Germline Variants In Patients Research Articles

Abstract 7335: Characterizing germline variants in patients with small cell lung cancer

Abstract Introduction: Small cell lung cancer (SCLC) has traditionally been considered to arise from environmental and lifestyle factors. Recent evidence has shown that germline mutations may also impact the development of SCLC, however, remains understudied. We sought to identify novel germline mutations in SCLC including unexplored copy-number variations (CNVs) in our cohort of patients. Methods: We applied a custom hybrid-capture gene panel of 191 cancer predisposition and commonly mutated genes in SCLC to a pre-treatment cohort of 67 patients with SCLC. Variant calls were performed using VarScan2 (2.3.8), Pindel (0.2.5b8) and CNVs were assessed using DeCON 1.0.2. Calls were annotated using the American College of Medical Genetics (ACMG) criteria and classified using gnomeAD (release 2.11), ESP6500 (ESP6500SI-V2), 1000Genomes, ExAC (release 0.3), COSMIC (v70), dbSNP (build 147), and ClinVar (NCBI ClinVar 20190305). We annotated variants of uncertain significance (VUS) with several in silico tools including MutationTaster, LRT, Polyphen2 HDIV, Polyphen2 HVAR, SIFT, PROVEAN, and Deepmind AlphaMissense. Kaplan-Meier survival analysis and log-rank tests were done to examine differences in overall survival (OS) and progression-free survival (PFS) from the date of diagnosis. Continuous variables were tested using Kruskal-Wallis H test and categorical variables using Fisher’s exact test. Results: The median age of our cohort was 68 years old, 64% (43/67) were male, 89% (60/67) were current/former smokers, and 58% (39/67) were Extensive-Stage. 64.6% (42/67) of patients self-reported a family history of cancer and 16% of the patients also self-reported personal history of cancer. In terms of self-reported ancestral background, 76% of were Caucasian, 1.5% were Middle-Eastern, 3% were Latin American, 14% were Asian, and 4.5% were Black. We identified pathogenic/likely pathogenic alterations in 7/67 patients. Five (71%) were novel alterations (BCORL1, FANCC, ATR, and BBC3) and a novel CNV (SLFN11) with the remaining two (29%) previously described mutations (CHEK1 and BRIP1). We identified 191 VUS in 60/67 patients. 4.7-14.1% of VUS were in silico predicted to be pathogenic. Patients with the 7 pathogenic alterations had a numerically larger OS (HR = 0.50, 95%CI = 0.18-1.39, p = 0.18) and PFS (HR = 0.45, 95%CI = 0.16 - 1.24, p = 0.11) compared to the rest of the cohort. We identified 20 variants at low variant allele fractions (0.05 to 0.24), likely somatic mutations. Some genes identified are implicated with clonal hematopoiesis such as GNAS, STAG, TET2, and MGA. Conclusion: In summary, we have identified several novel germline alterations (mutations and CNVs) in patients with SCLC. In addition, we utilized in silico prediction models to categorize potential high-risk VUS. Our findings suggest that beyond tobacco exposure germline alterations may also modulate development of tumorigenesis in SCLC patients. Citation Format: Sami Ul Haq, Gregory Downs, Luna Jia Zhan, Danielle Sacdalan, Janice J. Li, Vivek Philip, Raymond H. Kim, Geoffrey Liu, Scott V. Bratman, Peter J. Sabatini, Benjamin H. Lok. Characterizing germline variants in patients with small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7335.

Germline variants in patients developing second malignant neoplasms after therapy for pediatric acute lymphoblastic leukemia—a case-control study

Germline variants in patients developing second malignant neoplasms after therapy for pediatric acute lymphoblastic leukemia—a case-control study

Germline Predisposition in Myeloid Neoplasms Aged ≥50: A Novel Approach for Allogeneic Stem Cell -Transplantation Decision-Making

