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• W2098366973 abstract "Background & Aims: A significant proportion of Lynch syndrome cases are believed to be due to large genomic alterations in the mismatch repair genes hMLH1 and hMSH2. However, previous studies have not adequately identified the frequency and scope of such mutations, and routine clinical Lynch syndrome testing often does not include analysis for these mutations. Our aim was to characterize hMLH1 and hMSH2 genomic rearrangements in a large population of suspected Lynch syndrome patients. Methods: A total of 365 samples from probands referred for genetic testing for Lynch syndrome were analyzed for the presence of large genomic alterations in hMLH1 or hMSH2 by using a combination of techniques. Samples with a deletion in exons 1–6 in hMSH2 were further characterized by polymerase chain reaction to establish the presence of the hMSH2 American founder deletion. Results: An hMLH1 or hMSH2 mutation was identified in 153 cases, and, of these, 12 of 67 (17.9%) and 39 of 86 (45.3%) had a large genomic alteration in hMLH1 and hMSH2, respectively. Overall, 6 different hMLH1 and 12 different hMSH2 deletions/duplications, including 10 novel mutations, were identified. Analysis of the hMSH2 exon 1–6 deletion samples showed that 13 of 18 (72.2%) had the American founder deletion. Conclusions: These data show a high frequency and diverse spectrum of large genomic alterations in hMLH1 and hMSH2 in suspected Lynch syndrome patients. Thus, a comprehensive mutation identification strategy that includes the ability to detect large genomic rearrangements is imperative for the clinical genetic identification of Lynch syndrome patients and families. Background & Aims: A significant proportion of Lynch syndrome cases are believed to be due to large genomic alterations in the mismatch repair genes hMLH1 and hMSH2. However, previous studies have not adequately identified the frequency and scope of such mutations, and routine clinical Lynch syndrome testing often does not include analysis for these mutations. Our aim was to characterize hMLH1 and hMSH2 genomic rearrangements in a large population of suspected Lynch syndrome patients. Methods: A total of 365 samples from probands referred for genetic testing for Lynch syndrome were analyzed for the presence of large genomic alterations in hMLH1 or hMSH2 by using a combination of techniques. Samples with a deletion in exons 1–6 in hMSH2 were further characterized by polymerase chain reaction to establish the presence of the hMSH2 American founder deletion. Results: An hMLH1 or hMSH2 mutation was identified in 153 cases, and, of these, 12 of 67 (17.9%) and 39 of 86 (45.3%) had a large genomic alteration in hMLH1 and hMSH2, respectively. Overall, 6 different hMLH1 and 12 different hMSH2 deletions/duplications, including 10 novel mutations, were identified. Analysis of the hMSH2 exon 1–6 deletion samples showed that 13 of 18 (72.2%) had the American founder deletion. Conclusions: These data show a high frequency and diverse spectrum of large genomic alterations in hMLH1 and hMSH2 in suspected Lynch syndrome patients. Thus, a comprehensive mutation identification strategy that includes the ability to detect large genomic rearrangements is imperative for the clinical genetic identification of Lynch syndrome patients and families. Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder that accounts for approximately 2% of all cases of colorectal cancer. HNPCC is characterized by the early onset of colorectal cancer, with an average age of diagnosis in the early to mid 40s. Although colorectal cancer is the most common finding, cancers of other origins, such as endometrial, gastric, and ovarian, have been described in these patients.1Lynch H.T. de la Chapelle A. Hereditary colorectal cancer.N Engl J Med. 2003; 348: 919-932Crossref PubMed Scopus (1633) Google Scholar, 2Allen B.A. Terdiman J.P. Hereditary polyposis syndromes and hereditary non-polyposis colorectal cancer.Best Pract Res Clin Gastroenterol. 