presented as Poster A06. Citation Format: Geffen Kleinstern, Dennis Robinson, Tim G. Call, Mark Liebow, Silvia de Sanjosé, Yolanda Benavente, James R. Cerhan, Susan L. Slager. Association of environmental risk factors, family history, and polygenic risk scores with chronic lymphocytic leukemia. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr PR03.

Whole-Exome Sequencing Identifies Germline IDH2 and IDH3 mutations That Predispose to Myeloid Neoplasms

Background: Somatic mutations in isocitrate dehydrogenases 1 and 2 (IDH1/2MT) occur in up to 20% of certain types of myeloid neoplasms, chiefly MDS, MDS/MPN overlap and AML. These mutations induce a metabolic rewiring of cancer cells that affects alpha-ketoglutarate (aKG)-dependent dioxygenases such as TET2 DNA demethylases and Jumanji histone demethylases, which leads to global DNA and chromatin hypermethylation and leukemogenesis. In addition to somatic IDH1/2MT, germline IDH1/2MT occur in the context of Ollier and Maffucci syndromes which predispose to cartilaginous tumors and D 2HG aciduria, which predisposes to brain tumors. We hypothesized that germline mutations in IDH1/2 or the functionally related IDH3 may predispose to myeloid neoplasms.Methods: From 409 patients with MDS, MPN or AML, tumor samples from the myeloid compartment and germline samples from CD3+ lymphocytes were subjected to whole-exome sequencing. Myeloid cells were adhered to microscopy slides and maximal IDH3, IDH1/2 and, glucose-6-phosphate dehydrogenase (G6PD) glutamate dehydrogenase (GDH) activity was determined using quantitative enzyme cytochemistry.Results: In 409 patients with myeloid diseases, we found 8 patients with germline variants in IDH2 or IDH3. Combined, these variants occur more frequently in these 409 patients with myeloid neoplasms than in the general population (OR = 4.05, P =.0024), suggesting that germline IDH2/3MT predispose for myeloid diseases (Table 1). Of note, germline IDH2/3MT were completely mutually exclusive with somatic TET2MT, suggesting overlapping functions. Notably, all but one of these variants were indicated by two independent software programs to be deleterious for the enzymatic activity. To validate this, we determined maximal IDH3 activity in myeloid cells derived from a 47-year old AML patient with a germline IDH3MT (c.G626A, p.G209E) (and family history of leukemia) and her sister with IDH3WT. Maximal IDH3 activity was downregulated in the IDH3MT sample, while maximal IDH1/2, G6PD and GDH activity were unchanged (Fig. 1).1 patient had a family history of MDS and 3 patients had a family history of colon, prostrate, gastric, lung and head and neck carcinoma in multiple family members. One patient had 4 family members affected with different cancers. The high age of the affected patients suggest that although germline IDH2/3MT may predispose to myeloid neoplasms, the development of disease occurs slowly.Discussion: Whereas somatic IDH2MT are common in MDS and other myeloid neoplasms, somatic IDH3MT are not frequently observed, nor in myeloid neoplasms, nor in other types of cancer that are regularly affected by IDH1/2MT. We show that deleterious germline IDH2/3MT may predispose to myeloid neoplasms and we postulate that this may occur via decreases in IDH2/3 activity. IDH3G209E is deleterious for IDH3 enzymatic function and may decrease intracellular aKG levels. This will restrict the function of aKG-dependent dioxygenases such as TET2 and Jumonji and mimic somatic IDH1/2MT and somatic inactivating TET2MT. This suggests that IDH1/2/3 are key enzymes and aKG is a central metabolite in maintaining normal function in myeloid cells. Given the family histories of 5/8 of the affected patients, screenings for germline IDH2/3 variants may reveal novel recurring IDH2/3MT that relate to various types of cancer.Representative photomicrographs of primary IDH3G209E MDS and IDH3WT myeloid cells after staining IDH3 activity in the presence of various isocitrate concentrations, IDH2 activity (1 mM isocitrate) and GDH activity (5 mM glutamate) using quantitative enzyme cytochemistry. The conversion of colorless tetrazolium salt to the purple formazan directly reflects enzyme activity thus darker cells have a higher maximal activity of the investigated enzyme.Table 1Clinical characteristics from 6 patients with germline IDH2/3MT for which clinical information was available.Patient IDAgeDiagnosisGenderOS (months)VariantSNP nrOccurrence in general population150RCMDF23IDH2T495Mrs1180539400,004848266CMML-1M46IDH3AR360Crs1163749960,004161349RAEB-1F16IDH3BR359Wrs3776821520,000154470RCMDM67IDH2T495Mrs1180539400,004848576MDS-UF17IDH3BR334Wrs3746135880,00008675sAMLM5IDH2R261Hrs1181017770,00177 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

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.

