Partial duplications of the MSH2 and MLH1 genes in hereditary nonpolyposis colorectal cancer

Baert‐Desurmont, Stéphanie; Buisine, Marie‐Pierre; Bessenay, Emilie; Frerot, Stephanie; Lovecchio, Tonio; Martin, Cosette; Olschwang, Sylviane; Wang, Qing; Frébourg, Thierry

doi:10.1038/sj.ejhg.5201765

Cited by 18 publications

(11 citation statements)

References 25 publications

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“…22 Interestingly, duplications in the MMR genes also seem to be a less frequent mutational event than deletions, and they have been rarely reported. 10,22,23 Additionally, this novel MLH1 duplication was detected in two independent LS families from the Antioquia area in the Northwestern part of Colombia, and a founder mutation effect may be inferred. A number of this kind of mutations have been identified in the MMR genes, 17,24 several in the MLH1 gene.…”

Section: Discussionmentioning

confidence: 87%

Novel MLH1 duplication identified in Colombian families with Lynch syndrome

Alonso-Espinaco

Giraldez

Trujillo³

et al. 2011

Genetics in Medicine

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Purpose: Lynch syndrome accounts for 2-4% of all colorectal cancer, and is mainly caused by germline mutations in the DNA mismatch repair genes. Our aim was to characterize the genetic mutation responsible for Lynch syndrome in an extensive Colombian family and to study its prevalence in Antioquia. Methods: A Lynch syndrome family fulfilling Amsterdam criteria II was studied by immunohistochemistry and by multiplex ligation-dependent probe amplification (MLPA). Results were confirmed by additional independent MLPA, Southern blotting, and sequencing. Results: Index case tumor immunohistochemistry results were MLH1Ϫ, MSH2ϩ, MSH6ϩ, and PMS2Ϫ. MLPA analysis detected a duplication of exons 12 and 13 of MLH1. This mutation was confirmed and characterized precisely to span 4219 base pairs. Duplication screening in this family led to the identification of six additional carriers and 13 noncarriers. We also screened 123 early-onset independent colorectal cancer cases from the same area and identified an additional unrelated carrier. Conclusion: A novel duplication of exons 12 and 13 of the MLH1 gene was detected in two independent Lynch syndrome families from Colombia. A putative founder effect and prescreening Lynch syndrome Antioquia families for this specific mutation before thorough mismatch repair mutational screening could be suggested. Genet Med 2011:13(2):155-160.

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Section: Discussionmentioning

confidence: 87%

Novel MLH1 duplication identified in Colombian families with Lynch syndrome

Alonso-Espinaco

Giraldez

Trujillo³

et al. 2011

Genetics in Medicine

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“…A variety of point mutations, such as substitutions, small insertions/deletions and splice site alterations, as well as large genomic rearrangements have been reported in the international InSiGHT (LOVD) database [10]. Particularly, genomic deletions account for approximately 10% of MLH1 and MSH2 mutations, while genomic duplications have been observed in approximately 1% of the Lynch syndrome cases [11,22]. Furthermore, the fact that there are multiple susceptible genes that predispose to Lynch syndrome, immunohistochemistry and/or MSI should be used, where possible, as a pre-screening method to successfully identify the high risk families.…”

Section: Discussionmentioning

confidence: 99%

“…This is so, because no hotspots have been reported in the MMR genes while deletions/duplications account for a substantial part of mutations associated with Lynch syndrome [9-11]. Nevertheless, the presence of founder mutations have been well documented in some populations, thus facilitating the procedure of genetic testing [1].…”