2003; 17: 237-258Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Approximately two thirds of patients with a diagnosis of HNPCC have germline mutations in any one of several genes involved in DNA mismatch repair (MMR)3Peltomaki P. Role of DNA mismatch repair defects in the pathogenesis of human cancer.J Clin Oncol. 2003; 21: 1174-1179Crossref PubMed Scopus (580) Google Scholar and have what is now referred to as Lynch syndrome.4Baudhuin L.M. Burgart L.J. Leontovich O. Thibodeau S.N. Use of microsatellite instability and immunohistochemistry testing for the identification of individuals at risk for Lynch syndrome.Familial Cancer. 2005; 4: 255-265Crossref PubMed Scopus (90) Google Scholar, 5Hampel H. Frankel W.L. Martin E. Arnold M. Khanduja K. Kuebler P. Nakagawa H. Sotamaa K. Prior T.W. Westman J. Panescu J. Fix D. Lockman J. Comeras I. de la Chapelle A. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer).N Engl J Med. 2005; 352: 1851-1860Crossref PubMed Scopus (1105) Google Scholar Most Lynch syndrome tumors show the presence of microsatellite instability (MSI) and the absence of DNA MMR protein expression, as determined by immunohistochemistry (IHC).4Baudhuin L.M. Burgart L.J. Leontovich O. Thibodeau S.N. Use of microsatellite instability and immunohistochemistry testing for the identification of individuals at risk for Lynch syndrome.Familial Cancer. 2005; 4: 255-265Crossref PubMed Scopus (90) Google Scholar, 6Lynch H.T. de la Chapelle A. Genetic susceptibility to non-polyposis colorectal cancer.J Med Genet. 1999; 36: 801-818PubMed Google Scholar, 7Cunningham J.M. Kim C.Y. Christensen E.R. Tester D.J. Parc Y. Burgart L.J. Halling K.C. McDonnell S.K. Schaid D.J. Walsh Vockley C. Kubly V. Nelson H. Michels V.V. Thibodeau S.N. The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas.Am J Hum Genet. 2001; 69: 780-790Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar Germline mutations in the MMR genes hMSH2 and hMLH1 account for approximately 80% of the reported mutations in families with Lynch syndrome.6Lynch H.T. de la Chapelle A. Genetic susceptibility to non-polyposis colorectal cancer.J Med Genet. 1999; 36: 801-818PubMed Google Scholar, 8Peltomaki P. Deficient DNA mismatch repair a common etiologic factor for colon cancer.Hum Mol Genet. 2001; 10: 735-740Crossref PubMed Scopus (400) Google Scholar An additional approximately 10% of mutations are due to hMSH6, and a smaller percentage are due to PMS2. Therefore, screening for germline mutations in hMLH1 and hMSH2 is important for the diagnosis of this syndrome. Whereas point mutations and small genomic alterations are found at a high frequency in these genes, large genomic alterations have been suggested to account for 10%–20% of hMSH2 mutations and a lower percentage of hMLH1 mutations.9Nakagawa H. Hampel H. de la Chapelle A. Identification and characterization of genomic rearrangements of MSH2 and MLH1 in Lynch syndrome (HNPCC) by novel techniques.Hum Mutat. 2003; 22: 258Crossref PubMed Scopus (80) Google Scholar, 10Wijnen J. van der Klift H. Vasen H. Khan P.M. Menko F. Tops C. Meijers Heijboer H. Lindhout D. Moller P. Fodde R. MSH2 genomic deletions are a frequent cause of HNPCC.Nat Genet. 