High frequency of Lynch-like syndrome in early-onset non-familial colorectal cancer

ANTELO M.; MILITO, D.; SHIA J, ; ROCA, E.; BARUGEL, M; CUATRECASAS, M.; ARNOLD, M.; MOREIRA, L.; LEOZ, M.; CARBALLAL S; CASTELLS, A.; BOLAND, R.; GOEL, A.; BALAGUER, F.

Anaheim

Congreso; 17th. Annual Meeting of the Collaborative Group of the Americas on Inherited Colorectal Cancer; 2013

Collaborative Group of the Americas on Inherited Colorectal Cancer

Background: Early-onset non-polyposis colorectal cancer (CRC) (<50 years-old) with no family history of any neoplasm constitutes an increasingly common clinical challenge. Lynch syndrome and biallelic mutations in the MUTYH gene are associated with early-onset CRC; however, the frequency of mutations in these genes remains unknown in the early-onset non-familial cases. Besides, mismatch repair deficient cases (MMRd) with no constitutive mutation in the  MMR genes can be as frequent as 70%; these cases have been recently termed ?Lynch-like syndrome? and decisions about their management are complicated because of uncomfirmed suspicions of hereditary cancer. The aim of this study was to identify prediction variables of MMRd and to define the prevalence of Lynch, Lynch-like syndrome, and biallelic MUTYH mutations among early-onset non-familial CRCs. Methods: we retrospectively recruited 102 CRC patients <50 year-old attended in an Argentine Public Hospital. All patients lacked family history of CRC or any other Lynch syndrome associated neoplasia in first and second-degree relatives. Patients with >15 polyps and/or inflammatory bowel disease were excluded. The median follow up was 56 months. Tumor MMR protein expression, microsatellite instability (MSI) status, prevalent germline MUTYH mutations (with sequencing of all exons in heterozygous cases), somatic BRAF V600E mutation, and somatic MLH1 methylation levels were evaluated. In patients with MMRd tumors, germline analysis of the suspected mutated gene was performed by direct sequencing and large rearrangement analyses. We then designed a multivariate prediction model of MMRd. Results: Twenty-one (20.6%) tumors were classified as MMRd (MSI and/or loss of protein expression by IHC). Among these, only one tumor displayed somatic BRAF mutation and MLH1 hypermethylation. Therefore, 20/21 of the MMRd tumors were putative Lynch syndrome cases. Sixteen out of 20 MMRd cases were genetically tested. Three pathogenic mutations (MSH2: p.Gly614X; MLH1: c.1852delAAG; PMS2: large deletion) and one benign change were identified, with a mutation detection rate of 18.75% (3/16). In the multivariate model, three MMRd predictor variables were identified: CRC <31years old, tumor proximal to the splenic flexure, and MSI-suggestive pathology, with a sensitivity and negative predictive value of 100%. We only detected two p.G393D heterozygous MUTYH patients. The prevalence of Lynch and Lynch-like syndrome in this early-onset non-familial CRC cohort was 2.94% (3/102) and 12.7% (13/102), respectively. Conclusions: in young patients with apparently sporadic CRC, MMRd accounts for up to 20% of the cases. CRC before age 31, with proximal location and MSI-suggestive pathology are strong predictors of MMRd. Detection rate of germline mutations in these MMRd cases can be as low as 19%. Theses results emphasize the need to further investigate the underlying cause of Lynch-like syndrome cases to ascertain the risk of cancer and adequate surveillance strategies for these patients and their relatives.