Abstract P3-07-01: Young women with breast cancer and high risk family history but no high penetrance germline mutations have a higher load of rare high functional impact germline variants in cancer relevant genes
Authors: Rozenblit Mariya , Qing Tao , Ye Yixuan , Zhao Hongyu , Hofstatter Erin , Singh Vinit , Reisenbichler Emily , Murray Michael , Pusztai Lajos 
Published: March 2022

Background: There is an incomplete understanding of why some women develop breast cancer 20-25 years earlier than the majority of women. Only 30-40% of women with high risk family history are found to have known cancer predisposing mutations. This phenomenon is referred to as “missing heredity”. We hypothesize that women with high-risk cancer family history but no known high penetrance cancer predisposing mutations who develop breast cancer at a young age have a higher deleterious load of germline high functional impact (gHFI) single nucleotide variants in cancer relevant genes. Methods: 94 women diagnosed with breast cancer age &lt;50 with high risk cancer family history who tested negative for germline cancer predisposing mutations were identified at Yale Cancer Prevention Clinic (YCPC). 149 controls, healthy Caucasian individuals age &gt; 65 with no cancer family history were identified from Yale Generations project. Whole-exome sequencing (WES) was performed on peripheral blood from 94 cases, 149 controls, and 42 matched tumors. WES data was analyzed from 1,112 female breast cancer cases with first-degree breast cancer family history and 50,887 healthy women without breast cancer family history from UKBiobank. Rare gHFI variants were defined as nonsynonymous variants predicted as deleterious in MetaSVM, or loss-of-function in gnormAD, or pathogenic in ClinVar database with mutation frequency &lt;0.01. Hallmark genes were 1,558 genes involved in 21 cancer pathways and 83 cancer predisposition genes (CPGs). 468 somatic cancer genes were used. Rare gHFI in cases vs controls were compared using SNP-set (Sequence) Kernel Association Test (SKAT). Somatic mutations in YCPC vs 652 ER+ breast cancer TCGA cases were compared using 13/468 cancer genes mutated &gt;5% of cases using Fisher’s exact test. FDRs were calculated using Benjamini & Hochberg. Results: The majority of YCPC patients were Caucasian (78.7%), median age (43.5), with invasive ductal carcinoma (85.1%), ER+PR+HER2- (67.0%). YCPC patients had a higher average burden of rare gHFI variants in cancer hallmark genes (excluding CPGs) compared to controls (p=0.0075, adjusted for race), but did not show a higher germline burden in CPGs. Similarly, UKBiobank breast cancer patients with a family history had a higher germline variant burden in hallmark genes (excluding CPGs) compared to controls (p=0.0368). The main pathways affected by gHFI in the YCPC cohort were adaptive immunity (p=1.61 x 10-8) and extracellular matrix (p=0.0034). Thirty six (87.8%) YCPC matched tumors carried somatic mutations in known cancer related genes. Compared to TCGA, YCPC samples had fewer TP53 mutations (5% vs 17%, FDR = 0.27), but more mutations in CHEK2, GNAQ, APC, and SDHA (FDR&lt;0.028). Conclusions: Our cohort of young women with breast cancer and high risk family history with no known germline high penetrance cancer gene mutations showed a higher burden of germline high functional impact variants in hallmark cancer genes. This higher germline variant burden suggests that the totality of gHFI variants in cancer related genes could explain why these women develop breast cancer at a younger age.

CohortRace (%)AgeCases (N)Control (N)GenesetAverage Case BurdenAverage Case BurdenSKAT testYaleCaucasian (78.7)439414983 CPGs0.27660.30200.56921508 Hallmark4.23404.18790.0075UK BiobankBritish (100)5611125088783 CPGs0.37410.28064.19x10-51508 Hallmark3.36423.33990.0368

Citation Format: Mariya Rozenblit, Tao Qing, Yixuan Ye, Hongyu Zhao, Erin Hofstatter, Vinit Singh, Emily Reisenbichler, Michael Murray, Lajos Pusztai. Young women with breast cancer and high risk family history but no high penetrance germline mutations have a higher load of rare high functional impact germline variants in cancer relevant genes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-07-01.