1998; 20: 326-328Crossref PubMed Scopus (196) Google Scholar, 11Charbonnier F. Olschwang S. Wang Q. Boisson C. Martin C. Buisine M.P. Puisieux A. Frebourg T. MSH2 in contrast to MLH1 and MSH6 is frequently inactivated by exonic and promoter rearrangements in hereditary nonpolyposis colorectal cancer.Cancer Res. 2002; 62: 848-853PubMed Google Scholar Additionally, the identification of an American founder deletion of exons 1–6 in hMSH2 in a large outbred US population with a wide geographic distribution suggests that these large genomic alterations may be more common than previously indicated.12Lynch H.T. Coronel S.M. Okimoto R. Hampel H. Sweet K. Lynch J.F. Barrows A. Wijnen J. van der Klift H. Franken P. Wagner A. Fodde R. de la Chapelle A. A founder mutation of the MSH2 gene and hereditary nonpolyposis colorectal cancer in the United States.JAMA. 2004; 291: 718-724Crossref PubMed Scopus (75) Google Scholar Therefore, because of the presence and frequency of large genomic deletions and duplications in hMLH1 and hMSH2, analysis for these rearrangements should be part of a routine mutation detection protocol for Lynch syndrome. Mutation screening techniques such as conformation-sensitive gel electrophoresis (CSGE) and direct sequencing are limited because they do not detect large deletions, duplications, or other genomic rearrangements that are frequently found in Lynch syndrome kindreds. Historically, dosage differences in the MMR genes have been difficult to identify and characterize with traditional complementary DNA or genomic probes for Southern blot analysis.10Wijnen J. van der Klift H. Vasen H. Khan P.M. Menko F. Tops C. Meijers Heijboer H. Lindhout D. Moller P. Fodde R. MSH2 genomic deletions are a frequent cause of HNPCC.Nat Genet. 1998; 20: 326-328Crossref PubMed Scopus (196) Google Scholar, 13Miyaki M. Iijima T. Yamaguchi T. Shirahama S. Ito T. Yasuno M. Mori T. Novel germline hMSH2 genomic deletion and somatic hMSH2 mutations in a hereditary nonpolyposis colorectal cancer family.Mutat Res. 2004; 548: 19-25Crossref PubMed Scopus (5) Google Scholar We recently described a Southern blot method for the detection of exon deletions/duplications with resolution at the single exon level and compared this method with a novel polymerase chain reaction (PCR)-based method, multiplex ligation-dependent probe amplification (MLPA).14Baudhuin L.M. Mai M. French A.J. Kruckeberg K.E. Swanson R.L. Winters J.L. Courteau L.K. Thibodeau S.N. Analysis of hMLH1 and hMSH2 gene dosage alterations in hereditary nonpolyposis colorectal cancer patients by novel methods.J Mol Diagn. 2005; 7: 226-235Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar For this study, we used both of these techniques to identify and characterize hMLH1 and hMSH2 genomic rearrangements in a large cohort of patients referred for Lynch syndrome testing. The collection of clinical data and peripheral blood samples was approved by the institutional review board of the Mayo Clinic. Specimens used in this study (n = 365) were collected from probands referred for routine clinical testing for Lynch syndrome through the Clinical Molecular Genetics Laboratory at the Mayo Clinic. Many, but not all, of the probands had tumor MMR analyses performed either at the Mayo Clinic or externally. Tumor microsatellite studies performed at the Mayo Clinic incorporated 10 microsatellite markers (4 mononucleotide and 6 dinucleotide).4Baudhuin L.M. Burgart L.J. Leontovich O. Thibodeau S.N. Use of microsatellite instability and immunohistochemistry testing for the identification of individuals at risk for Lynch syndrome.Familial Cancer. 