Germline MSH2 and MLH1 mutational spectrum in HNPCC families from Poland and the Baltic States

Kurzawski, Grzegorz; Suchy, Joanna; Kładny, Józef; Safranow, Krzysztof; Jakubowska, Anna; Elsakov, Pavel; Kucinskas,; Gardovski, J; Irmejs, Arvids; Sibul, H; Huzarski, Tomasz; Byrski, Tomasz; Dębniak, Tadeusz; Cybulski, Cezary; Gronwald, Jacek; Oszurek, Oleg; Jw, Clark; Góźdż, Stanisław; Niepsuj, S; Słomski, Ryszard; Pławski, Andrzej; A, Łacka-Wojciechowska; Rozmiarek, Andrzej; Fiszer-Maliszewska, Ł; Bębenek, Marek; Сорокин, Д.Ю.; Stawicka, Małgorzata; Godlewski, Dariusz; Richter, Philipp; Brożek, Izabela; Wysocka, Barbara; Jawień, Arkadiusz; Banaszkiewicz, Zbigniew; Kowalczyk, Jerzy; Czudowska, D; Pe, Goretzki; Möeslein, Gabriela; Lubiński, Jan

doi:10.1136/jmg.39.10.e65

Cited by 27 publications

(16 citation statements)

References 17 publications

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“…It is possible that there are minor differences in the ethnic distribution of our cases and controls, but more importantly, our association study benefits from the general homogeneity of the Polish population, which is much less ethnically diverse than the populations of North America or of most western European countries. This ethnic homogeneity has been exploited in several genetic studies in the past [7,8]. This allele is present in other European countries and it will be of interest to see if our findings are replicated elsewhere.…”

Section: Discussionmentioning

confidence: 53%

The 3020insC allele of NOD2 predisposes to early-onset breast cancer

Huzarski

Lener

Domagała

et al. 2005

Breast Cancer Res Treat

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The NOD2 gene has been associated with susceptibility to Crohn's disease, and more recently with carcinoma of the colon as well. NOD2 is involved in the inflammatory response and the activation of the NFkB pathway. The range of cancer types associated with NOD2 has not been well studied. The 3020insC allele results in a truncated NOD2 protein and is present in approximately 7% of the population. We studied a possible association between the 3020insC allele of the NOD2 gene and breast cancer using 462 cases and 1910 controls from Poland. Patients were diagnosed with invasive breast cancer at are of two Szczecin regional hospitals between 2002 and 2004. Pathology specimens were reviewed for histological subtype and for the presence of ductal carcinoma in situ (DCIS). Overall there was no association between breast cancer and NOD2 (OR = 1.1; p = 0.76), but significant associations were observed between the presence of the allele and early-onset breast cancer (OR = 1.9; p = 0.01) and between the allele and ductal breast cancer with an in situ component (OR = 2.2; p = 0.006).

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Section: Discussionmentioning

confidence: 53%

The 3020insC allele of NOD2 predisposes to early-onset breast cancer

Huzarski

Lener

Domagała

et al. 2005

Breast Cancer Res Treat

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“…Therefore, we are suggesting that these alterations are neutral polymorphisms. Another series, both frequent and rare of MSH2 and MLH1 polymorphisms in the Polish population, are summarized in a previous study (23).…”

Section: Resultsmentioning

confidence: 99%

Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study)

et al. 2005

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Germline mutations in the DNA mismatch repair genes MSH2 and MLH1 account for a significant proportion of hereditary non-polyposis colorectal cancer (HNPCC) families. One approach by which development of an efficient DNA-testing procedure can be implemented is to describe the nature and frequency of common mutations in particular ethnic groups. Two hundred and twenty-six patients from families matching the Amsterdam II diagnostic criteria or suspected HNPCC criteria were screened for MSH2 and MLH1 germline mutations. Fifty different pathogenic mutations were found, 25 in MSH2 and 25 in MLH1. Twenty-four of these had not previously been described in other populations. Among our 78 families with MSH2 or MLH1 mutations, 54 (69.2%) were affected by recurrent mutations including 38 found at least twice in our own series. Two of the most frequent alterations were a substitution of A to T at the splice donor site of intron 5 of MSH2 and a missense change (A681T) of MLH1 found in 10 and eight families, respectively. Among large deletions detected by the multiplex ligation-dependent probe amplification assay, exon 9 deletions in the MSH2 gene were found in two families. Our results indicate that a screening protocol specific for the Polish population that is limited to the detection of all reported mutations will result in the identification of the majority of changes present in MLH1 and MSH2 genes in Polish HNPCC kindreds.

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“…T he known mutations are scattered throughout the coding regions of these genes, although, in particular populations (e.g. in Finland, Poland and in the United States), some recurrent changes have been found and described as founder mutations [9][10][11] . Predictive genetic testing for germline mutations in MMR genes can allow identification of HNPCC families, and are thus of great importance for counselling, sur veillance and manag ement of at-risk patients.…”

Section: Mutations In Mlh1 (Mim# 120436) and Ms H2mentioning

confidence: 99%

GermlineMLH1andMSH2mutational spectrum including frequent large genomic aberrations in Hungarian hereditary non-polyposis colorectal cancer families: Implications for genetic testing

Papp

Kovacs

Olàh

2007

WJG

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AIM:To analyze the prevalence of germline MLH1 and MSH2 gene mutations and evaluate the clinical characteristics of Hungarian hereditary non-polyposis colorectal cancer (HNPCC) families. M E T H O D S :T h i r t y -s i x k i n d r e d s w e r e t e s t e d f o r m u t a t i o n s u s i n g c o n f o r m a t i o n s e n s i t i v e g e l electrophoreses, direct sequencing and also screening for genomic rearrangements applying multiplex ligationdependent probe amplification (MLPA). RESULTS:Eighteen germline mutations (50%) were identified, 9 in MLH1 and 9 in MSH2 . Sixteen of these sequence alterations were considered pathogenic, the remaining two were non-conservative missense alterations occurring at highly conserved functional motifs. The majority of the definite pathogenic mutations (81%, 13/16) were found in families fulfilling the stringent Amsterdam Ⅰ/Ⅱ criteria, including three rearrangements revealed by MLPA (two in MSH2 and one in MLH1 ). However, in three out of sixteen HNPCCsuspected families (19%), a disease-causing alteration could be revealed. Furthermore, nine mutations described here are novel, and none of the sequence changes were found in more than one family. CONCLUSION:Our study describes for the first time the prevalence and spectrum of germline mismatch repair gene mutations in Hungarian HNPCC and suspected-HNPCC families. The results presented here suggest that clinical selection criteria should be relaxed and detection of genomic rearrangements should be included in genetic screening in this population.

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Germline MSH2 and MLH1 mutational spectrum in HNPCC families from Poland and the Baltic States

Cited by 27 publications

References 17 publications

The 3020insC allele of NOD2 predisposes to early-onset breast cancer

The 3020insC allele of NOD2 predisposes to early-onset breast cancer

Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study)

GermlineMLH1andMSH2mutational spectrum including frequent large genomic aberrations in Hungarian hereditary non-polyposis colorectal cancer families: Implications for genetic testing

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