Comprehensive characterization of HNPCC-related colorectal cancers reveals striking molecular features in families with no germline mismatch repair gene mutations.

A considerable fraction of families with HNPCC shows no germline mismatch repair (MMR) gene mutations. We previously detected 'hidden' MMR gene defects in 42% of such families, leaving the remaining 58% 'truly' mutation negative. Here, we characterized 50 colorectal carcinomas and five adenomas arising in HNPCC families; 24 truly MMR gene mutation negative and 31 MMR gene mutation positive.

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

Mismatch repair (MMR) deficiency in tumours from patients with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome is mainly caused by mutations in the MLH1, MSH2, and MSH6 genes. A major challenge in the clinical management of patients with suspected HNPCC is the frequent occurrence of missense mutations in MSH6. These can be considered neither deleterious nor clinically innocent a priori.

HNPCC mutation MLH1 P648S makes the functional protein unstable, and homozygosity predisposes to mild neurofibromatosis type 1.

Heterozygous germ-line mutations in DNA mismatch repair (MMR) genes predispose individuals to hereditary nonpolyposis colorectal cancer (HNPCC), whereas with homozygous MMR gene mutations children are diagnosed at an early age with de novo neurofibromatosis type 1 (NF1) and/or hematological malignancies. Here, we describe a mutation, MLH1 P648S, which was found in a typical HNPCC family, with one homozygous child displaying mild features of NF1 and no hematological cancers. To evaluate the pathogenicity of the mutation, we studied both the expression and the function of the mutated protein.

Pathogenicity of the hereditary colorectal cancer mutation hMLH1 del616 linked to shortage of the functional protein.

Background & Aims: Hereditary nonpolyposis colorectal cancer is associated with mismatch repair deficiency. Most predisposing mutations prevent the production of functional mismatch repair protein. Thus, when the wild-type copy is also inactivated, the cell becomes mismatch repair deficient, and this leads to a high degree of microsatellite instability in tumors.

Novel MLH1 and MSH2 germline mutations in the first HNPCC families identified in Slovakia.

Hereditary nonpolyposis colorectal cancer (HNPCC) is a dominantly-inherited cancer predisposition syndrome, in which the susceptibility to cancer of the colon, endometrium and ovary is linked to germline mutations in DNA mismatch repair (MMR) genes. We have recently initiated a cancer prevention program in suspected HNPCC families in the Slovak Republic. The first ten families fulfilling Amsterdam criteria or Bethesda guidelines were screened for germline mutations in MLH1 and MSH2, two MMR genes most frequently mutated in HNPCC families.

Two mismatch repair gene mutations found in a colon cancer patient--which one is pathogenic?

Hereditary nonpolyposis colorectal cancer (HNPCC) is a dominantly inherited cancer syndrome. Germline mutations in five different mismatch repair (MMR) genes, MSH2, MSH6, MLH1, MLH3, and PMS2 are linked to HNPCC. Here, we describe two colon cancer families in which the index patients carry missense mutations in both MSH2 and MSH6.

PTEN mutational spectra, expression levels, and subcellular localization in microsatellite stable and unstable colorectal cancers.

PTEN on 10q23.3 encodes a dual-specificity phosphatase that negatively regulates the phosphoinositol-3-kinase/Akt pathway and mediates cell-cycle arrest and apoptosis. Germline PTEN mutations cause Cowden syndrome and a range of several different hamartoma-tumor syndromes.

Functional analysis of MSH6 mutations linked to kindreds with putative hereditary non-polyposis colorectal cancer syndrome.

To date, five mismatch-repair (MMR) genes, MLH1, MSH2, MSH6, MSH3 and PMS2, are known to be involved in human MMR function. Two of those, MLH1 and MSH2, are further the most common susceptibility genes for hereditary non-polyposis colorectal cancer (HNPCC), while MSH3 and PMS2 are seldom (PMS2) or not at all (MSH3 ) reported to be involved in HNPCC. Despite the increasing number of MSH6 germline mutations, their pathogenicity remains questionable, because the mutations are mainly linked to putative HNPCC families lacking the typical clinical and molecular characteristics of the syndrome, such as early age at onset and high microsatellite instability (MSI).