2005; 4: 255-265Crossref PubMed Scopus (90) Google Scholar Tumors were considered to have a high level of MSI (MSI-H) if they showed instability at ≥3 of 10 markers, to have a low level of MSI (MSI-L) if they showed instability in 1 or 2 markers, and to be microsatellite stable (MSS) if no markers were unstable. IHC analyses performed at the Mayo Clinic were used to test for loss of protein expression of hMLH1, hMSH2, hMSH6, and PMS2. Genomic DNA was isolated from the peripheral blood leukocytes of the patients by using Puregene reagents (Gentra Systems, Inc, Minneapolis, MN) according to the manufacturer’s protocol. Southern blot was performed as previously described.14Baudhuin L.M. Mai M. French A.J. Kruckeberg K.E. Swanson R.L. Winters J.L. Courteau L.K. Thibodeau S.N. Analysis of hMLH1 and hMSH2 gene dosage alterations in hereditary nonpolyposis colorectal cancer patients by novel methods.J Mol Diagn. 2005; 7: 226-235Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar Briefly, genomic DNA (2.5 μg for each enzyme digestion) from each patient was digested with EcoRI, BglII, and HindIII in 3 separate reactions. Digested genomic DNA was then loaded onto a 0.8% agarose gel for overnight electrophoresis at 55 V. Probes corresponding to each exon of hMLH1 and hMSH2 were prepared by recombinant DNA technology as previously described,14Baudhuin L.M. Mai M. French A.J. Kruckeberg K.E. Swanson R.L. Winters J.L. Courteau L.K. Thibodeau S.N. Analysis of hMLH1 and hMSH2 gene dosage alterations in hereditary nonpolyposis colorectal cancer patients by novel methods.J Mol Diagn. 2005; 7: 226-235Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar and 10 ng of each probe was radioactively labeled with α-32P-deoxycytidine triphosphate by using a High Prime Kit (Roche, Basel, Switzerland). After capillary transfer of the gel containing the digested DNA to a hybridization membrane, the membrane was incubated with the radioactive probes (1 × 106 disintegrations per minute per milliliter) in 20 mL of hybridization solution overnight at 45°C. After hybridization, the membranes were washed in 3 changes of 2× standard saline citrate and 0.1% sodium dodecyl sulfate and 1 change of 0.2× standard saline citrate and 0.1% sodium dodecyl sulfate. Radioactive membranes were exposed to PhosphorImager screens (Amersham Biosciences, Piscataway, NJ), and data analysis and quantitation were performed with ImageQuant 5.0 software (Amersham Biosciences). MLPA, a PCR-based technique for identifying gene dosage alterations, has been previously described in detail.15Schouten J.P. McElgunn C.J. Waaijer R. Zwijnenburg D. Diepvens F. Pals G. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification.Nucleic Acids Res. 2002; 30: e57Crossref PubMed Scopus (2086) Google Scholar All reagents were provided by the manufacturer in a kit (SALSA P003 MSH2/MLH1 MLPA kit; MRC-Holland, Amsterdam, Holland), and testing was performed according to the manufacturer’s recommendations, with minor modifications, as previously described.14Baudhuin L.M. Mai M. French A.J. Kruckeberg K.E. Swanson R.L. Winters J.L. Courteau L.K. Thibodeau S.N. Analysis of hMLH1 and hMSH2 gene dosage alterations in hereditary nonpolyposis colorectal cancer patients by novel methods.J Mol Diagn. 2005; 7: 226-235Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar Briefly, 400 ng of patient genomic DNA was heated to 95°C for 5 minutes, cooled, and then mixed with the P003 probe set and MLPA buffer. The P003 probe set consists of contiguous probe pairs for each exon of hMLH1 and hMSH2. The probe pairs were hybridized to the genomic DNA at 60°C for 16 hours. Ligase was then added to the reaction mixture, and contiguous probe pairs that were bound to each exon of hMLH1 and hMSH2 were ligated together at 54°C for 10–15 minutes. The ligated probe pairs were then PCR-amplified in a single reaction by using 6-carboxyfluorescein–labeled universal primers and then separated via capillary electrophoresis on an ABI 3100 (Applied Biosystems, Foster City, CA). Each amplified ligated probe pair migrated to a specific point according to size and was fluorescently detected and represented as a