A comprehensive custom panel evaluation for routine hereditary cancer testing: improving the yield of germline mutation detection

1517 Background: Next-generation sequencing (NGS) for tumor molecular profiling is used in Oncology to identify ‘actionable alterations’ for clinical trials or on/ off-label therapy. Tumor NGS can also reveal potentially heritable germline mutations. The frequency of such incidental germline mutations has been estimated to be 4-15%. The 2015 ASCO Statement supports communication of medically relevant incidental germline findings from somatic mutation profiling to patients (PTS). The impact of tumor NGS testing on hereditary cancer risk assessment programs in the context of a wider population management strategy is unknown. We sought to evaluate this within our Kaiser Permanente Northern California (KPNC) population with ready access to tumor NGS and an ongoing hereditary cancer risk assessment program. Methods: Kaiser Permanente Northern California (KPNC) is part of a large, integrated health care system. NGS at KPNC is performed in collaboration with STRATA Oncology, a precision oncology partnership. All NGS results are reviewed by a multidisciplinary KPNC Genomic Oncology Committee (GOC)which also includes genetic counselors and pathologists. We examined all NGS reports between November 2017 through December 2019 to determine the types of cancers tested, number with a possible germline mutation and number referred for genetic counseling and testing (GCT). Results: 4,825 PTS with advanced cancer underwent STRATA NGS testing. A total of 207 PTS (4.3%) were identified as potential germline mutation carriers, all 207 were recommended for GCT referral. Of these, 92 (45.0%) separately met 2020 NCCN Criteria for Genetic/Familial High-Risk Assessment (2020NG/FA), prior to tumor NGS; 115 (53.6%) did not and 3 (1.4%) had insufficient information. The cancers most frequently meeting NCCN criteria were pancreatic, breast and colon. Of the 92 PTS who met 2020NG/FA, 60 (65%) underwent GCT and 34 (57%) were confirmed to have a germline mutation. Of the 115 PTS that did not meet 2020NG/FA, 47 (41%) underwent GCT and 19 (40%) were confirmed to have a germline mutation. Overall germline mutations were confirmed in 16.5% of patients who did not meet 2020NG/FA and 37% who did. Conclusions: In our community-based integrated healthcare system, systematic review of next-generation sequencing results by an expert GOC led to more robust identification of germline mutation carriers and navigated them to appropriate GCT. Ongoing work will clarify data on cascade testing. We are currently developing automated workflows for GCT.

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Tu1378 High Mutation Detection Rate and Novel Mutations Identified in Major and Minor- Risk Cancer Genes by Applying Multigene Panels in Hereditary Cancer Clinic

Gastroenterology ◽

10.1016/s0016-5085(16)33003-7 ◽

2016 ◽

Vol 150 (4) ◽

pp. S889

Author(s):

Guy Rosner ◽

Sivan Aharon Caspi ◽

Merav Ben-Yehoyada ◽

Dani Bercovich ◽

Zamir Halpern ◽

...

Keyword(s):

Hereditary Cancer ◽

Detection Rate ◽

Mutation Detection ◽

Cancer Genes ◽

Novel Mutations ◽

Mutation Detection Rate ◽

Multigene Panels ◽

Hereditary Cancer Clinic ◽

Cancer Clinic

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A comprehensive custom panel design for routine hereditary cancer testing: preserving control, improving diagnostics and revealing a complex variation landscape

Scientific Reports ◽

10.1038/srep39348 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 27

Author(s):

Elisabeth Castellanos ◽

Bernat Gel ◽

Inma Rosas ◽

Eva Tornero ◽

Sheila Santín ◽

...

Keyword(s):

Hereditary Cancer ◽

Complex Variation ◽

Custom Panel ◽

Panel Design

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Potential germline findings identified during somatic tumor testing: Room for improvement.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.1543 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 1543-1543

Author(s):

Sundas Khan ◽

Heather Wright ◽

Melissa Cuke ◽

Edmund Folefac ◽

Claire F. Verschraegen ◽

...

Keyword(s):