Introduction Patients aged 50 or older (≥50) with myeloid neoplasms (MNs), non-affected relatives, and no previous platelet or organ disorder are routinely not tested for germline predisposition. However, approximately 70% of myelodysplastic neoplasms (MDS) patients undergoing an allogeneic hematopoietic stem cell transplantation (alloHSCT) from familial donors, in 2021, were ≥50 years old (y.o.) (EBMT). Given the significant frequency of pathogenic/likely pathogenic (P/LP) germline variants in these patients (about 8%) along with the risk of transplanting cells with the same variant, it seems reasonable to perform universal germline testing in hematological neoplasms although challenging due to labor and cost constraints. Aims To address this, we developed a pragmatic approach incorporating a specific gene list to the diagnostic myeloid somatic panel to identify patients and exclude relatives with shared germline variants. To do that we: (1) Conducted a literature review to assess the gene-disease association's validity in this specific context. (2) Designed a germline-augmented virtual somatic panel (GASP) based on our findings. (3) Tested the virtual panel's performance in 133 MNs cases, aged ≥50, with matched germline-tumor exome sequencing, and no prior organ or platelet disorders. Methods We considered those genes included in the WHO Classification and NCCN Clinical Practice Guidelines as myeloid predisposition genes. For autosomal recessive disorders, heterozygous carriers were not considered. We analyzed the relation of these genes with MNs diagnosed ≥50 y.o. without prior organ or platelet dysfunction: To establish a valid association for a gene, we required the presence of P/LP variants in at least two peer-reviewed studies in the subset of interest. GASP combined genes with recurrent somatic mutations in myeloid disorders, as proposed by Duncavage et al. (Blood 2022), and those associated with the specific cohort of interest. WES was performed on paired tumoral-germline samples on a HiSeq 2000/Novaseq6000 instrument (Illumina Inc) with a target of 100x depth coverage. Results From 2018 to 2023, we collected samples from 133 patients (121 MDS and 12 CMML cases -FAB myelodysplastic variant) diagnosed with WHO-established MDS, aged ≥50, without prior organ or platelet disorders. Among the main characteristics at baseline, we highlight a median age at diagnosis of 57 years old (range, 50-88), and the presence of a first-degree relative with a myeloid neoplasm diagnosis in 7% of the cases. The literature search revealed 11 genes associated with germline predisposition within the cohort of interest. Seven were WHO/NCCN genes: DDX41, TERT, GATA2, CEBPA, SAMD9, ERCC6L2, and TP53. Additionally, four “recently associated genes” were incorporated based on recent descriptions in germline MNs ≥50 y.o. and reported at least in two peer-reviewed articles: CHEK2, DNAH9, ATM, and SH2B3 (Table 1). Next, we tested the accuracy of both the GASP and Duncavage's recommended somatic panel in our cohort of 133 myeloid neoplasms characterized by WES. Among these cases, we identified 15 (11%) P/LP germline variants in both WHO/NCCN and recently associated genes. Duncavage's somatic panel could only detect 8 out of 15 (53%) cases, while the expanded GASP detected 13 out of 15 (87%) variants (Figure 1). The GASP showed a C-index of 0.933, outperforming Duncavage's panel, which scored 0.767. Conclusions Eleven genes have been found to harbor P/LP germline variants in patients with MNs diagnosed ≥50 y.o. and no previous organ or platelet disorder. In our cohort, 11% of patients carried a P/LP germline variant in a MNs predisposition gene. Such a finding would have gone undetected as germline predisposition testing is not typically advised for these patients. Expanding the myeloid somatic panel (GASP) allows the identification of 87% of P/LP variants during the diagnosis process, enabling clinicians to exclude carrier relatives as potential allo-SCT donors.

MA14.08 Pathogenic Germline Variants in Patients with Non-Small Cell Lung Cancer (NSCLC) Detected by Tissue Comprehensive Genomic Profiling

MA14.08 Pathogenic Germline Variants in Patients with Non-Small Cell Lung Cancer (NSCLC) Detected by Tissue Comprehensive Genomic Profiling

Pathogenic germline variants in patients with endometrial cancer of diverse ancestry.

Racial disparities in outcomes exist in endometrial cancer (EC). The contribution of ancestry-based variations in germline pathogenic variants (gPVs) is unknown. Germline assessment of ≥76 cancer predisposition genes was performed in patients with EC undergoing tumor-normal Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets sequencing from January 1, 2015 through June 30, 2021. Self-reported race/ethnicity and Ashkenazi Jewish ancestry data classified patients into groups. Genetic ancestry was inferred from Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets. Rates of gPV and genetic counseling were compared by ancestry. Among 1625 patients with EC, 216 (13%) had gPVs; 15 had >1 gPV. Rates of gPV varied by self-reported ancestry (Ashkenazi Jewish, 40/202 [20%]; Asian, 15/124 [12%]; Black/African American (AA), 12/171 [7.0%]; Hispanic, 15/124 [12%]; non-Hispanic (NH) White, 129/927 [14%]; missing, 5/77 [6.5%]; p=.009], with similar findings by genetic ancestry (p<.001). We observed a lower likelihood of gPVs in patients of Black/AA (odds ratio [OR], 0.44; 95% CI, 0.22-0.81) and African (AFR) ancestry (OR, 0.42; 95% CI, 0.18-0.85) and a higher likelihood in patients of Ashkenazi Jewish genetic ancestry (OR, 1.62; 95% CI; 1.11-2.34) compared with patients of non-Hispanic White/European ancestry, even after adjustment for age and molecular subtype. Somatic landscape influenced gPVs with lower rates of microsatellite instability-high tumors in patients of Black/AA and AFR ancestry. Among those with newly identified gPVs (n=114), 102 (89%) were seen for genetic counseling, with lowest rates among Black/AA (75%) and AFR patients (67%). In those with EC, gPV and genetic counseling varied by ancestry, with lowest rates among Black/AA and AFR patients, potentially contributing to disparities in outcomes given implications for treatment and cancer prevention. Black women with endometrial cancer do worse than White women, and there are many reasons for this disparity. Certain genetic changes from birth (mutations) can increase the risk of cancer, and it is unknown if rates of these changes are different between different ancestry groups. Genetic mutations in 1625 diverse women with endometrial cancer were studied and the lowest rates of mutations and genetic counseling were found in Black and African ancestry women. This could affect their treatment options as well as their families and may make disparities worse.

