Gastroenterology Department, Institut de Malalties Digestives i Metaboliques, Hospital Clinic, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), IDIBAPS.
Clin Cancer Res. 2010 Oct 5.
Early-onset colorectal cancer (CRC) is suggestive for a hereditary predisposition. Lynch syndrome is the most frequent CRC hereditary cause. The MUTYH gene has also been related to inherited CRC. A systematic characterization of these two diseases has not been reported previously in this population.
We studied a retrospectively collected series of 140 non-polyposis CRC patients diagnosed <50 years. Demographic, clinical and familial features were obtained. Mismatch repair (MMR) deficiency was determined by means of microsatellite instability (MSI) analysis and immunostaining for MLH1/MSH2/MSH6/PMS2. Germline MMR mutations were evaluated in all MMR deficient cases. Tumor samples with loss of MLH1 or MSH2 protein expression were analyzed for somatic methylation. Germline MUTYH mutations were evaluated in all cases. BRAF V600E and KRAS somatic mutational status was also determined.
Fifteen tumors (11.4%) were MSI and 20 (14.3%) showed loss of protein expression (7 for MLH1/PMS2, 2 for isolated MLH1, 3 for MSH2/MSH6, 7 for isolated MSH6, and 1 for MSH6/PMS2). We identified 11 (7.8%) germline MMR mutations, 4 in MLH1, 1 in MSH2 and 6 in MSH6. Methylation analysis revealed one case with somatic MLH1 methylation. Biallelic MUTYH mutations were detected in 4 (2.8%) cases. KRAS and BRAF V600E mutations were present in 39 (27.9%) and 5 (3.6%) of cases, respectively.
Loss of MSH6 expression is the predominant cause of MMR deficiency in early-onset CRC. Our findings prompt the inclusion of MSH6 and MUTYH screening as part of the genetic counseling of these patients and their relatives.
PMID: 20924129 [PubMed - as supplied by publisher] Source: National Library of Medicine.