peak by the ABI software. Data were collected and analyzed with Genescan and Genotyper software (Applied Biosystems). The output for each patient displayed a peak that corresponded to the amount of amplified ligated probe present for each exon of the hMLH1 and hMSH2 genes, along with several peaks representative of extragenic regions used for ligation and PCR monitoring controls. Peak heights for fragments corresponding to specific exons and control regions were binned, appended to a table, and then saved as a text file, all within the Genotyper software. The contents of the tabular text file were then stored in a Microsoft Access (Redmond, WA) database, and calculations were performed by custom software. Samples were excluded from scoring if 2 requirements were not met: (1) the 96–base pair control peak height/74–base pair control peak height ratio was ≥5 and (2) all 7 extragenic control peaks in the sample were identified. To control for intersample PCR and loading differences, the peak heights from each sample were first normalized by dividing each hMLH1- and hMSH2-associated peak height by the average of the extragenic control peak heights for that sample. Each of the sample’s normalized peak heights was then compared with the average of at least 3 normal controls’ corresponding normalized peak heights, expressed as a percentage difference. Any exon with a decrease or increase in peak height of ≥35% was scored as a deletion or duplication, respectively. Samples observed to have a deletion in exons 1–6 of hMSH2 by Southern blot and MLPA were analyzed by long-range PCR for the presence of the American founder deletion.12Lynch H.T. Coronel S.M. Okimoto R. Hampel H. Sweet K. Lynch J.F. Barrows A. Wijnen J. van der Klift H. Franken P. Wagner A. Fodde R. de la Chapelle A. A founder mutation of the MSH2 gene and hereditary nonpolyposis colorectal cancer in the United States.JAMA. 2004; 291: 718-724Crossref PubMed Scopus (75) Google Scholar The protocol and primer sequences were kindly supplied by Dr Albert de la Chapelle (Ohio State University, Human Cancer Genetics Laboratory, Columbus, OH) and used as previously described.9Nakagawa H. Hampel H. de la Chapelle A. Identification and characterization of genomic rearrangements of MSH2 and MLH1 in Lynch syndrome (HNPCC) by novel techniques.Hum Mutat. 2003; 22: 258Crossref PubMed Scopus (80) Google Scholar, 12Lynch H.T. Coronel S.M. Okimoto R. Hampel H. Sweet K. Lynch J.F. Barrows A. Wijnen J. van der Klift H. Franken P. Wagner A. Fodde R. de la Chapelle A. A founder mutation of the MSH2 gene and hereditary nonpolyposis colorectal cancer in the United States.JAMA. 2004; 291: 718-724Crossref PubMed Scopus (75) Google Scholar Briefly, the Expand Long Template PCR system (Roche Diagnostics) was used to amplify genomic DNA with specific PCR primers that encompassed the breakpoint regions. A unique 1.7-kilobase amplicon was produced in samples with the American founder deletion and subsequently resolved by electrophoresis. To confirm the identity of the 1.7-kilobase product, sequencing was performed by using the reverse primer from the PCR reaction and a nested forward primer located 180 nucleotides upstream of the 5′ breakpoint. From May 2000 to July 2004, 539 DNA samples from symptomatic and asymptomatic patients who were suspected of having Lynch syndrome or who had a family history of suspected Lynch syndrome were tested for alterations in hMLH1 and hMSH2. This group consisted of both related and unrelated (to the best of our knowledge) individuals. For the 365 unrelated individuals (referred to as probands), reasons for referral varied, including (1) the proband’s tumor was MSI-H with IHC loss of hMLH1 or hMSH2 or had a loss of hMLH1 or hMSH2 only (n = 154); (2) the