Detection of germline variants using expanded multigene panels in patients with localized pancreatic cancer
Ashley N. KreplineJennifer L. GeurtsIdayat AkinolaKathleen K. ChristiansCallisia N. ClarkeBen GeorgePaul S. RitchAbdul H. KhanWilliam A. HallBradley A. EricksonMike GriffinDouglas B. EvansSusan Tsai
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244 Background: Pancreatic ductal adenocarcinoma (PC) is associated with multiple hereditary cancer syndromes. Genes implicated in hereditary PC include ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2 and PMS2. The advent of multi-gene hereditary cancer panel testing streamlines diagnoses and medical management for clinicians and patients. Our objective was to assess the yield of pathogenic/likely pathogenic variants (PV/LPV) in individuals with PC undergoing panel testing as an initial test at GeneDx. Methods: We retrospectively reviewed panel test results of 605 individuals reporting a personal history of PC. Panel testing evaluated up to 32 genes associated with hereditary cancer. Individuals reporting neuroendocrine pathology or previous BRCA1/BRCA2 testing were excluded. Results: In this cohort, 61 PV/LPV were detected in 57 individuals in the following genes: ATM (17), BRCA2 (14), BRCA1 (5), CDKN2A (5), PALB2 (5), CHEK2 (4), MLH1 (2), MUTYH (2), PMS2 (2), BARD1 (1), FANCC (1), MSH2 (1), RAD51D (1) and TP53 (1), corresponding to a positive yield of 9.4% (57/605). Fifty-one of 61 PV/LPV were detected in genes associated with PC (84%) while 10 PV/LPV (16%) were identified in other genes including BARD1, CHEK2, FANCC, MUTYH, and RAD51D. The diagnostic yield among those reporting a family history of PC (33/294, 11.2%) was not statistically different from those without a reported family history (24/311, 7.7%). However, PV/LPV in ATM were detected more often in individuals reporting a family history of PC compared to those without a family history (4.1% vs. 1.6%, p=0.018). Conclusions: In total, 9.4% of patients with PC tested positive for PV/LPV in 14 different genes by panel testing. Although the majority of PV/LPV were identified in known PC genes, 16% of positive findings occurred in genes not typically associated with PC. ATM was most commonly implicated and more frequently reported in patients reporting family histories of PC. Assessing whether these genes are indeed causally related to PC and/or are possibly associated with other cancer types requires further investigation. Based on our results we conclude multi-gene panel testing may be considered as a first option for patients with PC regardless of their family history.
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e13509 Background: Hereditary cancer accounts for approximately 10% of all cancers. An estimated 15-20% of all cancer patients have positive family history. However, until recently mutations in highly penetrant genes were only identified in approximately 20% of high-risk families. Technological advances in DNA sequencing, commonly designated as “Next Generation Sequencing-NGS” allowed to identify new genes responsible for the missing heritability, allowing the application of this knowledge in the diagnostic setting. Methods: Between 2015 and 2017, 276 patients were tested at two institutions in Dubai, UAE for BRCA1 and BRCA2 genes and the common CHEK2 c.1100delC mutation. In 2017, testing was extended to include 33 genes for 89 patients tested. Testing for all 276 patients was conducted at a single laboratory with testing criteria based on NCCN guidelines. Results: At the time of testing, median age was 44 years (range 26–72 years) with the majority of patients diagnosed with breast cancer. Patients tested were from a diverse ethnic group the majority of whom were from the Middle East and Asia pacific region. 24/276 (8.7%) had a pathogenic variant identified in the BRCA (n = 13), BRCA2 (n = 8) or c.1100delC in CHEK2 (n = 3) gene and 30 (10.8%) patients had a VUS in one of the three genes. Of the 89 patients tested with the 33 gene panel, additional pathogenic variants were identified in 7 (7.8%) patients involving the MUTYH (n = 4), RAD51C (n = 1), RAD50 (n = 1) and PALB2 (n = 1) genes and at least one VUS was reported in 35 (39%) patients. The most commonly mutated genes across the whole cohort were BRCA1 and BRCA2, accounting for 55% of the mutations identified. Two (11%) of the mutations identified were large genomic rearrangements of several exons of the BRCA1 and RAD51C genes. Conclusions: Our results support the clinical significance of analysis of a panel of genes involved in hereditary cancer predisposition. In our series, pathogenic variants were identified in all but one case in genes for which enough data has been collected allowing for the formulation of clinical management guidelines. These patients have therefore received results which will alter their clinical management.
