Background: Tumour mismatch repair (MMR) deficiency, determined by immunohistochemical (IHC) loss of MMR protein expression, is used diagnostically to identify individuals with Lynch syndrome. A high proportion of colorectal cancers (CRCs) and endometrial cancers (ECs) that demonstrate tumor MMR-deficiency are categorised as having “Lynch-like syndrome” due to the absence of tumor MLH1 methylation or germline MMR gene mutations after standard screening approaches. The aim of this study was to investigate somatic causes of tumor MMR-deficiency in patients with Lynch-like syndrome.

Methods: Population-based participants with incident MMR-deficient colorectal (n=193; ACCFR and MCCS) or endometrial cancer (n=197; ANECS and MCCS) were categorised as either Lynch syndrome, MLH1 methylated or Lynch-like after screening for germline MMR gene mutations and for tumor MLH1 gene promoter hypermethylation. Lynch-like tumors were tested for somatic MMR gene mutations (point mutations and loss of heterozygosity) using AmpliSeq-Ion Proton custom capture sequencing and for MSH2 or MSH6 gene promoter methylation. Overall survival for molecularly defined subgroups of Lynch-like CRCs were compared to Lynch syndrome related CRCs using cox regression models to estimate hazard ratios (HR) and 95% confidence intervals adjusting for age at CRC diagnosis, sex, AJCC stage and grade.

Results: Lynch-like tumors comprised 32% (63/193) and 23% (45/197) of the MMR-deficient CRCs and ECs, respectively compared with 27% and 15% for Lynch syndrome and 41% and 62% for MLH1 methylated CRCs and ECs, respectively. Two somatic mutations were identified in the MMR gene indicated by the pattern of MMR IHC loss of expression were identified in 36.7% (18/49) and 47.8% (11/23) of the Lynch-like CRCs and ECs tested. The proportion of tumors with double somatic alterations was highest for both CRC and EC tumors showing MSH2-deficiency (40% and 64.3%). The mean age at diagnosis for the Lynch-like CRCs with double somatic mutations was 49.7 ± 15.8years which was not significantly different from the Lynch syndrome CRCs (n=52; 45.4 ± 11.3years; p=0.2) but was significantly different compared with the MLH1 methylated CRCs (n=83; 70 ± 8.9years; p=0.0001). The adjusted HR for double somatic Lynch-like CRCs was 2.58 (95% CI, 0.77-8.67) compared with Lynch syndrome CRCs (p=0.1). No evidence of tumor MSH2 or MSH6 gene promoter methylation was identified in either MSH2-deficient or MSH6-deficient Lynch-like CRCs or ECs tested (n=34 and n=12, respectively).

Conclusions: Double somatic mutations in the MMR genes represent a significant proportion of the unexplained Lynch-like MMR-deficient subtype for both population-based CRC and EC. Triaging strategies used to identify Lynch syndrome for both CRC and EC should include tumor testing for somatic mutations in the MMR genes.

Note: This abstract was not presented at the meeting.

Citation Format: Daniel D. Buchanan, Mark Clendenning, Harindra Jayasekara, Jihoon E. Joo, Ee M. Wong, Melissa C. Southey, Rhiannon J. Walters, Bernard J. Pope, Aung K. Win, John L. Hopper, Mark A. Jenkins, Roger L. Milne, Graham G. Giles, Dallas R. English, Finlay A. Macrae, Amanda B. Spurdle, Ingrid M. Winship, Christophe Rosty. Double somatic mutations as a cause of tumor mismatch repair-deficiency in population-based colorectal and endometrial cancer with Lynch-like syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4266. doi:10.1158/1538-7445.AM2017-4266