The clinical and genomic landscape of patients with DDX41 variants identified during diagnostic sequencing

AbstractDeleterious germ line variants in DDX41 are a common cause of genetic predisposition to hematologic malignancies, particularly myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). Targeted next-generation sequencing was performed in a large cohort of sequentially recruited patients with myeloid malignancy, covering DDX41 as well as 30 other genes frequently mutated in myeloid malignancy. Whole genome transcriptome sequencing data was analyzed on a separate cohort of patients with a range of hematologic malignancies to investigate the spectrum of cancer predisposition. Altogether, 5737 patients with myeloid malignancies were studied, with 152 different DDX41 variants detected. Multiple novel variants were detected, including synonymous variants affecting splicing as demonstrated by RNA-sequencing. The presence of a somatic DDX41 variant was highly associated with DDX41 germ line variants in patients with MDS and AML, and we developed a statistical approach to incorporate the co-occurrence of a somatic DDX41 variant into germ line variant classification at a very strong level (as per the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines). Using this approach, the MDS cohort contained 108 of 2865 (3.8%) patients with germ line likely pathogenic/pathogenic (LP/P) variants, and the AML cohort 106 of 2157 (4.9%). DDX41 LP/P variants were markedly enriched in patients with AML and MDS compared with those in patients with myeloproliferative neoplasms, B-cell neoplasm, and T- or B-cell acute lymphoblastic leukemia. In summary, we have developed a framework to enhance DDX41 variant curation as well as highlighted the importance of assessment of all types of genomic variants (including synonymous and multiexon deletions) to fully detect the landscape of possible clinically relevant DDX41 variants.

Pathogenic germline variants in patients with breast cancer: conversations across generations, practices and patients' attitude.

Background: Breast cancer susceptibility genes such as BRCA1, BRCA2, PALB2, CHEK2 and many others are increasingly recognized among our patient population. In addition to their impact on treatment decisions of tested patients themselves, identifying at-risk family members offer opportunities for cancer preventive measures. Methods: This is an observational cross-sectional study of adult breast cancer patients with positive breast-cancer-susceptibility germline variants who received treatment at our institution. Patients with variants of uncertain significance (VUS), or who refused to give consent, were excluded. The data was collected from an eligible sample of breast cancer patients using a structured questionnaire developed by the study team and tested for validity and reliability, as well as a clinical chart review form. Patients were invited to participate in the study during their scheduled oncology clinics visit. Results: 169 patients were enrolled, including 42 (24.9%) with pathogenic/likely pathogenic (P/LP) BRCA1 variants, 84 (49.7%) with BRCA2 and 43 (25.4%) with non-BRCA variants. All patients were female and the mean age was 45 ± 9.9years. Among 140 eligible patients, 104 (74.3%) underwent prophylactic mastectomy, while 79 (59.0%) of 134 eligible patients had prophylactic bilateral salpingo-oophorectomy (BSO). Results were communicated with family members by majority (n = 160, 94.7%), including 642 first degree female relatives, and 286 (44.5%) of them have taken no action. Fear of positive test results, cost of testing, unwillingness to undergo preventive measures, and social stigma were cited as barriers to genetic testing in 54%, 50%, 34% and 15%, respectively. Conclusion: Risk-reducing interventions including mastectomy and BSO were carried by majority of patients with P/LP variants. However, though the rate of communication of genetic testing results with family members was high, proper preventive measures were relatively low. Cost and fear of cancer diagnosis, were the leading causes that prevented cascade testing in our cohort.

THU616 Analysis Of Germline Mutations In Patients With Sporadic Adrenocortical Carcinoma

