Atypical HNPCC owing to MSH6 germline mutations: analysis of a large Dutch pedigree

Abstract

Hereditary non-polyposis colorectal cancer (HNPCC) is the most common genetic susceptibility syndrome for colorectal cancer. HNPCC is most frequently caused by germline mutations in the DNA mismatch repair (MMR) genes MSH2 and MLH1. Recently, mutations in another MMR gene, MSH6 (also known as GTBP), have also been shown to result in HNPCC. Preliminary data indicate that the phenotype related to MSH6 mutations may diVer from the classical HNPCC caused by defects in MSH2 and MLH1.Here, we describe an extended Dutch HNPCC family not fulfilling the Amsterdam criteria II and resulting from a MSH6 mutation. Overall, the penetrance of colorectal cancer appears to be significantly decreased (p<0.001) among the MSH6 mutation carriers in this family when compared with MSH2 and MLH1 carriers (32% by the age of 80 v >80%).Endometrial cancer is a frequent manifestation among female carriers (six out of 13 malignant tumours). Transitional cell carcinoma of the urinary tract is also relatively common in both male and female carriers (10% of the carriers).Moreover, the mean age of onset of both colorectal cancer (MSH6 v MSH2/MLH1 = 55 years v 44/41 years) and endometrial carcinomas (MSH6 v MSH2/MLH1 = 55 years v 49/48 years) is delayed. As previously reported, we confirm that the pattern of microsatellite instability, in combination with immunohistochemical analysis, can predict the presence of a MSH6 germline defect.The detailed characterisation of the clinical phenotype of this kindred contributes to the establishment of genotypephenotype correlations in HNPCC owing to mutations in specific mismatch repair genes. (J Med Genet 2001;38:318-322)

MutSβ exceeds MutSα in dinucleotide loop repair

“…MLH1-and MSH2-deficient tumours are characterised by both mono-and dinucleotide repeat instability, whereas the level of MSI is lower in MSH6-deficient tumours (Bhattacharyya et al, 1995;Papadopoulos et al, 1995). MSH6-deficient cells are unable to repair single base mismatches, whereas they retain proficiency to repair two, three and four base loops (Drummond et al, 1995;Risinger et al, 1996;Umar et al, 1997), thus, causing only mononucleotide repeat instability in tumours (Wagner et al, 2001;Plaschke et al, 2004). Recently, EMAST and also low dinucleotide repeat instability have been associated with MSH3 deficiency both in tumour cell lines and in sporadic colorectal tumours (Haugen et al, 2008).…”

Phenotypic Heterogeneity by Germline Mismatch Repair Gene Defect in Lynch Syndrome Patients

“…It is intriguing that the only gene showing no mutation in this cases was MSH6, a gene usually described as associated with LS with EC phenotype. 41,44 It is also of notice that four female patients with CRC underwent prophylactic hysterectomy and adnexectomy, a valid option for LS female patients in menopause or perimenopausal, after informed consent.…”

“…41,44 That is considered to be the principal clinical manifestation for female patients with this mutation. 42,44 They are usually diagnosed in patients over 50 years of age 41,44 and it was observed that at the age of 70, 71% of female patients with this mutation will have EC. 44 Along with MSH2, MSH6 mutation is more related to EC than mutations in MLH1 or PMS2.…”

“…38,39 On the other hand, germline mutations in MSH6 and PMS2 lead to an atypical phenotype. 40,41 Those are patients expected to have less risk of developing CRC and older age of onset. 40,42 Considering particularly MSH6 patients, the penetrance of their mutation is thought to be lower 12 and also they do not show an ubiquitous MSI profile.…”

MSH6 missense mutations are often associated with no or low cancer susceptibility

“…Contrary to most mutations affecting the MLH1 and MSH2 genes, a significant proportion of MSH6 mutations occur in HNPCC families with less typical clinical features. Carriers of MSH6 mutations often display late age at onset, carcinomas of the endometrium, and low or no microsatellite instability (MSI) in tumours (Miyaki et al, 1997;Kolodner et al, 1999;Wijnen et al, 1999;Wu et al, 1999;Parc et al, 2000;Wagner et al, 2001;Berends et al, 2002;Peterlongo et al, 2003;Cederquist et al, 2004). Moreover, one-third of MSH6 mutations are nontruncating, and so do not necessarily destroy the encoded protein.…”