Positron emission tomography detection of synchronous colon cancer in a patient with chronic lymphocytic leukemia

Positron emission tomography detection of synchronous colon cancer in a patient with chronic lymphocytic leukemia

Associations between allergies and risk of hematologic malignancies: Results from the Vitamins and Lifestyle (VITAL) cohort study.

1527 Background: Several case-control studies have suggested a reduced risk of hematologic malignancies (HMs) for individuals with allergies, but results have been inconsistent, and prospective cohort studies have not confirmed this association. Herein, we used the large prospective VITAL study to examine this association. Methods: 64,847 men and women, aged 50-76, completed a baseline questionnaire in 2000-2002 and reported on their current allergies and history of physician-diagnosed asthma. Individuals with prior cancer other than non-melanoma skin cancer were excluded from this analysis. Incident HMs were identified through December 2009 by linkage to the SEER registry; those with a diagnosis of a non-HM during follow-up were censored at the time of that diagnosis. Multivariable Cox proportional hazards models were built with adjustment for sex, race/ethnicity, education, smoking, self-rated health, physical activity, history of anemia in the year before baseline, vegetable use and family history of leukemia or lymphoma. Results: Our analysis included 64,839 participants, among whom 681 (1.03%) incident HMs were found (MDS [69], AML (41], myeloproliferative disorders [60], mature B-cell neoplasms [262], chronic lymphocytic leukemia [107], plasma cell disorders [83], Hodgkin lymphoma [23], T-cell/NK-cell neoplasms [22], and others [14]). In multivariable analyses, a history of any allergy was associated with increased risk of HM (HR=1.21; 95% CI 1.02-1.43, p=0.02). This association was seen for current allergies to plants/grass/trees (HR 1.27 [1.06-1.52], p&lt;0.001) but not for allergies to mold/dust, animals, insects, food, or medications. We did not find an association between a history of asthma and incident HMs (HR=0.95 [0.72-1.26]). Conclusions: Our study indicates a moderately increased risk of HMs inindividuals with a history of allergy, especially to plant, grass or trees. While no causality can be inferred, this may suggest a possible carcinogenic role for chronic stimulation of the immune system. However, further mechanistic investigations focusing on the biochemical markers of immune system as well as on possible gene effect modifiers are needed.

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A 66-year-old woman was evaluated for nontraumatic right thigh pain. She had bilateral traumatic femur shaft fractures 27 years ago. She had a history of melanoma resection and a family history of leukemia. She had had osteoporosis for the past 6 years (baseline dual-energy x-ray absorptiometry scan showed a T score of -2.8 at the hip and -2.5 at the lumbar spine). Since then, she had been taking alendronate, 70 mg weekly, while in the care of a rural clinic and had no repeated bone mineral density measurements.

Long-Term Use of Acetaminophen, Aspirin, and Other Non-Steroidal Anti-Inflammatory Drugs and Risk of Hematologic Malignancies: Results From the Large, Prospective VITamins and Lifestyle (VITAL) Cohort Study