Abstract Disclosure: M. Terzolo: None. S. Grisanti: None. M. Scatolini: None. P. Tomaiuolo: None. E. Grosso: None. V. Basile: None. D. Cosentini: None. S. Puglisi: None. M. Laganà: None. P. Perotti: None. L. Saba: None. E. Rossini: None. S. Sigala: None. M. Volante: None. A. Berruti: None. Background: Adrenocortical carcinoma (ACC) is a rare cancer associated with hereditary syndromes in 10% of cases. Germline variants (GVs) in patients with ACC have been identified mainly in pediatric patients and in family cases, while data on GVs in adult patients with sporadic ACC are limited. Methods: We analyzed germline DNA from 150 adult patients with sporadic ACC sequentially referred to our centers between 1998 and 2019. We designed a custom panel of 17 genes potentially involved in the pathogenesis of ACC: AIP, APC, ARMC5, ARNT, BRCA1, BRCA2, CTNNB1, IGF2, MEN1, MSH2, MSH6, PDE8B, PDE11A, PRKACA, PRKACB, PRKAR1A, and TP53. NGS data were analyzed by a semi-automated bioinformatic pipeline. All GVs were studied using effect predictor tools (PolyPhen and SIFT). Specific databases (ClinVar, Varsome, gnomAD, IARC TP53, HGMD) were used for variant classification according to ACMG criteria. Variants interpreted as pathogenic (P) or likely pathogenic (LP) were considered as positive. Clinical, pathological and genomic data were analyzed in different Cox models to study prognostic impact of covariates for disease-free survival (DFS), progression-free survival (PFS) and overall survival (OS). Results: We identified 21 unique GVs in 24/150 patients (16%). GVs were found in 9 genes including APC (n=3), ARMC5 (n=3), MSH2 (n=3), PDE11A (n=3), TP53 (n=3), MSH6 (n=2), PDE8B (n=2), AIP (n=1) and CTNNB1 (n=1). Eleven positive GVs including 3 GVs with deleterious potential were found in 14/150 patients (9.3%). Some variants were particularly enriched, with a frequency of 0.02% compared to an overall frequency of 0.001-0.004% in the gnomAD database. We found a new GV in TP53 (G105D) in a patient who was later found to have a sister with ACC and, for the first time, 3 GVs in ARMC5 (P731R). Patients with ARMC5 GVs had large cortisol-secreting tumors and one case displayed pathologic features of ACC and combined macronodular cortical disease. Positive GVs were associated with a shorter OS (50 vs 142 months, HR 1.81; 95%CI, 0.86-3.82, p=0.118) and PFS (8 vs 30 months, HR 3.11; 95%CI, 1.57-6.16, p=0.001) but not DFS (27 vs 32 months, HR 1.07; 95%CI, 0.52-2.22, p=0.845). At multivariate analysis, known clinical factors (age, surgery of primary ACC, ENSAT stage, hypercortisolism) were found to have prognostic impact on OS. However, GVs remained independent predictors of PFS and OS in metastatic patients. Conclusions: In a series of 150 patients with ACC, we found that 9.3% of them had positive GVs, thus confirming findings from the TCGA analysis. We describe for the first time the presence of ARMC5 GVs in patients with ACC and we found a novel pathogenic variant of TP53. Pathologic features of one ARMC5 case suggest a possible progression from macronodular hyperplasia to ACC. Finally, the present findings suggest that GVs can affect ACC progression and survival of affected patients. Presentation: Thursday, June 15, 2023

Germline pathogenic variants in neuroblastoma patients are enriched in BARD1 and predict worse survival.

Neuroblastoma is an embryonal cancer of the developing sympathetic nervous system. The genetic contribution of rare pathogenic or likely pathogenic germline variants in patients without a family history remains unclear. Germline DNA sequencing was performed on 786 neuroblastoma patients. The frequency of rare cancer predisposition gene pathogenic or likely pathogenic variants in patients was compared with 2 cancer-free control cohorts. Matched tumor DNA sequencing was evaluated for second hits, and germline DNA array data from 5585 neuroblastoma patients and 23 505 cancer-free control children were analyzed to identify rare germline copy number variants. Patients with germline pathogenic or likely pathogenic variants were compared with those without to test for association with clinical characteristics, tumor features, and survival. We observed 116 pathogenic or likely pathogenic variants involving 13.9% (109 of 786) of neuroblastoma patients, representing a statistically significant excess burden compared with cancer-free participants (odds ratio [OR] = 1.60, 95% confidence interval [CI] = 1.27 to 2.00). BARD1 harbored the most statistically significant enrichment of pathogenic or likely pathogenic variants (OR = 32.30, 95% CI = 6.44 to 310.35). Rare germline copy number variants disrupting BARD1 were identified in patients but absent in cancer-free participants (OR = 29.47, 95% CI = 1.52 to 570.70). Patients harboring a germline pathogenic or likely pathogenic variant had a worse overall survival compared with those without (P = 8.6 x 10-3). BARD1 is an important neuroblastoma predisposition gene harboring both common and rare germline pathogenic or likely pathogenic variations. The presence of any germline pathogenic or likely pathogenic variant in a cancer predisposition gene was independently predictive of worse overall survival. As centers move toward paired tumor-normal sequencing at diagnosis, efforts should be made to centralize data and provide an infrastructure to support cooperative longitudinal prospective studies of germline pathogenic variation.

Rate of Pathogenic Germline Variants in Patients With Lung Cancer

PURPOSE Germline genetic testing (GGT) is now recommended for all patients diagnosed with ovarian or pancreatic cancer and for a large proportion of patients based solely on a diagnosis of colorectal or breast cancer. However, GGT is not yet recommended for all patients diagnosed with lung cancer (LC), primarily because of a lack of evidence that supports a significant frequency of identifying pathogenic germline variants (PGVs) in these patients. This study characterizes GGT results in a cohort of patients with LC. METHODS We reviewed deidentified data for 7,788 patients with GGT (2015-2022). PGV frequencies were compared to a control cohort of unaffected individuals. GGT results were stratified by genomic ancestry, history of cancer, and PGV clinical actionability per current guidelines. RESULTS Of all patients with LC, 14.9% (1,161/7,788) had PGVs. The rate was similar when restricted to patients with no cancer family history (FH) or personal history (PH) of other cancers (14.3%). PGVs were significantly enriched in BRCA2, ATM, CHEK2, BRCA1, and mismatch repair genes compared with controls. Patients of European (EUR) genomic ancestry had the highest PGV rate (18%) and variants of uncertain significance were significantly higher in patients of non-EUR genomic ancestry. Of the PGVs identified, 61.3% were in DNA damage repair (DDR) genes and 95% were clinically actionable. CONCLUSION This retrospective study shows a LC diagnosis identifies patients with a significant likelihood of having a cancer-predisposing PGV across genomic ancestries. Enrichment of PGVs in DDR genes suggests that these PGVs may contribute to LC cancer predisposition. The frequency of PGVs among patients with LC did not differ significantly according to FH or PH of other cancers.

Pathogenic Germline Mutational Landscape in Patients With Renal Cell Carcinoma and Associated Clinicopathologic Features.

A subset of renal cell carcinoma (RCC) cases occur because of a hereditary predisposition. However, the prevalence and profiling of germline alterations in RCC have not been fully characterized. Additionally, clinicopathologic factors associated with pathogenic or likely pathogenic (P/LP) germline variants in patients with RCC remain poorly understood. A retrospective analysis of patients with RCC who underwent genetic evaluation was performed. The frequency of P/LP germline variants and genes was evaluated in this cohort. The association between genetic testing outcomes and clinicopathologic features was also assessed. A total of 321 patients with RCC who had germline testing were identified. Within this cohort, 42 patients (13.1%) had P/LP variants. Genes with the most frequent germline mutations were FLCN (n = 10, 3.1%), SDHB (n = 4, 1.2%), VHL (n = 4, 1.2%), MLH1 (n = 3, 0.9%), and CHEK2 (n = 4, 1.2%). Among patients with P/LP variants, 19 (45.2%) had a potentially targetable mutation. The presence of bilateral or multifocal tumors was associated with P/LP variants (P = .0012 and P = .0098, respectively). Patients who had targeted gene testing had higher rates of P/LP variants compared with multigene panel testing (P = .015). Age and family history of cancers (RCC and non-RCC) did not have any statistically significant association with germline testing outcomes. Among patients with RCC, unselected for a known familial predisposition, 13.4% had P/LP variants. Almost half of patients with P/LP variants had a potentially targetable mutation. Targeted gene panel testing is a feasible option for patients, particularly if syndromic features are present. Age and family history were not associated with P/LP variants. Future studies are needed to optimize current genetic evaluation criteria to expand the detection of patients with RCC who may have germline mutations.

Performance of clinical risk scores and prediction models to identify pathogenic germline variants in patients with advanced prostate cancer

PurposeDetermining the frequency and distribution of pathogenic germline variants (PGVs) in Austrian prostate cancer (PCa) patients and to assess the accuracy of different clinical risk scores to correctly predict PGVs.MethodsThis cross-sectional study included 313 men with advanced PCa. A comprehensive personal and family history was obtained based on predefined questionnaires. Germline DNA sequencing was performed between 2019 and 2021 irrespective of family history, metastatic or castration status or age at diagnosis. Clinical risk scores for hereditary cancer syndromes were evaluated and a PCa-specific score was developed to assess the presence of PGVs.ResultsPGV presence was associated with metastasis (p = 0.047) and castration resistance (p = 0.011), but not with personal cancer history or with relatives with any type of cancer. Clinical risk scores (Manchester score, PREMM5 score, Amsterdam II criteria or Johns Hopkins criteria) showed low sensitivities (3.3–20%) for assessing the probability of PGV presence. A score specifically designed for PCa patients stratifying patients into low- or high-risk regarding PGV probability, correctly classified all PGV carriers as high-risk, whereas a third of PCa patients without PGVs was classified as low risk of the presence of PGVs.ConclusionApplication of common clinical risk scores based on family history are not suitable to identify PCa patients with high PGV probabilities. A PCa-specific score stratified PCa patients into low- or high-risk of PGV presence with sufficient accuracy, and germline DNA sequencing may be omitted in patients with a low score. Further studies are needed to evaluate the score.

Germ line variants in patients with acute myeloid leukemia without a suspicion of hereditary hematologic malignancy syndrome

AbstractGerm line predisposition in acute myeloid leukemia (AML) has gained attention in recent years because of a nonnegligible frequency and an impact on management of patients and their relatives. Risk alleles for AML development may be present in patients without a clinical suspicion of hereditary hematologic malignancy syndrome. In this study we investigated the presence of germ line variants (GVs) in 288 genes related to cancer predisposition in 47 patients with available paired, tumor-normal material, namely bone marrow stroma cells (n = 29), postremission bone marrow (n = 17), and saliva (n = 1). These patients correspond to 2 broad AML categories with heterogeneous genetic background (AML myelodysplasia related and AML defined by differentiation) and none of them had phenotypic abnormalities, previous history of cytopenia, or strong cancer aggregation. We found 11 pathogenic or likely pathogenic variants, 6 affecting genes related to autosomal dominant cancer predisposition syndromes (ATM, DDX41, and CHEK2) and 5 related to autosomal recessive bone marrow failure syndromes (FANCA, FANCM, SBDS, DNAJC21, and CSF3R). We did not find differences in clinical characteristics nor outcome between carriers of GVs vs noncarriers. Further studies in unselected AML cohorts are needed to determine GV incidence and penetrance and, in particular, to clarify the role of ATM nonsense mutations in AML predisposition.