proband’s tumor was MSI-H only, and no IHC was available (n = 7); (3) the proband’s tumor was MSS or MSI-L (n = 3); (4) the proband was suspected of having Lynch syndrome, but tumor was unavailable for MMR analysis (n = 77); (5) the patient had a family history of HNPCC, but genetic testing on other family members had not been performed (n = 36); (6) a mutation in hMLH1 or hMSH2 had been identified in a relative at an outside institution (n = 24); (7) sequencing was performed at an outside institution and had negative results, but large genomic alteration analyses of hMLH1 and/or hMSH2 had not been tested for (n = 38); and (8) the reason for referral could not be obtained from the referring physician (n = 26). For the purposes of this study, we report only proband data, or, if a familial mutation had been identified elsewhere, we report only the results obtained from 1 member of that family. Samples were analyzed for mutations in hMLH1 and/or hMSH2 by Southern blot analysis, CSGE, and, if required, follow-up DNA sequence analysis. As part of a previous method validation study, many of the proband samples described here were also run in parallel by both Southern blot and MLPA,14Baudhuin L.M. Mai M. French A.J. Kruckeberg K.E. Swanson R.L. Winters J.L. Courteau L.K. Thibodeau S.N. Analysis of hMLH1 and hMSH2 gene dosage alterations in hereditary nonpolyposis colorectal cancer patients by novel methods.J Mol Diagn. 2005; 7: 226-235Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar including all but 2 of those positive for a mutation and 152 of those negative for a mutation. Of the sample population, 180 and 185 were analyzed for hMLH1 and hMSH2 mutations, respectively, including 60 samples screened for mutations in both genes. Overall, 153 probands were identified and reported to have a germline mutation in hMLH1 or hMSH2. Of the probands who tested positive for any type of pathogenic mutation, 12 of 67 (17.9%) and 39 of 86 (45.3%) had a large genomic alteration in hMLH1 and hMSH2, respectively. Missense mutations of unknown significance (n = 5) are not included in the count. For the large genomic alterations, 6 different mutations in hMLH1 and 12 different mutations in hMSH2, including 10 novel mutations overall, were identified during the course of this study (Table 1). On the basis of the location of the MLPA probes and appearance of junction fragment(s) by Southern blot, a partial exon deletion could not be ruled out for 3 deletion-positive samples (Table 1). Clinical characteristics of positive probands with large genomic alterations in hMLH1 and hMSH2 are detailed in Table 2, Table 3, respectively.Table 1Large Genomic Alterations Identified in ProbandshMLH1hMSH2MutationnMutationnDel exons 1–21Promoter deletionaMLPA analysis could not confirm this deletion because of a lack of MLPA probes for this region.1Del exons 1–131Del exons 1–21Del exons 11–15bA possible breakpoint in exon 10 could not be ruled out (see text for more information).1Del exon 21Del exon 13cA possible breakpoint in exon 12 for one of these samples could not be ruled out (see text for more information).2Del exons 1–622Del exons 16–193Del exons 1–72Dup exons 6–124Del exons 1–83Del exons 3–82Del exons 4–81Dup exons 5–6dMLPA analysis could not be performed on this sample because of insufficient DNA.1Del exon 71Del exon 83Del exons 7–16eA possible breakpoint in exon 6 could not be ruled out (see text for more information).1Total12Total39Del, deletion; Dup, duplication.a MLPA analysis could not confirm this deletion because of a lack of MLPA probes for this region.b A possible breakpoint in exon 10 could not be ruled out (see text for more information).c A possible breakpoint in exon 12 for one of these samples could not be ruled out (see