Abstract 07: Challenges of applying tumor genome analysis to the germline: Examples from GI oncology
Authors: Amico Andrea , Nielsen Sarah , Geynisman Daniel , Rambo Brittany , Carey George Ben , Gulden Cassandra , Fackenthal Jim , Olopade Olufunmilayo , Catenacci Daniel 
Published: May 2015

Abstract
Purpose: To describe the spectrum of potential and confirmed germline genomic events identified incidentally during routine medium throughput somatic tumor DNA sequencing, and to provide a framework for pre- and post-test consent and counseling for these patients and families.
Patients and Methods: Targeted next generation sequencing was used to evaluate for possible actionable genomic events in tumor tissue obtained from consecutive new patients seen at the University of Chicago Gastrointestinal Medical Oncology clinic between 9/2012 and 9/2013. Patients had a diagnosis of either metastatic gastroesophageal, hepatobiliary or colorectal cancer. A panel consisting of medical oncologists, an oncology fellow, cancer geneticists and genetic counselors reviewed the results of each case (N=112). Patients were grouped based on their post-test probability of possessing a potentially inherited mutation in a cancer susceptibility gene. The patients within the high-risk group included those with a somatic mutation in one or more of the genes within accepted panels that test for inherited cancer syndromes. Patient age and family history were also taken into account. The high-risk patients were then contacted and formally evaluated and counseled by our cancer risk specialists. When possible and indicated, germline genetic testing was obtained.
Results: One hundred and twelve cases were analyzed. Of these, 23 cases (21%) were identified to have somatic, and potentially germline, mutations in BRCA1, BRCA2, PTEN, CDH1, STK11 or MLH1/MSH6 via routine NGS of tumor samples. Seven patients ultimately underwent germline testing of which three (43%) had confirmed germline mutations - interestingly, all were BRCA2. Most identified cases would not meet current criteria to refer for genetic counseling. Variants of unknown significance in germline BRCA2 posed a challenge with respect to counseling and recommendations. There was one positive control patient with a known clinical diagnosis of Gorlin syndrome, in whom routine NGS of his gastric tumor sample identified a PTCH1 gene mutation (previously unknown).
Conclusions: Next generation sequencing technology offers much promise, as we enter the age of individualized medicine, but also poses many challenges for both germline and somatic DNA testing. We identified, incidentally, several cases (∼20%) with a potentially inherited cancer susceptibility gene via routine somatic tumor DNA sequencing. Of patients available and willing to undergo further testing, several (43%, 3/7) of these cases were confirmed germline events. Many of these patients would not have been referred for counseling without the somatic sequencing information. This report raises awareness of the challenges facing NGS tumor analyses, and provides a framework for pre- and post-test consent and counseling of patients undergoing routine tumor sequencing.
Citation Format: Andrea Amico, Sarah Nielsen, Daniel Geynisman, Brittany Rambo, George Ben Carey, Cassandra Gulden, Jim Fackenthal, Olufunmilayo Olopade, Daniel Catenacci. Challenges of applying tumor genome analysis to the germline: Examples from GI oncology. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 07. doi:10.1158/1538-7445.CANSUSC14-07