Mean age of tumor onset in hereditary nonpolyposis colorectal cancer (HNPCC) families correlates with the presence of mutations in DNA mismatch repair genes

Pensotti, Valeria; Radice, Paolo; Presciuttini, Silvano; Calistri, Daniele; Gazzoli, Isabella; Perez, Ana Paula Grimalt; Mondini, P; Buonsanti, Giovanni; Sala, P.; Rossetti, Carlo; Ranzani, G N; Bertario, Lucio

doi:10.1002/(sici)1098-2264(199707)19:3<135::aid-gcc1>3.3.co;2-x

Cited by 14 publications

(16 citation statements)

References 19 publications

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“…This finding suggests that they strongly inactivate mismatch repair and, since the corresponding mutations in humans cosegregate with HNPCC (22,32,42,49), that they are important for cancer predisposition. Similar interpretations resulted from a recent study (40) of four homologous human MLH1 missense mutations, M35R (M32R in yeast), G67R (G64R), I68N (I65N), and T117M (T114M).…”

Section: Discussionmentioning

confidence: 97%

Mutator Phenotypes Conferred by MLH1Overexpression and by Heterozygosity for mlh1Mutations

Shcherbakova

Kunkel

1999

Molecular and Cellular Biology

168

176

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Loss of DNA mismatch repair due to mutation or diminished expression of the MLH1 gene is associated with genome instability and cancer. In this study, we used a yeast model system to examine three circumstances relevant to modulation of MLH1 function. First, overexpression of wild-type MLH1 was found to cause a strong elevation of mutation rates at three different loci, similar to the mutator effect of MLH1 gene inactivation. Second, haploid yeast strains with any of six mlh1 missense mutations that mimic germ line mutations found in human cancer patients displayed a strong mutator phenotype consistent with loss of mismatch repair function. Five of these mutations affect amino acids that are homologous to residues suggested by recent crystal structure and biochemical analysis of Escherichia coli MutL to participate in ATP binding and hydrolysis. Finally, using a highly sensitive reporter gene, we detected a mutator phenotype of diploid yeast strains that are heterozygous for mlh1 mutations. Evidence suggesting that this mutator effect results not from reduced mismatch repair in the MLH1/mlh1 cells but rather from loss of the wild-type MLH1 allele in a fraction of cells is presented. Exposure to bleomycin or to UV irradiation strongly enhanced mutagenesis in the heterozygous strain but had little effect on the mutation rate in the wild-type strain. This damage-induced hypermutability may be relevant to cancer in humans with germ line mutations in only one MLH1 allele.The stability of eukaryotic genomes depends heavily on several DNA repair processes, including correction of DNA replication errors by the DNA mismatch repair (MMR) system (reviewed in references 19, 26, and 46). Mutations in genes that inactivate mismatch repair strongly elevate spontaneous mutation rates and predispose humans to cancer. Current evidence suggests that germ line human MSH2 and MLH1 mutations account for a majority of hereditary nonpolyposis colorectal cancer (HNPCC) cases (31). Many of these result in loss of intact protein and are thus predicted to completely inactivate MMR. Others, such as the MLH1 missense mutations found in more than 30 HNPCC families (15,25,31), are often inferred to be pathogenic if they are nonconservative changes in evolutionary conserved amino acids, if they cosegregate with the disease, and/or if they are not observed in the normal population. However, unlike mutations that lead to protein truncation, single amino acid changes may not impair protein function or may only be partially inactivating.To assess the functional consequences of missense mutations in human MLH1, Shimodaira et al. (40) developed an assay in yeast, based on elimination of a dominant mutator phenotype conferred by expression of human MLH1 cDNA. They demonstrated that several human MLH1 missense mutations identified in HNPCC patients impair the function required for this dominant mutator effect. A more direct approach to address the effect of MLH1 missense mutations on MMR efficiency is based on the fact that the amino acid sequences of...

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Section: Discussionmentioning

confidence: 97%

Mutator Phenotypes Conferred by MLH1Overexpression and by Heterozygosity for mlh1Mutations

Shcherbakova

Kunkel

1999

Molecular and Cellular Biology

168

176

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“…Therefore, a young age at CRC diagnosis must alert the physician, mainly in small families or those difficult to characterize, that HNPCC is a possibility. 34 Our results did not show meaningful differences in the age of diagnosis between the group with detected germ-line mutations and that without (45.7 vs. 46.5 years). Fitzgibbons et al 36 found that the mean age of the CRC diagnosis in patients with HNPCC was 45.6 years.…”

Section: Discussioncontrasting

confidence: 76%

Contribuição para o estudo do câncer colorretal com predisposição hereditária no Brasil

Rossi¹

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“…In particular, the mutation c.731G[A was found in three families, all from Bari, the capital of the Apulia region with a total population of 317.000 inhabitants. This mutation was first identified in an Italian patient although no information was provided on his geographical origin [35]. In the 4 years follow-up of our study 625 CRCs were recorded in the area of Bari whereas 35 CRCs occurred among the hMLH1 G731A mutation carriers in the same interval time.…”

Section: Discussionmentioning

confidence: 75%

Identification and surveillance of 19 Lynch syndrome families in southern Italy: report of six novel germline mutations and a common founder mutation

et al. 2011

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Lynch syndrome (LS), or hereditary non-polyposis colorectal cancer (HNPCC), is an autosomal dominant condition responsible for early onset cancer mostly in the colonrectum and endometrium as well as in other organ sites. Lynch syndrome is caused by germline mutations in mismatch repair genes, prevalently in hMSH2, hMLH1, and less frequently in hMSH6 and hPMS2. Twenty-nine non-related index cases with colorectal cancer (CRC) were collected from a region in southeast Italy (Apulia). Among this set of patients, fifteen fulfilled the Amsterdam criteria II. The presence of tumor microsatellite instability (MSI) was assessed in all index cases and 19 (15 AC+/4 AC-) were classified as MSI-H. Mutation analysis performed on all patients, identified 15 pathogenic mutations in hMLH1 and 4 in hMSH2. 4/15 mutations in hMLH1 and 2/4 hMSH2 mutations have not been previously reported. Three previously reported mutations were further investigated for the possibility of a common founder effect. Genetic counseling was offered to all probands and extended to 183 relatives after molecular testing and 85 (46%) mutation carriers were identified. Eighty mutation carriers underwent an accurate clinical and instrumental surveillance protocol. Our results confirm that the identification of LS patients based exclusively on family history may miss patients carrying germline mutations in the MMR genes. Moreover, our results demonstrated that molecular screening and subsequent instrumental surveillance are very effective in identifying CRCs at earlier stages and reducing the number of deaths from secondary cancers in HNPCC patients.

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Mean age of tumor onset in hereditary nonpolyposis colorectal cancer (HNPCC) families correlates with the presence of mutations in DNA mismatch repair genes

Cited by 14 publications

References 19 publications

Mutator Phenotypes Conferred by MLH1Overexpression and by Heterozygosity for mlh1Mutations

Mutator Phenotypes Conferred by MLH1Overexpression and by Heterozygosity for mlh1Mutations

Contribuição para o estudo do câncer colorretal com predisposição hereditária no Brasil

Identification and surveillance of 19 Lynch syndrome families in southern Italy: report of six novel germline mutations and a common founder mutation

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