Abstract 1122: Germline mutation prevalence in young adults with cancer
Authors: Stadler Zsofia K. , Maio Anna , Padunan Angelika , Kemel Yelena , Salo-Mullen Erin , Sheehan Margaret , Belanfanti Kimeisha , Tejada Prince R. , Birsoy Ozge , Mandelker Diana , Zhang Liying , Galle Jesse , Feldman Darren , Boucai Laura , Bender Julia Glade , Piotrowski Anna , Aghajanian Carol , Cadoo Karen A. , Carlo Maria I. , Walsh Michael , Janjigian Yelena , O'Reilly Eileen , DeAngelis Lisa M. , Solit David B. , Taylor Barry , Cercek Andrea , Tap William , Robson Mark E. , Berger Michael F. , Offit Kenneth , Diaz Luis A. 
Published: September 2020

The identification of germline pathogenic variants in young adult cancer patients is especially critical given risk of second primary cancers, need for appropriate long-term surveillance, potential reproductive implications, and cascade testing of at-risk family members. We sought to determine the prevalence of germline susceptibility in cancer patients, age 18-39, across diverse solid tumor phenotypes. A total of 1201 cases, diagnosed between ages 18-39 were prospectively ascertained from 2015-2019 under a human subjects-approved protocol that provided result transmission of germline analysis. A next-generation sequencing panel consisting of up to 88 genes previously implicated in cancer predisposition (MSK-IMPACT) was utilized. Based on SEER data, we refined our population of young cancer patients into those with 1) early-onset cancer (EO-CA), defined as cancer wherein age 39 is &gt;1 standard deviation (STD) below the mean age of diagnosis for that cancer type and 2) young-adult cancer (YA-CA), defined as cancer wherein age 39 is &lt;1 STD below the mean age at cancer diagnosis. Among EO-CA (n=877) cases, the most common cancers included colorectal, breast, kidney, pancreas, and ovarian cancer, while among YA-CAs (n=324), the most frequent diagnoses were sarcoma, brain, testicular and thyroid cancer. Germline prevalence of likely pathogenic or pathogenic variants (PV) was 21% in the EO-CA versus 13% in YA-CA patients (p=0.002), with an enrichment of high- and moderate-penetrance PVs in the EO-CA cohort (15% vs 10%; p=0.01). Among EO-CAs, the most commonly mutated genes were BRCA2, BRCA1, CHEK2 and ATM, with pancreas, breast, and kidney cancer harboring the highest rates of germline PVs. In contrast, in the YA-CA cohort, TP53 and SDHA mutations predominated. Among YA-CA patients with sarcoma, the 18.1% mutation prevalence was similar to the prevalence in EO-CAs. Matched tumor analyses assessing biallelic inactivation is on-going and will be presented. Among young adults with early-onset phenotypes of malignancies typically presenting at later ages, the increased prevalence of germline PVs supports a role for genetic testing irrespective of tumor type.

Citation Format: Zsofia K. Stadler, Anna Maio, Angelika Padunan, Yelena Kemel, Erin Salo-Mullen, Margaret Sheehan, Kimeisha Belanfanti, Prince R. Tejada, Ozge Birsoy, Diana Mandelker, Liying Zhang, Jesse Galle, Darren Feldman, Laura Boucai, Julia Glade Bender, Anna Piotrowski, Carol Aghajanian, Karen A. Cadoo, Maria I. Carlo, Michael Walsh, Yelena Janjigian, Eileen O'Reilly, Lisa M. DeAngelis, David B. Solit, Barry Taylor, Andrea Cercek, William Tap, Mark E. Robson, Michael F. Berger, Kenneth Offit, Luis A. Diaz. Germline mutation prevalence in young adults with cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1122.