Clinical actionability of germline testing in patients with limited colorectal polyps.

Abstract

e13027 Background: As classic adenoma-carcinoma sequence is the main process underlying most colorectal cancer (CRC), early detection and removal of colorectal adenomas is crucial in preventing CRC. Although adenomatous polyps are usually sporadic, several inherited CRC syndromes such as Familial adenomatous polyposis, MUTYH-associated polyposis and Lynch syndrome can present initially with colon polyps. The identification of germline defects in patients with colon polyps is thus critical for proper cancer risk counseling and CRC prevention. Current guidelines recommend germline testing for patients with more than 20 polyps or those with more than 10 polyps and a family history of CRC. However, the diagnostic yield of germline testing on otherwise healthy individuals with 10 or fewer colon polyps has not been well studied. Here, we performed a pilot study to evaluate the clinical actionability of germline genetic testing on these patients. Methods: A total of 13 cancer-free adults, who presented with colon polyps (n < 10) and who otherwise were not selected based on age of onset or family history underwent germline Exome Sequencing. Variants in 13 well-established CRC risk genes ( APC, CHEK2, MYH, MLH1, MSH2, MSH6, PMS2, NTHL1, BMPR1A, SMAD4, PTEN, STK11, TP53) were evaluated for pathogenicity. Results: A total of 13 patients (12 male, 1 female) were evaluated. The median age of presentation was 69 (range 49 to 88). The median number of adenomatous colon polyps was 1 (range 1 to 8). Two (15.4%, 95% CI = 1.9 - 45.4, Binomial Exact) patients had at least one disruptive mutation in the examined genes. One of these patients had a truncating mutation in APC (p.Arg216*) and presented with two tubulovillous adenomas at age 49. The second patient had 8 adenomas in distal colon and rectum at age 64, and harbored a known pathogenic mutation in MSH6(p.Arg1035*). Conclusions: This pilot study provides evidence that a relatively high percentage of patients presenting with a few colon polyps may have inherited defects in highly actionable genes. If validated in larger cohorts with appropriate population controls, these findings may influence the clinical care of such patients and their families and suggest germline molecular testing in those patients.