Tumor sequencing with germline genetic testing: Identification of patients with hereditary cancer and precision treatment eligibility.

Authors

null

Scott T. Michalski

Invitae, San Francisco, CA

Scott T. Michalski , Daniel Esteban Pineda Alvarez , Meaghan Russell , Shan Yang , Guru Sonpavde , Edward D. Esplin

Organizations

Invitae, San Francisco, CA, Dana-Farber Cancer Institute, Boston, MA

Research Funding

Other

Background: Cancer is a fundamentally genetic disease, as such, somatic and germline mutation analysis is used in the comprehensive assessment of patients with cancer. Studies report that approximately 10% of patient’s tumors have clinically significant variants known to predispose to hereditary cancer, with medical implications for both patients and family members. We retrospectively reviewed a series of patients where providers suspected a somatic variant also existed in the germline and followed up with clinical germline genetic testing. We report the rate of concordance between germline and somatic results and their clinical impact. Methods: Our study used de-identified data from 1043 consecutive patients who underwent somatic genetic testing followed by germline testing with NGS-based hereditary cancer gene panels. Results: Somatic results most frequently prompting germline testing included variants in BRCA2 (290), BRCA1 (174), TP53 (158), ATM (70), MLH1 (65), APC (65), PMS2 (61), MSH6 (58), PTEN (54) and CDH1 (42). In 364/1043 cases (35%) the variant was detected as likely pathogenic or pathogenic (LP/P) in the germline. Genes confirmed as germline variants in 60-100% of cases included: FANCA, AXIN2, RAD50, MUTYH, BLM, PALB2, CHEK2, FANCD2, MITF, SDHB. Variants in: FH, BRCA2, RET, ATM, SDHA, BRIP1, MSH2, BRCA1, BAP1, EGFR and RAD51D confirmed in the germline in 25-60%. Variants were rarely germline for TP53 (3%), APC (3%), PTEN (2%) and none in CDKN2A, NF1 and STK11. In 24 (2%) cases a LP/P germline variant was detected but not reported in the tumor. Conclusions: Approximately ⅓ of patients suspected to have hereditary risk after tumor testing had LP/P germline variants. Notably, some genes had a high probability of variants occurring in the germline, while others were primarily seen in tumors. Interestingly, 6% of the germline variants were not included on the somatic report due to technical and gene content differences in either assays or due to differences of clinical classification between somatic and germline testing. Adding germline results to somatic testing may inform options for precision treatment, prevention, or early detection of, secondary malignancies and guide genetic counseling of family members.

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Abstract Details

Meeting

2019 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Cancer Prevention, Hereditary Genetics, and Epidemiology

Track

Prevention, Risk Reduction, and Genetics

Sub Track

Germline Genetic Testing

Citation

J Clin Oncol 37, 2019 (suppl; abstr 1580)

DOI

10.1200/JCO.2019.37.15_suppl.1580

Abstract #

1580

Poster Bd #

74

Abstract Disclosures

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