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

Kurzawski, Grzegorz; Suchy, Janina; Lener, Marcin; Klujszo-Grabowska, Ewa; Kładny, Józef; Safranow, Krzysztof; Jakubowska, Katarzyna; Jakubowska, Anna; Huzarski, Tomasz; Byrski, Tomasz; Dębniak, Tadeusz; Cybulski, Cezary; Gronwald, Jacek; Oszurek, Oleg; Oszutowska, Dorota; Kowalska, E; Góźdż, Stanisław; Niepsuj, S; Słomski, Ryszard; Pławski, Andrzej; A, Łacka-Wojciechowska; Rozmiarek, Andrzej; Fiszer-Maliszewska, Ł; Bębenek, Marek; Сорокин, Д.Ю.; Sąsiadek, MM; Stembalska, Agnieszka; Grzebieniak, Zygmunt; Kilar, Ewa; Stawicka, Małgorzata; Godlewski, Dariusz; Richter, Philipp; Brożek, Izabela; Wysocka, Barbara; Limon, Janusz; Jawień, Arkadiusz; Banaszkiewicz, Zbigniew; Janiszewska, Hanna; Kowalczyk, Jerzy; Czudowska, D; Scott, Rodney J.; Lubiński, Jan

doi:10.1111/j.1399-0004.2006.00550.x

Cited by 37 publications

(24 citation statements)

References 27 publications

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“…In these genes (MSH2, MLH1, PMS2, and MSH6), the majority of causative mutations (90%) have been found in MSH2 (MIM] 120435; GenBank: NM_000251.1) and MLH1 (MIM] 120436; GenBank: NM_000249.2) [Kurzawski et al, 2006].…”

Section: Introductionmentioning

confidence: 99%

Quantitative PCR high-resolution melting (qPCR-HRM) curve analysis, a new approach to simultaneously screen point mutations and large rearrangements: application toMLH1germline mutations in Lynch syndrome

Rouleau¹,

Lefol²,

Bourdon³

et al. 2009

Hum. Mutat.

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Several techniques have been developed to screen mismatch repair (MMR) genes for deleterious mutations. Until now, two different techniques were required to screen for both point mutations and large rearrangements. For the first time, we propose a new approach, called ''quantitative PCR (qPCR) high-resolution melting (HRM) curve analysis (qPCR-HRM),'' which combines qPCR and HRM to obtain a rapid and cost-effective method suitable for testing a large series of samples. We designed PCR amplicons to scan the MLH1 gene using qPCR HRM. Seventy-six patients were fully scanned in replicate, including 14 wild-type patients and 62 patients with known mutations (57 point mutations and five rearrangements). To validate the detected mutations, we used sequencing and/or hybridization on a dedicated MLH1 array-comparative genomic hybridization (array-CGH). All point mutations and rearrangements detected by denaturing high-performance liquid chromatography (dHPLC)1multiplex ligation-dependent probe amplification (MLPA) were successfully detected by qPCR HRM. Three large rearrangements were characterized with the dedicated MLH1 array-CGH. One variant was detected with qPCR HRM in a wild-type patient and was located within the reverse primer. One variant was not detected with qPCR HRM or with dHPLC due to its proximity to a T-stretch. With qPCR HRM, prescreening for point mutations and large rearrangements are performed in one tube and in one step with a single machine, without the need for any automated sequencer in the prescreening process. In replicate, its reagent cost, sensitivity, and specificity are comparable to those of dHPLC1MLPA techniques. However, qPCR HRM outperformed the other techniques in terms of its rapidity and amount of data provided.

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Section: Introductionmentioning

confidence: 99%

Quantitative PCR high-resolution melting (qPCR-HRM) curve analysis, a new approach to simultaneously screen point mutations and large rearrangements: application toMLH1germline mutations in Lynch syndrome

Rouleau¹,

Lefol²,

Bourdon³

et al. 2009

Hum. Mutat.

