Screening for mismatch repair deficiency in colorectal cancer: data from three academic medical centers.

Grainne M O’kane ,Kieran Sheahan,Conor Shields,Desmond C Winter,Robert Geraghty,Cian Muldoon,Niall Mulligan,Paul Mccormick,Andrew J Green,David J Gallagher,Ben Creavin,Michael Farrell,Delia Flannery,Denise Keegan,Carmel Nolan,Emily K Donovan ,Terri P Mcveigh ,John Hyland ,Brian Mehigan ,Michael J Kennedy ,Padraic Macmathúna ,Diarmuid O’donoghue ,Éanna J Ryan

doi:10.1002/cam4.1025

Abstract

Reflex immunohistochemistry (rIHC) for mismatch repair (MMR) protein expression can be used as a screening tool to detect Lynch Syndrome (LS). Increasingly the mismatch repair‐deficient (dMMR) phenotype has therapeutic implications. We investigated the pattern and consequence of testing for dMMR in three Irish Cancer Centres (CCs). CRC databases were analyzed from January 2005–December 2013. CC1 performs IHC upon physician request, CC2 implemented rIHC in November 2008, and CC3 has been performing rIHC since 2004. The number of eligible patients referred to clinical genetic services (CGS), and the number of LS patients per center was determined. 3906 patients were included over a 9‐year period. dMMR CRCs were found in 32/153 (21%) of patients at CC1 and 55/536 (10%) at CC2, accounting for 3% and 5% of the CRC population, respectively. At CC3, 182/1737 patients (10%) had dMMR CRCs (P < 0.001). Additional testing for the BRAF V600E mutation, was performed in 49 patients at CC3 prior to CGS referral, of which 29 were positive and considered sporadic CRC. Referrals to CGS were made in 66%, 33%, and 30% of eligible patients at CC1, CC2, and CC3, respectively. LS accounted for CRC in eight patients (0.8%) at CC1, eight patients (0.7%) at CC2, and 20 patients (1.2%) at CC3. Cascade testing of patients with dMMR CRC was not completed in 56%. Universal screening increases the detection of dMMR tumors and LS kindreds. Successful implementation of this approach requires adequate resources for appropriate downstream management of these patients.

Highlights

Lynch Syndrome (LS) is a common cancer predisposition syndrome caused by germ-line mutations in genes involved in the mismatch repair (MMR) pathway (MLH1, MSH2, MSH6, PMS2, and EPCAM)
At CC1 (IHC performed at physician request) 153/949 (16%) patients had tumor MMR testing of which 32 (21%) were dMMR accounting for 3% of the Colorectal cancer (CRC) population included
CC2 performed testing on 536/1220 (44%) patients of which 55(10%) had dMMR tumors resulting in a detection rate of 5% (P = 0.22)

Summary

Introduction

Lynch Syndrome (LS) is a common cancer predisposition syndrome caused by germ-line mutations in genes involved in the mismatch repair (MMR) pathway (MLH1, MSH2, MSH6, PMS2, and EPCAM). Colorectal cancer (CRC) is the most prevalent LS associated malignancy accounting for the highest mortality rates in this population [2]. Surveillance colonoscopy [2, 7], prophylactic gynecologic surgery [8], and total colectomy at CRC diagnosis [9,10,11,12] have the potential to reduce mortality and morbidity in this population. Medical prevention with aspirin has been shown to reduce the incidence of CRC in LS carriers [13], and may be offered to patients as a chemopreventative agent [14]

Methods

Results

Conclusion