Germline pathogenic variants in patients with high-grade gastroenteropancreatic neuroendocrine neoplasms.

High-grade gastroenteropancreatic (HG-GEP) neuroendocrine neoplasms (NENs) are highly aggressive cancers. The molecular etiology of these tumors remains unclear, and the prevalence of pathogenic germline variants in patients with HG-GEP NENs is unknown. We assessed sequencing data of 360 cancer genes in normal tissue from 240 patients with HG-GEP NENs; 198 patients with neuroendocrine carcinomas (NECs) and 42 with grade 3 neuroendocrine tumors (NET G3). Applying strict criteria, we identified pathogenic germline variants and compared the frequency with previously reported data from 33 different cancer types. We found a recurrent MYOC variant in three patients and a recurrent MUTYH variant in two patients, indicating that these genes may be important underlying risk factors for HG-GEP NENs when mutated. Further, germline variants were found in canonical tumor-suppressor genes, such as TP53, RB1, BRIP1 and BAP1. Overall, we found that 4.5% of patients with NEC and 9.5% of patients with NET G3 carry germline pathogenic or highly likely pathogenic variants. Applying identical criteria for variant classification in silico to mined data from 33 other cancer types, the median percentage of patients carrying pathogenic or highly likely pathogenic variants was 3.4% (range: 0-17%). The patients with NEC and pathogenic germline variants had a median overall survival of 9 months, similar to what is generally expected for metastatic GEP NECs. A patient with NET G3 and pathogenic MUTYH variant had much shorter overall survival than expected. The fraction of HG-GEP NENs with germline pathogenic variants is relatively high, but still <10%, meaning that that germline mutations cannot be the major underlying cause of HG-GEP NENs.

Prevalence of pathogenic germline variants in adult-type diffuse glioma.

No consensus germline testing guidelines currently exist for glioma patients, so the prevalence of germline pathogenic variants remains unknown. This study aims to determine the prevalence and type of pathogenic germline variants in adult glioma. A retrospective review at a single institution with paired tumor/normal sequencing from August 2018-April 2022 was performed and corresponding clinical data were collected. We identified 152 glioma patients of which 15 (9.8%) had pathogenic germline variants. Pathogenic germline variants were seen in 11/84 (13.1%) of Glioblastoma, IDH wild type; 3/42 (7.1%) of Astrocytoma, IDH mutant; and 1/26 (3.8%) of Oligodendroglioma, IDH mutant, and 1p/19q co-deleted patients. Pathogenic variants in BRCA2, MUTYH, and CHEK2 were most common (3/15, 20% each). BRCA1 variants occurred in 2/15 (13%) patients, with variants in NF1, ATM, MSH2, and MSH3 occurring in one patient (7%) each. Prior cancer diagnosis was found in 5/15 patients (33%). Second-hit somatic variants were seen in 3/15 patients (20%) in NF1, MUTYH, and MSH2. Referral to genetics was performed in 6/15 (40%) patients with pathogenic germline variants. 14/15 (93%) of patients discovered their pathogenic variant as a result of their paired glioma sequencing. These findings suggest a possible overlooked opportunity for determination of hereditary cancer syndromes with impact on surveillance as well as potential broader treatment options. Further studies that can determine the role of variants in gliomagenesis and confirm the occurrence and types of pathogenic germline variants in patients with IDH wild type compared to IDH mutant tumors are necessary.

Pathogenic germline variants in patients with endometrial cancer across diverse ancestries.

5596 Background: Racial/ethnic disparities in outcomes exist in endometrial cancer (EC), particularly amongst self-reported Black compared to Non-Hispanic White (NH-White) patients. However, the contribution of differences in germline pathogenic variants (gPV) and genetics care to disparities is unknown. We seek to describe the spectrum of gPV in unselected patients with EC by ancestry to characterize variations and describe any differences in subsequent genetic counseling follow-up. Methods: Germline assessment of ≥76 cancer predisposition genes was performed in patients with EC undergoing clinical tumor-normal MSK-IMPACT sequencing from 1/1/15-6/30/21. Self-reported data on race/ethnicity and Ashkenazi Jewish (AJ) ancestry were used to classify patients into mutually exclusive ancestry groups: AJ, Asian, Black, Hispanic, NH-White, or Unknown. Genetic ancestry was inferred from MSK-IMPACT, and those with single population ancestral fraction &gt;0.8 were assigned to African (AFR), European (EUR), East Asian (EAS), Native American (NAM), South Asian (SAS), and AJ (ASJ) ancestry populations or considered admixed (Mixed). Clinicopathologic variables were reported using summary statistics and compared by ancestry using non-parametric tests. Results: Among 1,625 patients with EC, self-reported ancestry [202 AJ (12.4%), 124 (7.6%) Asian, 171 Black (10.5%), 124 Hispanic (7.6%), 927 NH-White (57.1%), and 77 missing (4.7%)] correlated with genetic ancestry. In those identifying as Black, 122 (71%) had &gt;80% African ancestry, 45 (26%) were considered Mixed, and 4 (3%) had missing data. We observed gPV in 216 (13.3%) patients (73 high, 36 moderate and 107 low/uncertain penetrance), with 15 patients having &gt;1 gPV. Rates of gPV varied significantly by self-reported ancestry [AJ: 40 (19.8%), Asian: 15 (12.1%), Black: 12 (7.0%), Hispanic: 15 (12.1%), NH-White: 129 (13.9%), Missing: 5; p=0.009] and genetic ancestry [AFR: 9 (6.4%), AJ: 53 (19.3%), EAS: 9 (11.0%), EUR: 112 (13.3%), NAM: 2 (40%), SAS: 7(20%), Mixed: 17 (8.6%), Missing: 7; p&lt;0.001]. Self-reported Black patients had the lowest rate with 13 gPV observed in 12 patients (7.0%); 5 gPV had biallelic inactivation within the tumor (2 MSH2, 1 MSH6, 1 BRCA2 and 1 FANCA). Biallelic inactivation was observed in 70 (32%) patients overall with highest rates in Black (42%), Asian (40%), AFR (67%) and SAS (71%) populations. In those with new gPV (n=114), 102 (89%) overall were seen in genetics clinic for follow-up care, with the lowest rates in patients identifying as Black (75%) and of AFR ancestry (67%). Conclusions: Although rates of gPV varied by ancestry, they are drivers of disease in all populations, emphasizing the importance of germline assessment in EC. Differences in gPV and subsequent genetics care may contribute to racial/ethnic disparities in outcomes in EC by affecting treatment and cancer prevention and should be studied further.

Prevalence of germline variants in patients with pancreatic neuroendocrine tumors.

4135 Background: About 10% of pancreatic neuroendocrine tumors (pNETs) are thought to be related to inherited syndromes, including multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 4 (MEN4), von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). Here, we report the prevalence of pathological/likely pathological germline variants (PV/LPV) in 2 cohorts: 1) High-risk and 2) Unselected. Methods: We retrospectively collected clinical data of patients with biopsy proven pNETs seen at MD Anderson Cancer Center (MDACC) and Johns Hopkins Hospital (JHH). Cohort 1 (high risk cohort) included 132 patients seen at MDACC, who underwent germline testing based on high-risk criteria such as early onset, personal or family history of cancer and syndromic features between 2013 -2019. Cohort 2 (unselected cohort) included 106 patients seen at JHH, who underwent germline testing following their diagnosis of pNETs between 2020 to 2022. Results: In the high-risk cohort (n = 132), 33% (n = 44) had PV/LPV, and 17 % (n = 22) had a variant of unknown significance (VUS). Amongst the 132 patients, 35% underwent multigene panel testing, 53% had targeted germline testing and 12% had a physician documented outside test diagnosis. The demographics consisted of 52%(n = 69) females, 67% (n = 88) white, 54%(n = 71) had metastatic disease, 58%(n = 76) underwent surgical resection. WHO grading (n = 77) is as follows G1 (39%), G2 (59%), G3 (2%). In the unselected cohort (n = 106), 21% (n = 22) had PV/LPV, 28 % (n = 30) had a VUS. Of these, 93% of the patients underwent multigene panel testing. The demographics consisted of 42% (n = 44) females, 67% (n = 88) white, 48% (n = 51) had metastatic disease, 60% (n = 64) underwent surgical resection, WHO grading (n = 93) is as follows G1 (37%), G2 (49%), G3 (14%). Conclusions: PV/LPV are prevalent in patients with sporadic pNET irrespective of high-risk features or family history. While in the high-risk patients there is a higher prevalence, we also identified a 21% prevalence of PV/LPV with universal germline testing in the unselected cohort. In both cohorts, we identified a high number of mutations in the DNA repair pathway not previously described, which could affect subsequent therapies and surveillance for patients and their family members. The findings support upfront universal germline testing in all patients with diagnosis of pNETs. [Table: see text]

Abstract 6064: Patient-partnered research enables germline characterization of angiosarcoma predisposition genes

