Incidence of germline hMLH1 and hMSH2 mutations (HNPCC patients) among newly diagnosed colorectal cancers in a Slovenian population

Ravnik‐Glavač, Metka

doi:10.1136/jmg.37.7.533

Cited by 33 publications

(12 citation statements)

References 37 publications

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“…LS causes 2.3% of all CRC in Iceland which is similar to the prevalence in two CRC population-based studies from Finland19 and the US6 but it is higher than LS prevalence in Southern Europe20212223. The distribution of mutations among the MMR genes in Iceland is unique.…”

Section: Discussionsupporting

confidence: 61%

Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2

et al. 2017

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Lynch syndrome, caused by germline mutations in the mismatch repair genes, is associated with increased cancer risk. Here using a large whole-genome sequencing data bank, cancer registry and colorectal tumour bank we determine the prevalence of Lynch syndrome, associated cancer risks and pathogenicity of several variants in the Icelandic population. We use colorectal cancer samples from 1,182 patients diagnosed between 2000–2009. One-hundred and thirty-two (11.2%) tumours are mismatch repair deficient per immunohistochemistry. Twenty-one (1.8%) have Lynch syndrome while 106 (9.0%) have somatic hypermethylation or mutations in the mismatch repair genes. The population prevalence of Lynch syndrome is 0.442%. We discover a translocation disrupting MLH1 and three mutations in MSH6 and PMS2 that increase endometrial, colorectal, brain and ovarian cancer risk. We find thirteen mismatch repair variants of uncertain significance that are not associated with cancer risk. We find that founder mutations in MSH6 and PMS2 prevail in Iceland unlike most other populations.

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Section: Discussionsupporting

confidence: 61%

Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2

et al. 2017

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“…PMRP detected 7 patients with a germline MMR defect. The detection rate of MMR germline mutation carriers did not differ at all from that in our previous study, in which only point mutations in MLH1 and MSH2 were searched for [28]. This was a surprising finding, because in the present study, we significantly extended the analysis and more sensitive methods were used.…”

Section: Discussionmentioning

confidence: 57%

Screening for germline mutations of MLH1, MSH2, MSH6 and PMS2 genes in Slovenian colorectal cancer patients: implications for a population specific detection strategy of Lynch syndrome

et al. 2009

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Microsatellite instability (MSI) is present in more than 90% of colorectal cancers of patients with Lynch syndrome, and is therefore a feasible marker for the disease. Mutations in MLH1, MSH2, MSH6 and PMS2, which are one of the main causes of deficient mismatch repair and subsequent MSI, have been linked to the disease. In order to establish the role of each of the 4 genes in Slovenian Lynch syndrome patients, we performed MSI analysis on 593 unselected CRC patients and subsequently searched for the presence of point mutations, larger genomic rearrangements and MLH1 promoter hypermethylation in patients with MSI-high tumours. We detected 43 (7.3%) patients with MSI-H tumours, of which 7 patients (1.3%) harboured germline defects: 2 in MLH1, 4 in MSH2, 1 in PMS2 and none in MSH6. Twenty-nine germline sequence variations of unknown significance and 17 deleterious somatic mutations were found. MLH1 promoter methylation was detected in 56% of patients without detected germline defects and in 1 (14%) suspected Lynch syndrome. Due to the minor role of germline MSH6 mutations, we adapted the Lynch syndrome detection strategy for the Slovenian population of CRC patients, whereby germline alterations should be first sought in MLH1 and MSH2 followed by a search for larger genomic rearrangements in these two genes. When no germline mutations are found tumors should be further tested for the presence of germline defects in PMS2 and MSH6. The choice about which gene should be tested first can be guided more accurately by the immunohistochemical analysis. Our study demonstrates that the incidence of MMR mutations in a population should be known prior to the application of one of several suggested strategies for detection of Lynch syndrome.

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“…Using this strategy, Salovaara et al 11 examined 535 colorectal cancers and found that 12 percent showed MSI and 3.4 percent had germline mutations of hMSH2 or hMLH1. Ravnik-Glavac et al 25 reported that 9.7 percent showed MSI and 1.4 percent had germline mutations of hMSH2 or hMLH1 among 300 colorectal cancers in Slovenia. In the current study, we used the same molecular genetic approach with an initial MSI screening followed by a mutational analysis for the identification of a subset of HNPCC, which do not have familial histories of colorectal or HNPCC-related tumors (endometrial, small-bowel, ureter, and renal pelvis cancers).…”

Section: Discussionmentioning

confidence: 98%

Microsatellite Instability and Mutations in DNA Mismatch Repair Genes in Sporadic Colorectal Cancers

Jeong¹,

Shin²,

Shin³

et al. 2003

Diseases of the Colon &Amp; Rectum

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Incidence of germline hMLH1 and hMSH2 mutations (HNPCC patients) among newly diagnosed colorectal cancers in a Slovenian population

Cited by 33 publications

References 37 publications

Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2

Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2

Screening for germline mutations of MLH1, MSH2, MSH6 and PMS2 genes in Slovenian colorectal cancer patients: implications for a population specific detection strategy of Lynch syndrome

Microsatellite Instability and Mutations in DNA Mismatch Repair Genes in Sporadic Colorectal Cancers

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