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Hereditary nonpolyposis colorectal cancer and related conditions
Author(s) -
LucciCordisco Emanuela,
Zito Ilaria,
Gensini Francesca,
Genuardi Maurizio
Publication year - 2003
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.20475
Subject(s) - pms2 , msh2 , msh6 , mlh1 , lynch syndrome , dna mismatch repair , microsatellite instability , genetics , cancer research , biology , neurofibromatosis , colorectal cancer , mutation , cancer , medicine , allele , gene , microsatellite
Hereditary nonpolyposis colorectal cancer (HNPCC) is a cancer‐predisposing condition caused by inactivating mutations in at least four genes ( MSH2 , MLH1 , MSH6 , and PMS2 ) belonging to the mismatch repair system. At present, availability of the microsatellite instability (MSI) test allows screening of a relevant fraction of patients with a constellation of features suggestive of HNPCC. By analogy with several other genetic disorders, it is clearly emerging that the term HNPCC encompasses a wide spectrum of different clinical presentations, including Muir‐Torre syndrome, Turcot syndrome, and the neurofibromatosis‐hematological malignancy association. Notwithstanding the remarkable genetic and allelic heterogeneity, a few consistent phenotype‐genotype associations can be recognized. Mutations in the MSH2 gene entail higher risks of developing cancer, including extraintestinal ones, than MLH1 alterations. MSH2 also accounts for most cases of Muir‐Torre syndrome, which is characterized by the presence of sebaceous skin tumors. The few known PMS2 mutations show a striking association with the presence of gliomas, which are the hallmark of the Turcot variant of HNPCC. Homozygotes for mismatch repair gene mutations present with stigmata of neurofibromatosis 1 and usually die in childhood due to a variety of leukemias and lymphomas. While such correlations are being defined, the underlying reasons have only partially been elucidated, and may include heterogeneous gene functions and properties; types of mutation, some of which may exert dominant negative effects; and genetic and environmental modifiers. © 2003 Wiley‐Liss, Inc.