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Breast cancer (BC) in men is rare and genetic predisposition is likely to play a relevant role in its etiology. Inherited mutations in BRCA1/2 account for about 13% of all cases and additional genes that may contribute to the missing heritability need to be investigated. In our study, a well‐characterized series of 523 male BC (MBC) patients from the Italian multicenter study on MBC, enriched for non‐ BRCA1/2 MBC cases, was screened by a multigene custom panel of 50 cancer‐associated genes. The main clinical‐pathologic characteristics of MBC in pathogenic variant carriers and non‐carriers were also compared. BRCA1/2 pathogenic variants were detected in twenty patients, thus, a total of 503 non‐ BRCA1/2 MBC patients were examined in our study. Twenty‐seven of the non‐ BRCA1/2 MBC patients were carriers of germline pathogenic variants in other genes, including two APC p.Ile1307Lys variant carriers and one MUTYH biallelic variant carrier. PALB2 was the most frequently altered gene (1.2%) and PALB2 pathogenic variants were significantly associated with high risk of MBC. Non‐ BRCA1/2 pathogenic variant carriers were more likely to have personal ( p = 0.0005) and family ( p = 0.007) history of cancer. Results of our study support a central role of PALB2 in MBC susceptibility and show a low impact of CHEK2 on MBC predisposition in the Italian population. Overall, our data indicate that a multigene testing approach may benefit from appropriately selected patients with implications for clinical management and counseling of MBC patients and their family members.
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e16276 Background: Pancreatic cancer is one of the most fatal malignancies. It accounts for 2% of all cancers and 5% of cancer-related deaths. Hence, it is essential to identify pancreatic cancer at an earlier stage to improve outcomes. A variety of hereditary cancer syndromes have been associated with an increased risk of developing pancreatic cancer, and these individuals may benefit from surveillance plans. PARP inhibitor therapy is currently being applied as precision medicine to pancreatic cancer patients harboring germline variant in the Homologous recombination repair (HRR) genes. Our aim was to determine the prevalence of germline pathogenic/likely pathogenic variants in cancer predisposing genes in patients with pancreatic cancer. Methods: In total, 113 patients diagnosed with pancreatic cancer were referred to our laboratory for genetic testing. The analysis of 52 genes involved in hereditary cancer predisposition was performed using a NGS approach. Results: A germline pathogenic/likely pathogenic variant was identified in 20% of patients analyzed. Among individuals with germline pathogenic/likely pathogenic variants, 60% had a positive finding in a pancreatic cancer susceptibility gene; ATM (20%), BRCA1 (20%), BRCA2 (12%), CDKN2A (4%), PALB2 (4%) while 40% carried positive findings in other cancer susceptibility genes. More specifically, in CHEK2 (16%), MRE11 (4%), RAD50 (4%), RAD51C (4%), MUTYH (8%) and NTLH1 (4%). Notably, 84% of pathogenic variants were identified in genes associated with the HRR pathway ( ATM, BRCA1, BRCA2, CHEK2, MRE11, PALB2, RAD50 and RAD51C). Conclusions: Our results indicate that multigene genetic testing is meaningful for pancreatic cancer patients as in 20% of tested individuals we identified findings associated with pancreatic or other cancer predisposition. Moreover, pathogenic/likely pathogenic variants in HRR genes, were identified in 16.6% patients and these patients might benefit from targeted treatments, such as PARP inhibitors or platinum-based treatment.
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Patients with germline pathogenic variants (GPV) in cancer predisposition genes are at increased risk of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer. The genes most frequently found to harbor GPV in unselected PDAC cases are ATM, BRCA1, BRCA2, CDKN2A, CHEK2, and PALB2. However, GPV prevalence and gene-specific associations have not been extensively studied in the general population. To further explore these associations, we analyzed genomic and phenotypic data obtained from the UK Biobank (UKB) and Geisinger MyCode Community Health Initiative (GHS) cohorts comprising 200,600 and 175,449 participants, respectively. We estimated the frequency and calculated relative risks (RRs) of heterozygotes in both cohorts and a subset of individuals with PDAC. The combined frequency of heterozygous carriers of GPV in the general population ranged from 1.22% for CHEK2 to 0.05% for CDKN2A. The frequency of GPV in PDAC cases varied from 2.38% (ATM) to 0.19% (BRCA1 and CDKN2A). The RRs of PDAC were elevated for all genes except for BRCA1 and varied widely by gene from high (ATM) to low (CHEK2, BRCA2). This work expands our understanding of the frequencies of GPV heterozygous carriers and associations between PDAC and GPV in several important PDAC susceptibility genes.
