Evidence of a preferred molecular pathway in patients with synchronous colorectal cancer

BACKGROUND. A small proportion of patients with colorectal carcinoma (CRC) have synchronous tumors at the time of diagnosis. A subset of sporadic CRCs display microsatellite instability (MSI) that is associated with MLH1 silencing due to promoter methylation. In the current study, the authors investigated the proportion of tumors with MSI in patients with synchronous colorectal carcinoma (SCRC) and the concordance in MSI status among tumors in a given individual. In addition, the authors examined MLH1 and MSH2 expression and MLH1 promoter methylation in SCRCs. METHODS. The current study included 77 patients, with a combined total of 170 invasive SCRCs, who were identified from a database of 2884 patients with CRC. Instability was determined by polymerase chain reaction (PCR) amplification using a set of five markers. Tumors that were unstable at two or more markers were considered unstable (MSI); otherwise, they were considered microsatellite stable (MSS). Expression of MLH1 and MSH2 was determined by immunohistochemistry. Methylation of the MLH1 gene promoter was determined by a methylation-specific PCR assay. Statistical comparisons were made using the chi-square test or the Student t test. RESULTS. Of the 77 patients in the study, 21 (27%) had a family history of hereditary nonpolyposis colon carcinoma-related malignancy, but none fulfilled the Amsterdam II criteria. Fifty-four of 170 tumors (32%) were found to be MSI. Patients with MSI tumors were older and more frequently female. All but 1 MSI tumor lacked expression of MLH1 (n = 44) or MSH2 (n = 8), or both (n = 1). All MLH1-negative tumors, compared with only 3 MLH1-positive tumors, were methylated at the MLH1 promoter. Most patients (n = 67; 87%) had either all MSS tumors (n = 48; 62%) or all MSI tumors (n = 19; 25%); 10 patients (13%) had both MSS and MSI tumors. The observed MSI/MSS distribution was significantly different from the distribution expected based on an assumption of independence (P < 0.0001). CONCLUSIONS. There is a strong concordance in MSI/MSS status among tumors in the same individual. This finding suggests that the tumors in patients with SCRC develop along a preferred molecular pathway.