Abstract Background: Angiosarcoma (ASC) represents 1-2% of soft tissue sarcomas. Due to its rarity, to date, no large-scale studies have been done to systematically identify ASC-predisposition genes and the broader landscape of pathogenic germline variants in patients with ASC remains unclear. Methods: Through the Angiosarcoma Project, an ongoing patient-partnered research approach that allows patients living anywhere in the U.S. or Canada with angiosarcoma to participate through a website, blood and saliva samples were collected from more than 300 patients and whole-exome-sequencing was performed. Machine-learning frameworks were used to identify germline short variants (SNPs, indels) and rare germline copy number variants (CNVs). The pathogenicity of variants in 107 curated cancer-predisposition and sarcoma-related genes were evaluated according to the ACMG guidelines. A short-variant-based gene-burden analysis was then performed using 223 unrelated ASC patients and 4557 ancestry-matched unrelated cancer-free controls. Results: In total, 38 patients (17.04%) carried at least one pathogenic short variant, including 37 carrying germline heterozygous pathogenic variants in POT1 (9, 4.04%), BRCA2 (3, 1.35%), CHEK2 (3, 1.35%), MUTYH (3, 1.35%), BRCA1 (2, 0.90%), PRF1 (2, 0.90%), ERCC3 (1, 0.45%), TP53 (2, 0.90%), ATM (1, 0.45%), TSHR (1, 0.45%), TSC2 (1, 0.45%), SDHA (1, 0.45%), SBDS (1, 0.45%), MSH6 (1, 0.45%), MITF (1, 0.45%), MET (1, 0.45%), LZTR1 (1, 0.45%), FH (1, 0.45%), ERCC2 (1, 0.45%), XPC (1, 0.45%). In addition, one patient harbored pathogenic short variants in both BRCA1 and ERCC3. In the 8 unique CNVs detected in 10 (4.55%) patients, 6 were classified as pathogenic including 3 heterozygous duplications overlapping MSH2, LZTR1, SMARCB1, and 3 heterozygous deletions overlapping NF1, MSH2, and WRN. Two unique heterozygous duplications met VUS criteria including one overlapping ERCC2 and one overlapping SMARCB1. In a comparison between ASC patients and cancer-free controls of predominantly European ancestry, we found ASC patients tobe 40 times more likely to carry a pathogenic variant in POT1 (OR: 42.91, CI: [15.40-174.08], q &amp;lt; 0.001, p &amp;lt; 0.001), while TP53 was nominally significant (OR: 7.37, CI: [1.19 - 41.13], p = 0.037). Conclusion: We confirmed prior observations of POT1 being responsible for ASC and called for attention to investigate the effect of germline CNVs in ASC. Overall, the elucidation of various germline elements associated with ASC risk highlighted the value and importance of patient-partnered research, particularly for rare cancers, and the analysis support using germline testing of patients for more precise clinical management. Citation Format: Hoyin Chu, Marissa Hollyer, Seunghun Han, Sabrina Y. Camp, Riaz Gillani, Eliezer Van Allen, Nikhil Wagle, Corrie A. Painter, Saud H. AlDubayan. Patient-partnered research enables germline characterization of angiosarcoma predisposition genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6064.

Identification of Germline Variants in Patients with Hereditary Cancer Syndromes in Northeast Mexico.

Hereditary cancer syndromes (HCS) are genetic diseases with an increased risk of developing cancer. This research describes the implementation of a cancer prevention model, genetic counseling, and germline variants testing in an oncologic center in Mexico. A total of 315 patients received genetic counseling, genetic testing was offered, and 205 individuals were tested for HCS. In 6 years, 131 (63.90%) probands and 74 (36.09%) relatives were tested. Among the probands, we found that 85 (63.9%) had at least one germline variant. We identified founder mutations in BRCA1 and a novel variant in APC that led to the creation of an in-house detection process for the whole family. The most frequent syndrome was hereditary breast and ovarian cancer syndrome (HBOC) (41 cases with BRCA1 germline variants in most of the cases), followed by eight cases of hereditary non-polyposic cancer syndrome (HNPCC or Lynch syndrome) (with MLH1 as the primarily responsible gene), and other high cancer risk syndromes. Genetic counseling in HCS is still a global challenge. Multigene panels are an essential tool to detect the variants frequency. Our program has a high detection rate of probands with HCS and pathogenic variants (40%), compared with other reports that detect 10% in other populations.

Incidence of Germline Variants in Familial Bladder Cancer and Among Patients With Cancer Predisposition Syndromes.

The familial aggregation of bladder cancers has been observed, but the incidence and association of familial bladder cancer with germline pathogenic and likely pathogenic (P/LP) variants is unknown. A retrospective analysis was conducted of patients with bladder cancer treated at the Dana-Farber Cancer Institute to identify those with a first-degree relative with bladder cancer. A second cohort of patients referred to DFCI for suspicion of a cancer predisposition syndrome was analyzed for candidate P/LP germline variants. Descriptive statistics were generated. Among 885 patients with bladder cancer, 38 patients (4.3%) had a family history of bladder cancer in a first-degree relative. No significant association of age of diagnosis was observed between patients with and without a first-degree family history of bladder cancer (P = .3). In the second cohort, 27 of 80 (34%) patients with bladder cancer evaluated for cancer predisposition syndromes harbored a P/LP germline variant. P/LP variants were identified most commonly in the following genes: BRCA1 (n=5), MSH2 (n=5), MLH1 (n=4), ATM (n=3), and CHEK2 (n=2). Of the 27 patients with identified germline P/LP variants, 20 (74%) had a family history of a tumor component syndrome in a first- or second-degree relative and 3 were subsequently diagnosed with another genetically-linked associated cancer. Familial bladder cancer defined as bladder cancer in the proband and a first-degree relative, was present in 4.3% of patients with bladder cancer and was not associated with age of diagnosis. Additionally, among patients suspected to have a familial cancer syndrome, one-third harbored a germline P/LP variant. Further study of germline variants in patients with familial bladder cancer including somatic testing for loss of heterozygosity may provide insights regarding disease pathogenesis and inform therapy.