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“…Q402X is a stop mutation that was previously identified in an LS kindred from Poland [18] and we have identified it here for the first time here in association with PC. Whether K618A is pathogenic remains a debated question.…”

Section: Discussionmentioning

confidence: 74%

Germline MLH1 and MSH2 mutations in Italian pancreatic cancer patients with suspected Lynch syndrome

et al. 2009

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Lynch syndrome is an inherited cancer syndrome caused by germline mutations in mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. LS predisposes to high risk of early-onset colorectal, endometrial and other tumors. Patients with Lynch syndrome have also been shown to have an elevated risk for pancreatic cancer (PC). In this study, we aimed to estimate the frequency of suspected Lynch syndrome among a series of 135 PC patients. Further, we wanted to determine the frequency of MMR gene mutations in the suspected Lynch syndrome cases. We also aimed to verify the pathogenicity of any novel non-truncating variants we might detect with a functional assay. Based on personal and/or familial cancer history, 19 patients were classified as suspected Lynch syndrome cases. DNA material for mutation analysis was available for eleven of them. Four patients were found to carry a total of five MLH1 or MSH2 variants. Of these, MSH2-Q402X, MSH2-G322D, and MLH1-K618A had been previously reported, while the MSH2-E205Q and MSH2-V367I variants were novel. MSH2-Q402X is a known stop mutation and reported here for the first time here in association with PC. MLH1-K618A was found in the unaffected branch of a kindred, suggesting that it may be a polymorphism or a low penetrance variant. MSH2-G322D likely does not cause a MMR defect, although this variant has also been associated with breast cancer as indeed seen in our patient. The novel variants MSH2-E205Q and MSH2-V367I were found in the same patient. Both novel variants were however functional in the applied MMR assay. Our findings suggest that only a small subset of pancreatic cancer patients carry pathogenic MMR mutations.

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“…Consequently, genetic testing for abnormalities in susceptible genes and the organization of the registries of CRC families are gaining increased popularity worldwide. Large genetic studies performed in Poland have revealed that fifty MSH2 and MLH1 mutations were characteristic for the local population [13]. Our previous study had demonstrated that these abnormalities were also present in the Lower Silesian population [14].…”

Section: Discussionmentioning

confidence: 99%

Incidence of colorectal cancer in Lower Silesia (Poland) between 1984 and 2003 — trends and perspectives

Bębenek¹,

Pudełko²,

Błaszczyk³

2008

Open Medicine

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AbstractThe purpose of the present study was to demonstrate the epidemiological characteristics of colorectal cancers (CRCs) diagnosed in Lower Silesia between 1984 and 2003. Data from the Lower Silesian Cancer Registry on the incidence of CRC in the Lower Silesian province were subjected to analysis. The age adjusted incidence of CRC in both genders increased markedly. A higher relative increase of incidence was recorded for colon cancer. The age-specific incidence of either colon or rectal cancer increased markedly with age in both genders. No constant time-trend toward the earlier diagnosis of CRC was noted in the period studied. Although the number of CRC surgeries performed at the Regional Comprehensive Cancer Center in Wroclaw has increased over time, most of the cases that were diagnosed were treated outside that reference center. If an intensive increase in new case numbers, demonstrated in both the locations by 2003, is not moderated, the incidence of colorectal malignancies in Lower Silesia would become one of the highest in Europe.

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

Cited by 37 publications

References 27 publications

Quantitative PCR high-resolution melting (qPCR-HRM) curve analysis, a new approach to simultaneously screen point mutations and large rearrangements: application toMLH1germline mutations in Lynch syndrome

Quantitative PCR high-resolution melting (qPCR-HRM) curve analysis, a new approach to simultaneously screen point mutations and large rearrangements: application toMLH1germline mutations in Lynch syndrome

Germline MLH1 and MSH2 mutations in Italian pancreatic cancer patients with suspected Lynch syndrome

Incidence of colorectal cancer in Lower Silesia (Poland) between 1984 and 2003 — trends and perspectives

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