AbstractAbstract 2153 Background:Several epidemiological studies have examined the association of aspirin use and other over-the-counter analgesics or anti-inflammatory drugs and the incidence of hematologic malignancies. Although previous results have been inconsistent, some studies have suggested a reduced risk of leukemia or lymphoma with regular use of aspirin or non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs). On the other hand, some but not all studies have reported an increased risk of leukemia or lymphoma with regular use of acetaminophen. Methods:We evaluated the association of analgesic use to hematologic malignancies in a prospective cohort of 64,839 men and women aged 50 to 76 years from Washington State recruited in 2000 to 2002 to the VITamins And Lifestyle (VITAL) study. Eligible participants completed a 24-page baseline questionnaire, including detailed questions about medication use during the previous 10 years. Incident cases of hematologic malignancies (n=577, including MDS [n=54], AML [n=36], myeloproliferative disorders [n=46], CLL/SLL [n=88] and other non-Hodgkin lymphomas [n=235], Hodgkin lymphomas [n=22], plasma cell disorders [n=66], mature NK/T cell neoplasms [n=17], and other entities [n=13]) were identified through December 2008 by linkage to the Seattle-Puget Sound Surveillance, Epidemiology, and End Results (SEER) cancer registry. The censored date was the date of withdrawal from the study, death, move out of the SEER catchment area, or last date of linkage to SEER for diagnosis of hematologic malignancy. In addition, participants were excluded if they had any cancer prior to baseline other than non-melanoma skin cancer and were censored at the time of diagnosis of a non-hematologic malignancy during follow-up to remove treatment for a prior cancer as a cause of any subsequent hematologic cancer. Medication use was categorized as “no use”, “low use” (use for either less than 4 days/week or less than 4 years), and “high use” (use for at least 4 days/week and at least 4 years). Hazards ratios (HRs) and 95% confidence intervals (95% CI) associated with use of acetaminophen, aspirin, and non-aspirin NSAIDs for total incident hematologic malignancies and cancer subcategories were estimated by Cox proportional hazards models. Multivariable-adjusted models were fit by adjusting for age, sex, race/ethnicity, education, smoking, self-rated health, history of fatigue/lack of energy, and family history of leukemia or lymphoma. All models except low-dose aspirin were further adjusted for history of rheumatoid arthritis, history or non-rheumatoid arthritis or chronic neck/back/joint pain, and history of migraines or frequent headaches. The model for low-dose aspirin was further adjusted for history of coronary artery disease, stroke, diabetes, or use of antihypertensive or lipid-lowering medications. Results:After adjustment, there was an increased risk of incident hematologic malignancies associated with increasing use of acetaminophen (HR=1.81 [95% CI: 1.33–2.46] for high use; p=0.009 for trend). The association with high use of acetaminophen was seen for MDS/AML (HR=2.23 [1.09-4.56]), non-Hodgkin lymphomas (HR=1.82 [1.14-2.92]), and plasma cell disorders (HR=2.32 [0.98-5.50]) but not CLL/SLL (HR=0.83 [0.30-2.35]). By comparison, there was no association with risk of incident hematologic malignancies for increasing use of low-dose aspirin (HR=1.04 [0.81-1.33] for high use; p=0.856 for trend), regular-dose aspirin (HR=0.86 [0.67-1.11] for high use; p=0.329 for trend), non-aspirin NSAIDs (HR=1.04 [0.75-1.43] for high use; p=0.820 for trend), or ibuprofen (HR=0.98 [0.67-1.44] for high use; p=0.956 for trend). Conclusion:Use of acetaminophen increased the risk of incident hematologic malignancies other than CLL/SLL in a usage-dependent manner, with an almost 100% increased risk for use least 4 days/week for of at least 4 years. Neither aspirin nor non-aspirin NSAIDs decreased risk and are unlikely to be useful for chemoprevention. Disclosures:No relevant conflicts of interest to declare.

Vitamins, Minerals, and Specialty Supplements and Risk of Hematological Malignancies In the VITamins and Lifestyle (VITAL) Cohort Study