Distinct PTEN mutational spectra in hereditary non-polyposis colon cancer syndrome-related endometrial carcinomas compared to sporadic microsatellite unstable tumors.

Germline PTEN mutations cause Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR), two hamartoma-tumor syndromes with an increased risk of breast, thyroid and endometrial cancers. Somatic genetic and epigenetic inactivation of PTEN is involved in as high as 93% of sporadic endometrial carcinomas (EC), irrespective of microsatellite status, and can occur in the earliest precancers. EC is the most frequent extra-colonic cancer in patients with hereditary non-polyposis colon cancer syndrome (HNPCC), characterized by germline mutations in the mismatch repair (MMR) genes and by microsatellite instability (MSI) in component tumors.

Functional analysis of MLH1 mutations linked to hereditary nonpolyposis colon cancer.

Hereditary nonpolyposis colon cancer (HNPCC) is associated with malfunction of postreplicative mismatch repair (MMR). While a majority of HNPCC-associated mutations in the MMR genes MLH1, MSH2, or MSH6 genes cause truncations-and thus loss of function--of the respective polypeptides, little is currently known about the biochemical defects associated with nontruncating mutations. We studied the interactions of six MLH1 variants, carrying either missense mutations or in-frame deletions, with normal PMS2 and tested the functionality of these heterodimers of MLH1 and PMS2 (MutL(alpha)) in an in vitro MMR assay.

Tolerance of human MSH2+/- lymphoblastoid cells to the methylating agent temozolomide.

Members of hereditary nonpolyposis colon cancer (HNPCC) families harboring heterozygous germline mutations in the DNA mismatch repair genes hMSH2 or hMLH1 present with tumors generally two to three decades earlier than individuals with nonfamilial sporadic colon cancer. We searched for phenotypic features that might predispose heterozygous cells from HNPCC kindreds to malignant transformation. hMSH2(+/-) lymphoblastoid cell lines were found to be on average about 4-fold more tolerant than wild-type cells to killing by the methylating agent temozolomide, a phenotype that is invariably linked with impairment of the mismatch repair system.

Lack of MSH2 and MSH6 characterizes endometrial but not colon carcinomas in hereditary nonpolyposis colorectal cancer.

Hereditary nonpolyposis colorectal cancer syndrome is associated with an inherited predisposition to primarily colorectal cancer (CRC) and endometrial cancer (EC); however, the biological basis of the organ involvement remains unknown. As an attempt to explore whether the expression levels of MLH1, MSH2, and MSH6 may play a role, we used immunohistochemistry to study 42 ECs and 35 CRCs from patients carrying the same predisposing mutations. Among MSH2 mutation carriers, MLH1 was expressed in both tumor types, whereas MSH2 and, in many cases, also MSH6, were absent.

Mismatch repair defects in cancer.

Post-replicative mismatch repair in humans utilises the hMSH2, hMSH6, hMSH3, hMLH1 and hPMS2 genes and possibly the newly identified hMLH3 gene. Recently, a link has been established between hMSH6 mutations and 'atypical' hereditary non-polyposis colon cancer (HNPCC) with an increased incidence of endometrial cancers. To satisfy the need for a diagnostic test capable of differentiating between pathogenic mutations and polymorphisms, several functional assays that fulfil these criteria have been described.

Predictive genetic testing for hereditary non-polyposis colorectal cancer: uptake and long-term satisfaction.

The aim of this prospective study was to assess the uptake of predictive genetic testing for hereditary non-polyposis colorectal cancer (HNPCC) and its associations with sociodemographic and other factors, and long-term satisfaction with taking the test. The test was offered to all high-risk members (n = 446) of 36 Finnish HNPCC families in which the mutation was known. The procedure comprised an educational counselling session, a period for reflection, and a test disclosure session.

Identification of hMutLbeta, a heterodimer of hMLH1 and hPMS1.

hMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutLalpha. Tumors or cell lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 and hPMS2 genes predispose to hereditary non-polyposis colon cancer. A third MutL homologue, hPMS1, has also been reported to be mutated in one cancer-prone kindred, but the protein encoded by this locus has so far remained without function.

Epigenetic phenotypes distinguish microsatellite-stable and -unstable colorectal cancers.

Aberrant DNA methylation is a common phenomenon in human cancer, but its patterns, causes, and consequences are poorly defined. Promoter methylation of the DNA mismatch repair gene MutL homologue (MLH1) has been implicated in the subset of colorectal cancers that shows microsatellite instability (MSI). The present analysis of four MspI/HpaII sites at the MLH1 promoter region in a series of 89 sporadic colorectal cancers revealed two main methylation patterns that closely correlated with the MSI status of the tumors.

Missense and nonsense mutations in codon 659 of MLH1 cause aberrant splicing of messenger RNA in HNPCC kindreds.

Germline mutations that give rise to premature termination codons in mRNAs have frequently been associated with aberrant processing of the nascent transcripts. This can take the form either of nonsense-mediated mRNA decay or of aberrant splicing of the pre-mRNA. In a family affected by hereditary nonpolyposis colorectal cancer, a two-nucleotide deletion in codon 659, which introduces a frameshift and a new stop codon in exon 17 of the DNA mismatch repair gene MLH1, has been reported to lead to skipping of the exon.

Mutation sharing, predominant involvement of the MLH1 gene and description of four novel mutations in hereditary nonpolyposis colorectal cancer. Mutations in brief no. 144. Online.

Worldwide, the DNA mismatch repair genes MSH2 and MLH1 account for a major share and almost equal proportions of hereditary nonpolyposis colorectal cancer (HNPCC). Furthermore, the predisposing mutation usually varies from kindred to kindred. In this study, we screen 29 verified or putative HNPCC kindreds from Finland for mutations in these two genes and found 8 different mutations, 7 in MLH1 and 1 in MSH2, occurring in 13 families.

MSH2 and MLH1 mutations in sporadic replication error-positive colorectal carcinoma as assessed by two-dimensional DNA electrophoresis.

Replication errors (RER) are frequently seen in both sporadic and hereditary forms of colorectal cancer. In hereditary nonpolyposis colorectal cancer (HNPCC), RER is associated with defects in DNA mismatch repair genes. Two of these genes, MSH2 and MLH1, account for a major share of this cancer syndrome.

DNA mismatch repair gene mutations in 55 kindreds with verified or putative hereditary non-polyposis colorectal cancer.

The DNA mismatch repair genes MSH2 and MLH1 have been shown to account for a major share of hereditary non-polyposis colorectal cancer (HNPCC). We searched for germline mutations in these genes in 35 HNPCC kindreds fulfilling the Amsterdam diagnostic criteria and in a further 20 kindreds with an average of four affected members per family but not meeting the formal criteria. We first screened for truncations by reverse transcriptase (RT)-PCR.

Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome.

Identification of hereditary non-polyposis colorectal cancer (HNPCC) indicates theoretical life-time risks of 50% for the descendants of an affected family member and of 100% for the true gene carriers. However, besides colorectal cancer (CRC), many other cancer types and sites are also involved, which gives reason to evaluate the magnitude of risk for various other cancer types. A detailed pedigree analysis of 40 families with HNPCC identified 414 patients affected with cancer.

Founding mutations and Alu-mediated recombination in hereditary colon cancer.

By screening members of Finnish families displaying hereditary nonpolyposis colorectal cancer (HNPCC) for predisposing germline mutations in MSH2 and MLH1, we show that two mutations in MLH1 together account for 63% (19/30) of kindreds meeting international diagnostic criteria. Mutation 1, originally detected as a 165-base pair deletion in MLH1 cDNA comprising exon 16, was shown to consist of a 3.5-kilobase genomic deletion most likely resulting from Alu-mediated recombination.