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23 Background: New technologies for identifying hereditary predisposition to breast cancer have led to the discovery of novel genes associated with cancer risk. This has prompted re-evaluation of patients who previously tested negative for BRCA1/2 gene mutations, with a possibility of discovering new genes which may impact management. This study reports on the results of retesting patients who previously were negative for BRCA1/2. Methods: Patients who tested negative for BRCA1/2 mutations who had significant personal and family history were referred back to the Cancer Genetics Center between February 1, 2012 and May 30, 2105 for discussion of additional testing. A detailed personal and family history was reviewed, and patients were counseled about the genetics and clinical implications of panel testing for multiple breast cancer genes. Panel testing using next generation sequencing technologies was ordered. Patients were seen in follow up for discussion of results and management. Results: A total of 12 pathogenic mutations were identified during the study period. The genes and frequencies of these mutations were: CHEK2(3), PALB2(3), ATM(2), APC(1), BARD(1), CDH(1), MUTYH(1). There were 33 variants of undetermined significance(VUS) in 27 patients. 5 of these were seen in patients with a known pathogenic mutation; 3 others were later classified as benign. The frequencies of these VUSs were: ATM (9), PALB2(3), BARD1 (3), PTEN(3), PMS2(3), MSH6(2), CHEK2 (1), MYH(1), RAD51(1), BRIP1(2), NF1(1), BMPR1A(1). Of the 46 patients who had their initial BRCA testing and repeat panel testing between February 1, 2012 and May 30, 2015, 6 (13%) tested positive for a pathogenic mutation. Conclusions: This study demonstrates the feasibility and potential clinical benefit of retesting individuals who previously tested negative for BRCA1/2 mutation. This approach had a significant management impact on patients and their families, with a 13% detection rate of pathogenic mutations. The success of retesting is predicated upon an infrastructure of provider and patient education, pre and post genetic counseling and serves as a model for other centers.
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e20527 Background: Lung cancer is currently a leading cause of cancer-associated mortality worldwide. Germline mutations potentially predisposing patients to lung cancer have not been systematically defined. In this study, we sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline mutations in patients with NSCLC. Methods: A total 1562 patients with NSCLC were included in this study. Leukocyte DNA was extracted and detected were using next generation sequencing technology. Allele frequencies were compared with publicly available database. Interpretation of sequence variations was classified according to the American College of Medical Genetics and Genomics guidelines. Results: Overall, median age at testing of individuals was 63 years (range 12 to 91). The majority of individuals tested were male (56.15%, 877/1562). of 1562 NSCLC, P/LP mutations were identified in 94 (6.02%) in 42 Cancer Susceptibility genes. No individuals carried more than 1 germline variant. The most common P/LP mutations in genes were MUTYH (n = 11, 0.70%), TP53 (n = 10, 0.64%), BRCA2 (n = 8, 0.51%), PALB2(n = 5, 0.32%), PTEN(n = 4, 0.26%), BLM(n = 3, 0.19%), WRN(n = 3, 0.19%), and ATR, BRCA1 and BRIP1 (n = 2, 0.13% each). Twenty eight patients were carried germline mutations in homologous recombination repair(HRR), including BRCA2 (8), PALB2 (5), PTEN (4), BRCA1 (2), BRIP1 (2), CHEK2 (2), FANCA (2), ATM (1), RAD51B (1), RAD54L(1). Of note, the clinical features of patients with HRR mutations were not young adult (median age [range], 57 [41-80] years). Conclusions: Of 1562 patients with NSCLC, 94 (6.02%) had germline mutations and 27 (1.73%) had mutations in HRR genes. The presence of HRR germline mutations could guide cancer screening for patients and their families and serve as predictive biomarkers of response to targeted or immunotherapies. More extensive germline testing in NSCLC should be considered.
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Detection of inherited mutations in Brazilian breast cancer patients using multi-gene panel testing.
e13610 Background: Genetic diversity among populations in the spectrum and frequency of germline variants in BRCA1/2 genes has been well documented. It is unclear whether this extends to other breast cancer predisposition genes, particularly in Latin American populations, where access to genetic testing and counseling is very scarce. Methods: Study participants included a nationwide sample of 1554 Brazilian patients with breast cancer referred for hereditary cancer panel testing at a single clinical diagnostic laboratory from 2015 through 2017. NGS panels included comprehensive analysis of 21–39 known or proposed cancer susceptibility genes, depending on the panel ordered. De-identified data were used to determine the spectrum and frequencies of pathogenic germline variants and variants of uncertain significance (VUS) according to patients’ clinical variables. Results: In total, 153 (10%) participants carried germline pathogenic mutations in BRCA1/2 and 146 (9%) in other cancer predisposition genes. The prevalence of pathogenic variants in breast cancer patients diagnosed under 35 years-old was 27% (15% BRCA1/2, 4% TP53, 8% other genes). 315 distinctive pathogenic mutations were identified in 22 genes, most frequently in BRCA1 (29%), BRCA2 (21%), TP53 (11%), MUTYH heterozygous (10%), ATM (8%), CHEK2 (6%), and PALB2 (4%). The Brazilian TP53 c.1010G > A (p.Arg337His, R337H) founder mutation corresponded to 71% of all TP53 mutations, was related to 1.5% of all breast cancer cases, and was concentrated in South, Southeast and Central-West regions of Brazil. A total of 778 individuals had 1 or more VUS (50%). Conclusions: The inclusion of cancer susceptibility genes other than BRCA1/2 to the search for hereditary breast cancer through the use of panel testing almost doubled the identification of mutation carriers in Brazil. In our population, special attention has to be given to TP53 mutations which represented a substantial fraction of the total mutations identified and has the potential to impact significantly medical treatment options and screening recommendations for carriers and their relatives.
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