AbstractAbstract 4143 Introduction:The use of vitamins and dietary supplements is a common health practice in many parts of the world, in part because of the belief that they will prevent diseases, including cancer. However, results of epidemiologic studies regarding their efficacy in reducing the risk of any cancer, particularly hematologic malignancies, are inconsistent and are mostly limited to case-control studies. Materials:Participants were male and female members of the VITamins And Lifestyle (VITAL) cohort. Between 2000 and 2002, 64,839 men and women, aged 50 to 76 years, who lived in the region of Washington State covered by the Surveillance, Epidemiology, and End Results (SEER) registry, were recruited. Participants were excluded if they had any cancer prior to baseline other than non-melanoma skin cancer and were censored at the time of diagnosis of a non-hematologic malignancy during follow-up; after exclusions, there were 64,839 participants available for study. Incident cases of hematologic malignancies were identified through December 2008 by linkage to the SEER registry. Participants answered questions on the frequency (days/week), duration (years), and dose per day of their supplemental use of vitamins, including A, B3, B6, B12, C, D, E, multivitamin compounds, and folic acid; minerals, including calcium, selenium, iron, magnesium, chrome, and zinc during the 10 years before baseline. For the non-vitamin, non-mineral “specialty” supplements, garlic, ginseng, and fish oil, only frequency and duration were ascertained. Use of vitamin and mineral supplements was categorized into non-users and tertiles of use, such that the highest category was greater than could be achieved only by use of a common multivitamin (Centrum Silver). 10-year average use of specialty supplements was categorized into: non-user; low use, <4 days/week or <3 years; and high use, ≥4 days/week and ≥3 years. Multivariable-adjusted Cox proportional hazards models were used to estimate hazards ratios (HR) and 95% confidence intervals (95% CI) of the use of dietary supplements with the risk of total hematologic malignancies. Models were adjusted for age, sex, race/ethnicity (white/hispanic/other), education, smoking, self-rated health, physical activity, history of anemia in the year before baseline, and family history of leukemia or lymphoma. Results:A total of 577 case of hematological malignancies were identified including MDS [n=54], AML [n=36], myeloproliferative disorders [n=46], CLL/SLL [n=88] and other non-Hodgkin lymphomas [n=235], Hodgkin lymphomas [n=22], plasma cell disorders [n=66], mature NK/T cell neoplasms [n=17], and other entities [n=13]). None of the vitamin 10-year average intakes were associated with decreased risk of incident hematologic malignancies There was no evidence that high use of vitamins A (HR=0.79, 95% CI: 0.58–1.08; p-trend=0.28), B12 (HR=0.98, 95%CI: 0.73–1.31; p-trend=0.26), C (HR=0.97, 95% CI: 0.77–1.22; p-trend=0.99), D (HR=0.90, 95% CI: 0.62–1.31; p-trend=0.45), or folic acid (HR=1.00, 95% CI: 0.73–1.39; p-trend=0.19) was associated with the risk of blood cancer. Among specialty supplements, only high 10-year average use of garlic was significantly associated with a reduced risk of development of blood cancers (HR=0.64,95% CI: 0.42–0.98); however the association was not linear (p-trend=0.14). Conclusions:We observed no reduction in the risk of incident hematologic malignancies with dietary supplement and vitamin use with the exception of garlic when used at a high amount (≥4 days/week for ≥ 3 years). Disclosures:No relevant conflicts of interest to declare.

Family history of cancer and risk of breast cancer in the Black Women’s Health Study

Relatively little research has been conducted on familial breast cancer in African American women. Data from the Black Women's Health Study, a prospective cohort study of African American women, were used to assess breast cancer risk in relation to family history of cancer. Since 1995, participants have completed biennial postal questionnaires on health status, risk factors, and family history of cancer. Cox proportional hazards analyses were used to calculate incidence rate ratios (IRRs) and 95% confidence intervals (CI) for family history of breast and other types of cancer. Among 57,364 participants who were cancer-free at baseline, 1,306 incident breast cancer cases occurred during 12 years of follow-up. The IRR for a first-degree family history of breast cancer relative to no family history was 1.78 (95% CI 1.55-2.06). IRRs varied by the age at diagnosis, from 1.60 (>or=age 55) to 2.76 (<age 35). Results were consistent across subtypes of breast tumor defined by estrogen and progesterone receptor status. Breast cancer risk was also associated with family history of colon cancer (IRR 1.35, 95% CI 1.12-1.63) and possibly with family history of leukemia (IRR 1.42, 95% CI 0.82-2.46). These findings indicate a strong familial relationship for breast cancer in African American women. The associations with family history of colon cancer and leukemia warrant further investigation.

Identification and characterization of mutations in FANCL gene: A second case of Fanconi anemia belonging to FA-L complementation group

Fanconi anemia (FA) is a rare autosomal recessive or X-linked disorder characterized by aplastic anemia, cancer susceptibility and cellular sensitivity to DNA crosslinking agents. Eight FA proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL and FANCM) and three non-FA proteins (FAAP100, FAAP24 and HES1) form an FA nuclear core complex, which is required for monoubiquitination of the FANCD2-FANCI dimer upon DNA damage. FANCL possesses a PHD/RING-finger domain and is a putative E3 ubiquitin ligase subunit of the core complex. In this study, we report an FA patient with an unusual presentation belonging to the FA-L complementation group. The patient lacks an obvious FA phenotype except for the presence of a café-au-lait spot, mild hypocellularity and a family history of leukemia. The molecular diagnosis and identification of the FA subgroup was achieved by FA complementation assay. We identified bi-allelic novel mutations in the FANCL gene and functionally characterized them. To the best of our knowledge, this is the second reported case belonging to the FA-L complementation group.