MSH6 germline mutations are rare in colorectal cancer families

Abstract

Germline mutations in MSH6 can cause HNPCC, which is associated with a tumor phenotype featuring MSI. However, tumors arising in persons with disease-causing mutations of MSH6 may or may not exhibit MSI. We used D-HPLC to screen for germline mutations in the promoter region, the coding region and the 3-UTR of MSH6. Eighty-four families, enrolled on the basis of Amsterdam I and II criteria (HNPCC families) and less stringent criteria (HNPCC-like families), were tested for MMR gene mutations; 27 families had a disease-causing mutation in MLH1 or MSH2, and the remaining 57 families were tested for mutations in MSH6. Two protein-truncating mutations were identified in each of 2 families fulfilling the Amsterdam I criteria, being present in persons affected with early-onset colorectal cancers exhibiting MSI. Immunohistochemical analysis showed that expression of both MSH2 and MSH6 proteins was lost in the cancer cells of the 2 mutation carriers but only MSH6 protein expression was lost in 2 adenomatous polyps. A third possibly disease-causing mutation was found in a person affected with a tumor that did not exhibit MSI. In addition, we found 4 new polymorphisms and determined that neither of the 2 studied by association analysis conferred susceptibility to colorectal or endometrial cancer. HNPCC is an autosomal dominant syndrome characterized by susceptibility to CRC with a mean age at diagnosis of approximately 45 years. 1 In HNPCC patients, the risk of developing cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, renal pelvis and brain is increased. 2,3 Germline mutation in one of the genes of the DNA MMR system is most often responsible for the syndrome. DNA-based genetic testing usually is offered to persons who satisfy certain family history criteria. The Amsterdam I criteria select families that have (i) 3 or more relatives affected with CRC in at least 2 consecutive generations, one person being a first-degree relative of the other 2; (ii) at least one CRC diagnosed before age 50; and (iii) absence of gastrointestinal polyposis. 4 Because these criteria did not include the noncolonic cancers that are associated with MMR gene mutations, the Amsterdam I criteria were modified to include cancers of the endometrium, small bowel and renal pelvis (Amsterdam II). 5 HNPCC is caused primarily by inactivating mutations in one of the genes that constitute the MMR system, most commonly MLH1 or MSH2. 6,7 Mutations in these 2 genes are associated with a tumor phenotype featuring accumulation of mutations at microsatellite repeat sequences, which is referred to as MSI. 8 -10 MSI results from failure of the MMR system to repair deletions or insertions of repeat units of microsatellite loci that spontaneously occur during DNA replication. A tumor is classified as MSI-high when a fraction greater than one-third of the microsatellite loci tested display novel locus-specific fragments; a tumor is classified as non-MSIhigh when a fraction Ͻ0.3 of the microsatellite loci tested exhibit novel fragments...

MSH6 germline mutations in early-onset colorectal cancer patients without family history of the disease

“…On the other hand, the missense mutation p.V878A has previously been reported as a possible diseasecausing mutation by some investigators (Wijnen et al, 1999; ICG-HNPCC database) and as a polymorphism by others (Peterlongo et al, 2003). Our finding of this alteration in the normal population corroborates that of Peterlongo et al (2003) and this change should now be classified as a polymorphism.…”

Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33

“…Preparation of genomic DNA from blood was performed as previously described (29). Genotyping was carried out by using Affymetrix GeneChip Early Access Version 3 (EAv3) Human Mapping Arrays.…”

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

“…The Amsterdam and Revised Bethesda criteria have both been used to assess risk of Lynch syndrome for many years (See Fig. 3) (Gologan and Sepulveda, 2005;Jass, 2007;Peterlongo et al, 2003). More recently, computer based calculators (e.g.…”

“…MMR-pro, PREMM, MMR predict) have become available that attempt to quantify patient risk for the presence of dMMR Green et al, 2009;Kastrinos et al, 2011). Diagnoses of Lynch Syndrome using clinical strategies, such as the Amsterdam criteria, have a lower sensitivity and specificity than those incorporating the use of MSI/MMR testing within the algorithm, such as the Bethesda guidelines (Gologan and Sepulveda, 2005;Jass, 2007;Peterlongo et al, 2003). Universal tumor screening further increases the sensitivity compared to selective testing strategies, with more at risk relatives undergoing genetic evaluation and receiving appropriate cancer surveillance (EGAPP, 2009;Palomaki et al, 2009;Snowsill et al, 2014).…”