title: The importance of functional testing in the genetic assessment of Muir-Torre syndrome, a clinical subphenotype of HNPCC.
abstract: A majority of families with hereditary nonpolyposis colorectal cancer (HNPCC) are attributable to germline mutations in three DNA mismatch repair (MMR) genes, MLH1, MSH2 and MSH6. However, the clinical phenotype appears to reflect a complex interplay between the predisposing mutation and putative constitutional and somatic modifiers. Certain MMR gene mutations predispose to combined occurrence of cutaneous sebaceous gland neoplasms and visceral malignancies, which is known as Muir-Torre syndrome (MTS) and regarded as a phenotypic variant of HNPCC. The sebaceous tumors associated with MTS appear in many patients before visceral malignancies providing important predictability of HNPCC-related integral cancers in mutation carriers. Since most sebaceous skin tumors are, however, sporadic, the contribution of non-truncating mutations found in skin cancer patients is difficult to interpret and genetic assessment of MTS requires a functional test. Here, we studied the repair efficiency of the two MSH2 missense mutations, L187P and C697F, found in HNPCC families including a few mutation carriers with sebaceous skin tumors. Both mutations were completely deficient in an MMR assay, which together with tumor findings suggested their predisposing role in both internal and skin malignancies in the families.
authors.affiliation: Department of Biological and Environmental Sciences, Genetics, University of Helsinki, Helsinki, Finland.
authors.forename: Saara
authors.initials: S
authors.lastname: Ollila
authors.forename: Roslyn
authors.initials: R
authors.lastname: Fitzpatrick
authors.forename: Laura
authors.initials: L
authors.lastname: Sarantaus
authors.forename: Reetta
authors.initials: R
authors.lastname: Kariola
authors.forename: Ingrid
authors.initials: I
authors.lastname: Ambus
authors.forename: Lea
authors.initials: L
authors.lastname: Velsher
authors.forename: Eugene
authors.initials: E
authors.lastname: Hsieh
authors.forename: Mette Klarskov
authors.initials: MK
authors.lastname: Andersen
authors.forename: Tiina E
authors.initials: TE
authors.lastname: Raevaara
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Gerdes
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mangold
authors.forename: Päivi
authors.initials: P
authors.lastname: Peltomäki
authors.forename: Henry T
authors.initials: HT
authors.lastname: Lynch
authors.forename: Minna
authors.initials: M
authors.lastname: Nyström
mesh_terms: D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004260:DNA Repair; D020022:Genetic Predisposition to Disease; D006801:Humans; D051718:MutS Homolog 2 Protein / Q000235:genetics* / Q000502:physiology; D020125:Mutation, Missense; D010641:Phenotype; D013577:Syndrome
chemical_list: C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein