Familial endometrial cancer in female carriers of MSH6 germline mutations

Wijnen, Juul T.; Leeuw, W de; Vasen, Hans F. A.; Klift, Heleen van der; Møller, Pål; Stormorken, Astrid; Meijers-Heijboer, Hanne; Lindhout, Dick; Menko, FH; Vossen, Sandra; Möslein, Gabriela; Tops, Carli M.J.; Bröcker‐Vriends, A. H. J. T.; Wu, Ying; Hofstra, Robert; Sijmons, Rolf H.; Cornelisse, Cees J.; Morreau, Hans; Fodde, Riccardo

doi:10.1038/13773

Cited by 364 publications

(288 citation statements)

References 12 publications

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“…On the other hand, the missense mutation p.V878A has previously been reported as a possible diseasecausing mutation by some investigators (Wijnen et al, 1999; ICG-HNPCC database) and as a polymorphism by others (Peterlongo et al, 2003). Our finding of this alteration in the normal population corroborates that of Peterlongo et al (2003) and this change should now be classified as a polymorphism.…”

Section: Discussionsupporting

confidence: 87%

“…The MSH6 mutation p.G1186fsX1190 is in all likelihood disease causing, as it leads to a premature stop codon at position 1190 and the predicted truncated protein looses one of the two MSH2-and the Mg 2 þ -binding domains (Kariola et al, 2002). In addition, the patient's tumour presented MSI-H phenotype only in mononucleotide markers, a feature reported to occur preferentially in tumours associated with MSH6 germline mutations (Verma et al, 1999;Wijnen et al, 1999), and screening for MLH1 and MSH2 mutations was negative. On the other hand, neither the 54-year-old father (Figure 2) nor the 47-year-old healthy blood donor carrying this mutation presented clinical symptoms of CRC (they had never performed colonoscopy screening), suggesting variable penetrance of this mutation.…”

Section: Discussionmentioning

confidence: 99%

“…We analysed the Bethesda marker panel (Boland et al, 1998), which includes two mononucleotide repeats (BAT25 and BAT26) and three dinucleotide repeats (D2S123, D5S346, and D17S250). Another three mononucleotide repeat markers (BAT34C4, BAT-RII, and BAX) were also analysed, as MSI in MSH6 carriers has been mainly observed in this type of markers (Verma et al, 1999;Wijnen et al, 1999). DNA was amplified by PCR using fluorescence-labelled 5 0 primers, as described previously (Oliveira et al, 1998;Zhou et al, 1998;Pyatt et al, 1999;Loukola et al, 2001), and analysed in an ABI PRISM 310 automatic sequencer.…”

Section: Msi Analysismentioning

confidence: 99%

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MSH6 germline mutations in early-onset colorectal cancer patients without family history of the disease

et al. 2006

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Germline MLH1 and MSH2 mutations are scarce in young colorectal cancer patients with negative family history of the disease. To evaluate the contribution of germline MSH6 mutations to early-onset colorectal cancer, we have analysed peripheral blood of 38 patients diagnosed with this disease before 45 years of age and who presented no family history of hereditary nonpolyposis colorectal cancer-related cancers. Blood samples from 108 healthy volunteers were analysed for those genetic alterations suspected to affect the function of MSH6. Of the seven (18.4%) MSH6 alterations found, we have identified three novel germline mutations, one 8 bp deletion leading to a truncated protein and two missense mutations resulting in the substitution of amino acids belonging to different polarity groups. High-frequency microsatellite instability was found in the patient with the MSH6 deletion, but not in the other 27 carcinomas analysed. No MLH1 promoter methylation was detected in tumour tissue. Our findings suggest that germline MSH6 mutations contribute to a subset of early-onset colorectal cancer. Further studies are warranted to understand the genetic and environmental factors responsible for the variable penetration of MSH6 germline mutations, as well as to identify other causes of early-onset colorectal cancer.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Msi Analysismentioning

confidence: 99%

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MSH6 germline mutations in early-onset colorectal cancer patients without family history of the disease