text for more information).d MLPA analysis could not be performed on this sample because of insufficient DNA.e A possible breakpoint in exon 6 could not be ruled out (see text for more information). Open table in a new tab Table 2Characteristics of Probands With Large Genomic Alterations in hMLH1Patient no.MutationSexAge at diagnosis/testing (y)CancerFamily historyaFamily history was obtained at referral.1Del exons 1–2M32/33ColonGrandmother (colon)2Del exons 1–13MNA/45Patient symptomaticYes (colon)3Del exons 11–15MNA/44ColonNA4Del exon 13M(49; 60)/60Colon; colon cancer at splenic fixtureBrother (age 45 y), mother (age 40 y), and maternal aunt (age 40 y), all with colon cancer5Del exon 13FNA/43ColonNA6Del exons 16–19FNA/53ColonSister, nephew affected7Del exons 16–19M53/54Sebaceous skinNA8Del exons 16–19FNA/77ColonYes9Dup exons 6–12MNA/49ColonNA10Dup exons 6–12FNA/53NANA11Dup exons 6–12F(32; 36)/42Colon; ovarianBrother (age 31 y) with colon cancer12Dup exons 6–12M48/67ColonYesNA, not available; Del, deletion; Dup, duplication.a Family history was obtained at referral. Open table in a new tab Table 3Characteristics of Probands With Large Genomic Alterations in hMSH2Patient no.MutationSexAge at diagnosis/testing (y)CancerFamily historyaFamily history was obtained at referral.1Del promoterFNA/58ColonConsistent with Lynch syndrome2Del exons 1–2MNA/32ColonColorectal adenocarcinoma3Del exon 2FNA/49NAMother (44 y) cecal cancer, sister (33 y) colon cancer, sister (38 y) uterine cancer, brother (35 y) glioblastoma4Del exons 1–6bNegative for American founder mutation (AFM).MNA/58ColonNA5Del exons 1–6bNegative for American founder mutation (AFM).M24/24ColonPaternal grandfather and 2 paternal uncles, all with colon cancer6Del exons 1–6bNegative for American founder mutation (AFM).M29/41ColonPaternal grandfather (73 y), bone Brother (1 y), brain7Del exons 1–6bNegative for American founder mutation (AFM).M(31; 55; 59; 60; 68)/70Colon; colon; prostate; colon; kidneyDaughter (34 y) cervical cancer, father (40s) colon cancer, uncle (78 y) prostate cancer, paternal grandfather (60s) colon cancer, maternal grandmother (50s) kidney cancer8Del exons 1–6bNegative for American founder mutation (AFM).FNA/41NABrother (colon)9Del exons 1–6 (AFM)MNA/34NANA10Del exons 1–6 (AFM)M42/61ColonMother (45 y) uterine and (60 y) colon, maternal aunt (43 y) ovarian and (51 y) colon, maternal grandmother (69 y) colon11Del exons 1–6 (AFM)FNA/28ColonNA12Del exons 1–6 (AFM)F(46; 56)/57Duodenal; transverse colonTen first- and second-degree relatives affected13Del exons 1–6 (AFM)FMid 30s/39ColonFather, 2 brothers, sister, and nephew, all with colon cancer and some with sebaceous adenomas14Del exons 1–6 (AFM)MNA/63ColonYes15Del exons 1–6 (AFM)F(37; 40)/43Endometrial and cervical; colonColon, endometrial, breast16Del exons 1–6 (AFM)FNA/48ColonBrother (colon)17Del exons 1–6 (AFM)MNA/25AppendicealNA18Del exons 1–6 (AFM)F39/40ColonEndometrial and colon19Del exons 1–6 (AFM)FEarly 20s/35ColonSister (colon) and others (consistent with Lynch syndrome)20Del exons 1–6 (AFM)MNA/56ColonFather (colon)21Del exons 1–6 (AFM)NA/49Gastric, upper urothelial, colonNA22Del exons 1–6cNot tested for AFM.M(51; 60)/60Renal pelvic; colonMeets Amsterdam criteria23Del exons 1–6cNot tested for AFM.F43/44ColonAsymptomatic sister (45 y) with mutation24Del exons 1–6cNot tested for AFM.MNA/45ColonNA25Del exons 1–6cNot tested for AFM.MNA/58ColonNA26Del exons 1–7M49/NASebaceous adenomaNo family history27Del exons 1–7FNA/50RectalNA28Del exons 1–8MNA/42ColonFather (bilateral ureter), sister (endometrial), uncle (colon)29Del exons 1–8F26/31ColonNA30Del exons 1–8FNA/68Endometrial, ureter, and breastMother, 2 sisters, and maternal uncle affected31Del exons 3–8MNA/53ColonNA32Del exons 