Germline-Somatic Interactions and Association with Treatment Response in Cancer

Division Of Basic Sciences - Nci

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Linked publications, trials & patents

Abstract

(A) Systematic Review: Major Activities: We completed the systematic review and a draft of the manuscript has been submitted for publication (PROSPERO ID: CRD42022326884). Significant Results: Of 8,613 studies screened, 197 met inclusion criteria. Over 1,200 articles were excluded despite reporting germline and somatic data because they did not include associations with outcomes. Gene-level alterations were most reported (germline: 82%, somatic: 74%). The most common germline-somatic mutation pairs evaluated across all studies were germline BRCA2/somatic TP53 and germline BRCA1/somatic TP53 (n=40 and n=38 studies, respectively). Statistical testing was performed in 41.6% (n=82) of studies to assess germline-somatic interactions, with other studies providing only descriptive or enumerative analysis. Among studies assessing the direction of effect, 31 showed benefit associated with co-occurrence of germline and somatic alterations, while 28 showed harm. These findings suggest that upfront consideration of germline-somatic interactions with outcomes could improve analysis and application in translational and clinical cancer genetics. (B) Germline-Somatic Interactions in Breast Cancer: Major Activities: We reviewed breast cancer datasets in CBioPortal and papers published in the past 15 years for germline and somatic sequencing with reported variants, treatment information, and associated responses. We identified 3 datasets: The Cancer Genome Atlas (TCGA), The Metastatic Breast Cancer Project (MBC), Fudan University Shanghai Cancer Center (BC cohort) (FUSCC). We evaluated a total of 7 co-occurring gene pairs associated with differences in treatment response as obtained from the literature review: BRCA1 and BRCA2; BRCA2 and RB1, BRCA1/2 and TP53, PTEN, PIK3CA, MYC; and PALB2 and NOTCH2. We used the variant calls that already exist for these datasets as obtained from CBioPortal. We also harmonized clinical information, with a focus on harmonizing what treatment responses we had available. For early-stage disease, we assessed disease-free survival (DFS) in response to the classes of chemotherapy or hormone therapy. For metastatic disease, we assessed duration of treatment response for specific treatments. Differences were evaluated statistically using a Fisher's exact test. We are now in the process of validating this data in BEAUTY and FELINE studies available through dbGAP and writing up these findings in a manuscript. This project was awarded an AACR Minority Scholar in Cancer Research award. Significant Results: The only combinations we could assess with adequate representation (where each category had > 1 patient) were: *BRCA1/2 and TP53: Early-stage chemotherapy and hormone therapy -> we identified a statistically significant difference in DFS for both chemotherapy and hormone therapy, where patients with a germline * BRCA1/2 and somatic TP53 mutation showed shorter DFS in response to treatment relative to either group alone or no mutations.