Section: Introductionmentioning

confidence: 99%

Screening of the DNA mismatch repair genes MLH1, MSH2 and MSH6in a Greek cohort of Lynch syndrome suspected families

et al. 2010

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BackgroundGermline mutations in the DNA mismatch repair genes predispose to Lynch syndrome, thus conferring a high relative risk of colorectal and endometrial cancer. The MLH1, MSH2 and MSH6 mutational spectrum reported so far involves minor alterations scattered throughout their coding regions as well as large genomic rearrangements. Therefore, a combination of complete sequencing and a specialized technique for the detection of genomic rearrangements should be conducted during a proper DNA-testing procedure. Our main goal was to successfully identify Lynch syndrome families and determine the spectrum of MLH1, MSH2 and MSH6 mutations in Greek Lynch families in order to develop an efficient screening protocol for the Greek colorectal cancer patients' cohort.MethodsForty-two samples from twenty-four families, out of which twenty two of Greek, one of Cypriot and one of Serbian origin, were screened for the presence of germline mutations in the major mismatch repair genes through direct sequencing and MLPA. Families were selected upon Amsterdam criteria or revised Bethesda guidelines.ResultsTen deleterious alterations were detected in twelve out of the twenty-four families subjected to genetic testing, thus our detection rate is 50%. Four of the pathogenic point mutations, namely two nonsense, one missense and one splice site change, are novel, whereas the detected genomic deletion encompassing exon 6 of the MLH1 gene has been described repeatedly in the LOVD database. The average age of onset for the development of both colorectal and endometrial cancer among mutation positive families is 43.2 years.ConclusionThe mutational spectrum of the MMR genes investigated as it has been shaped by our analysis is quite heterogeneous without any strong indication for the presence of a founder effect.

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“…Germline deletions in cancer genes have been associated with a number of hereditary cancer syndromes including neurofibromatosis, HNPCC, hereditary breast cancer, and FAP. Duplications have been detected, albeit at a lower frequency (19 ). Various techniques have simplified this type of analysis: MLPA is one widely used method (15 ), real-time PCR methods have also been successfully developed (20 ), and QMPSF is a simple semiquantitative method that had already been used in the analysis of germline and somatic copy number variations (12)(13)(14)21 ).…”

Section: Discussionmentioning

confidence: 99%

Detection of APC Gene Deletions Using Quantitative Multiplex PCR of Short Fluorescent Fragments

et al. 2008

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Background: Approximately 20% of classic familial adenomatous polyposis (FAP) cases and 70% to 80% of attenuated FAP (AFAP) cases are negative for the APC/MUTYH point mutation. Quantitative multiplex PCR of short fluorescent fragments (QMPSF), a technique for detecting copy number alterations, has been successfully applied to several cancer syndrome genes. We used QMPSF for the APC gene to screen FAP APC/MUTYH mutation-negative families to improve their diagnostic surveillance. Methods: We set up and validated APC-gene QMPSF using 23 negative and 1 positive control and examined 45 (13 FAP and 32 AFAP) unrelated members of APC/MUTYH mutation-negative families for copy number alterations. We confirmed the results using multiplex ligation-dependent probe amplification (MLPA). We used different approaches such as sequencing, quantitative real time-PCR (QRT-PCR), and fluorescence in situ hybridization (FISH) to further characterize the identified deletions. Results: APC QMPSF was capable of detecting deletions with an acceptable variability, as shown by mean values (SD) of allele dosage for the deleted control obtained from intra- and interexperimental replicates [0.52 (0.05) and 0.45 (0.10)]. We detected 3 gross deletions in 13 (23%) of the classic FAP cases analyzed (1 complete gene deletion and 2 partial deletions encompassing exons 9 and 10 and exons 11–15, respectively). No rearrangements were detected in the 32 AFAP cases. Conclusions: QMPSF is able to detect rearrangements of the APC gene. Our findings highlight the importance of using a copy number alteration methodology as a first step in the routine genetic testing of FAP families in the clinical setting.

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Partial duplications of the MSH2 and MLH1 genes in hereditary nonpolyposis colorectal cancer

Cited by 18 publications

References 25 publications

Novel MLH1 duplication identified in Colombian families with Lynch syndrome

Novel MLH1 duplication identified in Colombian families with Lynch syndrome

Screening of the DNA mismatch repair genes MLH1, MSH2 and MSH6in a Greek cohort of Lynch syndrome suspected families

Detection of APC Gene Deletions Using Quantitative Multiplex PCR of Short Fluorescent Fragments

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