3–8FNA/51ColonNA33Del exons 4–8MNA/64ColonColon34Dup exons 5–6F49/51ColonFather, brother, son (all colon) under the age of 50 y35Del exon 7MNA/46ColonMeets Amsterdam criteria36Del exon 8M41/41ColonFather (61 y) colon cancer, sister (38 y) colon cancer, maternal grandmother (50 y) uterine cancer, paternal grandfather (64 y) pancreas cancer, paternal aunt (41 y) skin cancer, paternal cousin (26 y) unknown primary tumor37Del exon 8M32/32ColonMaternal uncle (42 y) colon, maternal grandmother (43 y) cervical, maternal aunt (62 y) lung, paternal grandfather (?) prostate, paternal grandmother (59 y) cervical, paternal uncle (54 y) prostate38Del exon 8aFamily history was obtained at referral.FNA/58Colon, endometrial, sebaceous adenomaNo family history39Del exons 7–16MNA/52ColonNADel, deletion; Dup, duplication; NA, not available.a Family history was obtained at referral.b Negative for American founder mutation (AFM).c Not tested for AFM. Open table in a new tab Del, deletion; Dup, duplication. NA, not available; Del, deletion; Dup, duplication. Del, deletion; Dup, duplication; NA, not available. A large genomic deletion spanning exons 1–6 was identified in 22 of 39 (56.4%) of the hMSH2 deletion–positive samples studied. Of these, 18 were further analyzed for the presence of the American founder deletion, and 13 (72.2%) were identified to have this alteration (Table 3). The nature of the deletion in the remaining 5 of 18 (27.8%) patients remains under investigation. Of the 365 probands in our study, 153 were positive for any type of pathogenic mutation in hMLH1 or hMSH2. For these mutation-positive cases, 67 had a mutation in hMLH1, and 86 had a mutation in hMSH2. Additional testing for mutations in either hMSH6 or PMS2 was not performed in these cases. Most mutations (55/68 and 47/86 for hMLH1 and hMSH2, respectively) identified in both of these genes were point mutations and small insertions/deletions. However, large genomic rearrangements of hMLH1 and hMSH2 were also present at high frequencies in these mutation-positive cases (17.9% and 45.3%, respectively). Other studies have determined a wide range of frequencies for large deletion/insertion types of alterations: from 5% to 30% for hMLH1 and 10% to 60% for hMSH2.10Wijnen J. van der Klift H. Vasen H. Khan P.M. Menko F. Tops C. Meijers Heijboer H. Lindhout D. Moller P. Fodde R. MSH2 genomic deletions are a frequent cause of HNPCC.Nat Genet. 1998; 20: 326-328Crossref PubMed Scopus (196) Google Scholar, 11Charbonnier F. Olschwang S. Wang Q. Boisson C. Martin C. Buisine M.P. Puisieux A. Frebourg T. MSH2 in contrast to MLH1 and MSH6 is frequently inactivated by exonic and promoter rearrangements in hereditary nonpolyposis colorectal cancer.Cancer Res. 2002; 62: 848-853PubMed Google Scholar, 16Gille J.J. Hogervorst F.B. Pals G. Wijnen J.T. van Schooten R.J. Dommering C.J. Meijer G.A. Craanen M.E. Nederlof P.M. de Jong D. McElgunn C.J. Schouten J.P. Menko F.H. Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach.Br J Cancer. 2002; 87: 892-897Crossref PubMed Scopus (137) Google Scholar, 17Taylor C.F. Charlton R.S. Burn J. Sheridan E. Taylor G.R. Genomic deletions in MSH2 or MLH1 are a" @default.
• W2098366973 created "2016-06-24" @default.
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• W2098366973 creator A5055367957 @default.
• W2098366973 creator A5078969076 @default.
• W2098366973 creator A5086141666 @default.
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• W2098366973 date "2005-09-01" @default.
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• W2098366973 title "Characterization of hMLH1 and hMSH2 Gene Dosage Alterations in Lynch Syndrome Patients" @default.
• W2098366973 cites W139509402 @default.
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