et al. 2006

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“…Considerably less data are available on the mechanisms of inactivation of the wt allele in HNPCC spectrum tumors other than CRC, notably endometrial cancer (EC) that is the most common extracolonic malignancy in HNPCC. In occasional EC tumors studied from HNPCC patients, LOH (for MSH2 and MSH6; Ollikainen et al, 2005) and somatic frameshift mutations (for MSH6; Wijnen et al, 1999) have been implicated. Sporadic EC resembles sporadic CRC, in that MLH1 promoter methylation appears to be the primary mechanism of MSI (Esteller et al, 1998;Simpkins et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach

et al. 2007

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Mutations in the DNA mismatch repair gene MLH1 are a major cause of hereditary nonpolyposis colorectal cancer (HNPCC). No mutant phenotype is observed before the wild-type (wt) allele is somatically inactivated in target tissue. We addressed the mechanisms of MLH1 inactivation in 25 colorectal (CRC) and 32 endometrial cancers (ECs) from MLH1 mutation carriers (Mut1, in-frame genomic deletion; Mut2, out-of-frame splice site mutation; Mut3, missense mutation). By a quantitative method, matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF), utilizing four intragenic single nucleotide polymorphisms and mutations, loss of heterozygosity (LOH) was present in 31/57 (54.4%) of tumors. The wt allele displayed LOH more often than the mutant allele (23/57 vs 8/57, P ¼ 0.006). For Mut1, LOH was more frequent in CRC than EC (10/11 vs 1/13, Po0.0001), whereas Mut2 and Mut3 displayed opposite LOH pattern. Moreover, although wt LOH predominated in CRC irrespective of the predisposing mutation, LOH often affected the mutant allele in EC from Mut2 and Mut3 carriers (6/19, 31.6%). MLH1 promoter methylation, which reflected a more widespread hypermethylation tendency, occurred in 4/55 (7.3%) of tumors and was inversely associated with LOH. In conclusion, the patterns of somatic events (LOH and promoter methylation) differ depending on the tissue and germline mutation, which may in part explain the differential tumor susceptibility of different organs in HNPCC. MALDI-TOF provides a novel approach for the detection and quantification of LOH.

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“…Tumours due to MSH6 mutations may or may not show MSI (Berends et al, 2002). Germline mutations in MMR genes can lead to a variety of clinical presentations, including sporadic early-onset colorectal cancer and familial endometrial cancer (Farrington et al, 1998;Wijnen et al, 1999). Therefore, additional clinical criteria were developed which may indicate an MMR gene defect, in particular the Bethesda and Amsterdam II criteria (Rodriguez-Bigas et al, 1997;Vasen et al, 1999).…”

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confidence: 99%

Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach

et al. 2002

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Hereditary non-polyposis colorectal cancer is an autosomal dominant condition due to germline mutations in DNA-mismatchrepair genes, in particular MLH1, MSH2 and MSH6. Here we describe the application of a novel technique for the detection of genomic deletions in MLH1 and MSH2. This method, called multiplex ligation-dependent probe amplification, is a quantitative multiplex PCR approach to determine the relative copy number of each MLH1 and MSH2 exon. Mutation screening of genes was performed in 126 colorectal cancer families selected on the basis of clinical criteria and in addition, for a subset of families, the presence of microsatellite instability (MSI-high) in tumours. Thirty-eight germline mutations were detected in 37 (29.4%) of these kindreds, 31 of which have a predicted pathogenic effect. Among families with MSI-high tumours 65.7% harboured germline gene defects. Genomic deletions accounted for 54.8% of the pathogenic mutations. A complete deletion of the MLH1 gene was detected in two families. The multiplex ligation-dependent probe amplification approach is a rapid method for the detection of genomic deletions in MLH1 and MSH2. In addition, it reveals alterations that might escape detection using conventional diagnostic techniques. Multiplex ligation-dependent probe amplification might be considered as an early step in the molecular diagnosis of hereditary non-polyposis colorectal cancer.

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Familial endometrial cancer in female carriers of MSH6 germline mutations

Cited by 364 publications

References 12 publications

MSH6 germline mutations in early-onset colorectal cancer patients without family history of the disease

MSH6 germline mutations in early-onset colorectal cancer patients without family history of the disease

Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach

Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach

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