Germline ATM mutations in families with early-onset and familial gastroesophageal and colorectal cancers.

Abstract

11 Background: ATM is involved in repair of DNA damage due to radiation and environmental toxins via downstream interaction with CHEK2, BRCA1, and other proteins involved in double strand break repair. Mutations in ATM (Ataxia-Telangiectasia Mutated, 11q22) are among the most common hereditary cancer risk mutations in the general population (0.5-1.0% carrier rate), yet beyond risks of breast (BC) and pancreatic cancer (PC), the spectrum of clinically relevant cancer risks in ATM+ individuals remains uncertain. Thompson (JNCI 2005) previously reported possible risk of colorectal (CRC) (RR 2.54; 1.06-6.09) and gastric cancer (GC)(RR 3.39; 0.86-13.4) in ATM+ individuals, while more recently Hansford (JAMA Onc 2015) performed panel gene testing including CDH1 in patients meeting criteria for hereditary diffuse gastric cancer, and found possibly pathogenic ATM mutations in 3/144 (2%) CDH1-negative probands. In addition to GC, families contained multiple cases of BC, PC and CRC (5 cases, 2 < 50). To further describe the frequency of upper and lower GI cancer in ATM+ families, we reviewed pedigrees from 20 families seen for risk assessment in two high-risk clinics and found to have germline ATM mutations. Methods: Pedigrees from ATM+ families evaluated at Fox Chase Cancer Center and the University of Chicago are included in this analysis. Cancer type, age at diagnosis, number of genes clinically tested, and ATM mutation were collected. Cancers < 50 yrs are considered early-onset. Results: Among 20 total ATM+ families, 22 GI cancers were reported, with 5 families containing 16/22 (73%) of all GI cancers (see Table). Early-onset GI cancers were common in the 5 families (7/16, 44%), including 2/6 (33%) cases of GC, a 23 yr old man and his 45 yr old father both with GEJxn cancer (2/2, 100%), and 3/6 (50%) cases of CRC all from one large family. Conclusions: Our data lend evidence to support the need for early CRC and GC screening in ATM+ patients. [Table: see text]