COLORECTAL CANCER AND MICROSATELLITE INSTABILITY: DIFFERENT FEATURES AND MOLECULAR BASIS ACCORDING TO THE AGE OF ONSET

ABSTRACT Introduction Most colorectal cancers (CRC) with microsatellite instability (MSI) are associated with hereditary CRC syndromes, such as Lynch syndrome (5% of all CRC), an hereditary form of CRC caused by germline mutations in DNA Mismatch repair genes. However, there is a great percentage of sporadic CRC with MSI (10%) secondary to other genetic disorders such as MLH1 promoter hypermethylation and BRAF oncogene mutation. The aim of our study was to identify the percentage of MSI CRC according to different ages of onset, and their possible differential molecular, clinicopathological and familial features. Methods From January 2002 to December 2008, 88 patients were diagnosed of CRC at an age younger than 46 years old. We select as well other 96 patients diagnosed consecutively of CRC at an age greater or equal to 70 in the same period of time. Patients diagnosed of Familial Adenomatous Polyposis were excluded of the study. We analyzed the MSI status in all patients. We carried out in all patients with MSI Mismatch repair genes mutations analysis (MLH1, MSH2, MSH6, PMS2). In those patients who unexpressed Mlh1 protein in immunohistochemistry, we analyzed MLH1 promoter hypermethylation and BRAF mutation. We compared both MSI groups of age according to their clinicopathological and familiar features, and also compared which molecular alterations were more frequent in each one. Results Thirteen of the 88 early-onset CRC showed MSI (14.7%). Four of them had MLH1 mutations (30.7%), four cases showed MSH2 mutations (30.7%), and one a MSH6 mutation (7%). We did not identify any mutation in the other two cases. Only in one of these last cases an MLH1 promoter hypermethylation was detected. Nine of the ninety-six CRC patients with advanced age had MSI (9.3%). Only one of them showed MLH1 gene mutation (11.1%), while four showed BRAF mutation (44.4%), and other four MLH1 promoter hypermethylation (44.4%). Comparing both groups of age-onset, we found some differential features: 77% of early-onset CRC were male, compared with 11% of elderly patients CRC (p=0.008). Seventy-seven percent of early-onset CRC met Amsterdam type II criteria, while 67% of CRC in elderly patients were sporadic (p=0.001). Other differences that did not reach statistical signification were: more frequent location at the right colon in elderly group; and a higher frequency of mucinous and “signet ring” cells tumours in the early-onset group. Conclusion The great majority of our patients had microsatellite stability. The MSI percentages were similar for both groups, being higher the patients diagnosed with Lynch syndrome in the early-onset group. Most patients with MSI CCR in the elderly had molecular alterations different from those found in young people, such as BRAF mutation and MLH1 promoter hypermethylation (sporadic cases). All of this gives as consequence differential features, a circumstance which would influence in screening, treatment and long-term follow up. This work was funded by the Spanish Fondo de Investigaciones Sanitarias (grant number FIS-PI10/0683).