Genetic Testing ◽

Germline Mutation ◽

Hereditary Cancer ◽

Germline Mutations ◽

Cancer Center ◽

Genomic Testing ◽

Test Results ◽

Genomic Test ◽

Tumor Types ◽

Germline Testing

1543 Background: Genomic testing, useful for treatment planning and identification of patients for clinical trials, may indicate the presence of a germline mutation. We sought to evaluate the incidence of potentially actionable germline mutations detected via genomic testing and determined rates of germline testing among patients with potential germline mutations. Methods: This was a retrospective review of patients undergoing genomic testing at The University of Vermont Cancer Center (UVMCC) between 03/02-11/19. Testing was reviewed for mutations in 60 genes associated with hereditary cancer and recognized as clinically actionable by the American College of Medical Genetics. Records were reviewed for clinical follow-up. Positive (pathogenic or likely pathogenic) genomic test results were evaluated with descriptive analyses. Proportions with 95% confidence intervals are presented and comparisons made using a χ2 test. Results: 342 patients underwent genomic testing at UVMCC over the study period, with a median age of 61. Common tumor types include: CNS (19%), NSCLCA (17%), ovarian (8%), and sarcoma (7%). 59% (203/342) had a mutation in ≥ 1 gene associated with hereditary cancer. Most common tumor types with potential germline mutations include: NSCLCA (25%), CNS (18%), ovarian (8%), sarcoma (8%), and endometrial (7%). Potential germline mutations were most commonly identified in TP53, CDKN2A, PTEN, and RB1 (each with mutations in >6% of patients). 58 patients in the cohort have undergone germline testing, of which 19% were positive for germline mutations. Of patients with mutations in the highly penetrant BRCA, PALB2, and Lynch genes, 71% were positive for germline mutations. Young age ( < 50) did not enrich for germline mutations (p > 0.05). Only 18% (36/203) of patients with potential germline results were referred for genetic counseling. Conclusions: Genomic testing can reveal hereditary cancer syndromes. While the majority of patients with tumor mutations in genes associated with hereditary cancer will not have germline mutations, genetic testing is the only way to confirm this. 19% of patients who underwent genetic testing in this cohort had a pathogenic germline mutation. This was enriched to 71% when considering genes rarely mutated in tumors (BRCA, PALB2, and Lynch genes). Only 17% of this cohort underwent genetic testing, representing a significant missed opportunity given the implications of these findings for both patients and families. Patients and their providers should be aware of the potential for germline findings when genomic testing is performed.

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The prevalence of BRCA1/2 germline mutation in Chinese pan-cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e13684 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e13684-e13684

Author(s):

Fei Ma ◽

Lixi Li ◽

Zongbi Yi ◽

Jianming Shi ◽

Hua Jiang ◽

...

Keyword(s):

Ovarian Cancer ◽

Germline Mutation ◽

Hereditary Cancer ◽

Cancer Risk Assessment ◽

Founder Mutations ◽

Breast And Ovarian Cancer ◽

Brca1 And Brca2 ◽

Variant Of Uncertain Significance ◽

Pathogenic Variants ◽

Pan Cancer

e13684 Background: Pathogenic variants in cancer predisposition genes BRCA1/2 confer susceptibility to breast and ovarian cancer and well-studied. But the characteristics of BRCA in other cancers is unknown, we identified and characterized BRCA germline variants in a large pan-cancer in China. Methods: NGS was performed on genomic DNA from 29,676 pan-cancer patients. Large fragment deletions were all verified by QPCR. We integrated guidelines of ACMG/AMP, ENIGMA and China expert consensus. Based on the in-house system, variants were interpreted one-by-one and classified into 5 grades: Benign (B), Likely Benign(LB), Variant of Uncertain significance(VUS), Likely pathogenic (LP), Pathogenic (P). Results: Among 29,676 patients, 300 BRCA1 mutations and 440 BRCA2 mutations were detected in our study. The proportion among P/LP/VUS/LB/B were 36.1%, 11.6%, 36.6%, 11.1% and 4.6%. Consistent with previous reports, the mutations spread around the whole genes. Missense and frameshift were most common types in BRCA1 (40%, 25.3%) and BRCA2 (42.3%, 29.3%). 192(25.9%) mutations were not reported in any of the databases. Among these newly reported mutations, 32 (16.7%) were classified as P, 62 (32.3%) LP and 98 (51%) VUS. Totally, 522 (1.8%) patients were identified with P/LP BRCA1/2 mutations. No founder mutations in Chinese population were defined, but BRCA1 5470_5477delATTGGGCA (I1824Dfs*3) and BRCA2 3109C > T (Q1037*) had the highest prevalence indicating the common P/LP mutations in Chinese. On the whole, BRCA-associated hereditary cancer harbored higher P/LP percent than other cancer types (11.1% vs 0.7%). Different distribution and percent were observed in BRCA1 and BRCA2, the P/LP mutations were found in double primary cancers of breast and ovary (76.9% vs 38.5%), followed by ovarian cancer (15.5% vs 6.3%), breast cancer(3.8% vs 4.0%), endometrial cancer(1.6% vs 2.4%), prostatic cancer(1.3% vs 1.9%), pancreatic cancer (0.3% vs 1.8%), biliary tract tumor (0% vs 1%), thyroid cancer (0% vs 0.9%), NSCLC(0.2% vs 0.5%) and colorectal cancer(0.08% vs 0.4%). Except for SNV/Indels, large range heterozygous deletions were found in 9 patients, including 4 (0.6%) OC, 4 (0.2%) BC and 1 NSCLC, almost all interfering with BRCA1. Conclusions: This analysis depicted a comprehensive landscape of germline BRCA1/2 variants in Chinese pan-cancer. Besides breast and ovarian cancer, lots of other cancers also harbor BRCA germline mutation, retrospective family history and hereditary cancer risk assessment needs further study.

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