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Anja Wagner - One of the best experts on this subject based on the ideXlab platform.

  • a high incidence of msh6 mutations in Amsterdam Criteria ii negative families tested in a diagnostic setting
    Gut, 2008
    Co-Authors: Dewkoemar Ramsoekh, Dicky J. J. Halley, Monique E Van Leerdam, Wmn Dinjens, Ernst J Kuipers, Ewout W Steyerberg, Anja Wagner, Dennis Dooijes
    Abstract:

    Background and aims: In Lynch syndrome, the clinical phenotype in MSH6 mutation families differs from that in MLH1 and MSH2 families. Therefore, MSH6 mutation families are less likely to fulfil diagnostic Criteria such as the Amsterdam II Criteria (AC II) and the revised Bethesda guidelines (rBG), and will be underdiagnosed. The aim of the present study was to evaluate the contribution of MSH6 gene mutations in families that were analysed for Lynch syndrome in a diagnostic setting. Methods: Families that had molecular analysis for Lynch syndrome were included in this study. Complete molecular screening of the MLH1 , MSH2 and MSH6 genes was performed in all families. Microsatellite instability (MSI) and immunohistochemical (IHC) analysis was performed in almost all families. Clinical data were collected from medical records and family pedigrees. Results: A total of 108 families were included. MSI and IHC analysis was performed in 97 families, and in 40 an MSI-high phenotype with absent protein expression was found. Germline mutation analysis detected mutations in 23 families (7 MLH1 , 4 MSH2 and 12 MSH6 ). The majority of MSH6 families were AC II negative, but fulfilled the rBG. Conclusions: There is a high incidence of MSH6 mutations in families tested for Lynch syndrome in a diagnostic setting. Many of these families remain underdiagnosed using the AC II. The rBG are more useful to select these families for further analysis. However, to optimise the detection of MSH6 families, MSI and IHC analysis should also be performed in families with clustering of late-onset endometrial carcinoma.

  • molecular analysis of hereditary nonpolyposis colorectal cancer in the united states high mutation detection rate among clinically selected families and characterization of an american founder genomic deletion of the msh2 gene
    American Journal of Human Genetics, 2003
    Co-Authors: Anja Wagner, Juul T Wijnen, Alicia Barrows, Heleen M Van Der Klift, Patrick Franken, Paul Verkuijlen, Hidewaki Nakagawa, Marjan Geugien, Shantie Jaghmohanchangur, Cor Breukel
    Abstract:

    The identification of germline mutations in families with HNPCC is hampered by genetic heterogeneity and clinical variability. In previous studies, MSH2 and MLH1 mutations were found in approximately two-thirds of the Amsterdam-Criteria–positive families and in much lower percentages of the Amsterdam-Criteria–negative families. Therefore, a considerable proportion of HNPCC seems not to be accounted for by the major mismatch repair (MMR) genes. Does the latter result from a lack of sensitivity of mutation detection techniques, or do additional genes underlie the remaining cases? In this study we address these questions by thoroughly investigating a cohort of clinically selected North American families with HNPCC. We analyzed 59 clinically well-defined U.S. families with HNPCC for MSH2, MLH1, and MSH6 mutations. To maximize mutation detection, different techniques were employed, including denaturing gradient gel electrophoresis, Southern analysis, microsatellite instability, immunohistochemistry, and monoallelic expression analysis. In 45 (92%) of the 49 Amsterdam-Criteria–positive families and in 7 (70%) of the 10 Amsterdam-Criteria–negative families, a mutation was detected in one of the three analyzed MMR genes. Forty-nine mutations were in MSH2 or MLH1, and only three were in MSH6. A considerable proportion (27%) of the mutations were genomic rearrangements (12 in MSH2 and 2 in MLH1). Notably, a deletion encompassing exons 1–6 of MSH2 was detected in seven apparently unrelated families (12% of the total cohort) and was subsequently proven to be a founder. Screening of a second U.S. cohort with HNPCC from Ohio allowed the identification of two additional kindreds with the identical founder deletion. In the present study, we show that optimal mutation detection in HNPCC is achieved by combining accurate and expert clinical selection with an extensive mutation detection strategy. Notably, we identified a common North American deletion in MSH2, accounting for ∼10% of our cohort. Genealogical, molecular, and haplotype studies showed that this deletion represents a North American founder mutation that could be traced back to the 19th century.

  • atypical hnpcc owing to msh6 germline mutations analysis of a large dutch pedigree
    Journal of Medical Genetics, 2001
    Co-Authors: Anja Wagner, E J Meijersheijboer, W J F De Leeuw, C Tops, Annette H J T Brockervriends, C Van Der Meer, Yvonne M C Hendriks, Robert M.w. Hofstra, Hans Morreau, Dick Lindhout
    Abstract:

    Hereditary non-polyposis colorectal cancer (HNPCC) is the most common genetic susceptibility syndrome for colorectal cancer. HNPCC is most frequently caused by germline mutations in the DNA mismatch repair (MMR) genes MSH2 and MLH1. Recently, mutations in another MMR gene, MSH6 (also known as GTBP), have also been shown to result in HNPCC. Preliminary data indicate that the phenotype related to MSH6 mutations may diVer from the classical HNPCC caused by defects in MSH2 and MLH1. Here, we describe an extended Dutch HNPCC family not fulfilling the Amsterdam Criteria II and resulting from a MSH6 mutation. Overall, the penetrance of colorectal cancer appears to be significantly decreased (p 80%). Endometrial cancer is a frequent manifestation among female carriers (six out of 13 malignant tumours). Transitional cell carcinoma of the urinary tract is also relatively common in both male and female carriers (10% of the carriers). Moreover, the mean age of onset of both colorectal cancer (MSH6 v MSH2/MLH1 = 55 years v 44/41 years) and endometrial carcinomas (MSH6 v MSH2/MLH1 =5 5 years v 49/48 years) is delayed. As previously reported, we confirm that the pattern of microsatellite instability, in combination with immunohistochemical analysis, can predict the presence of a MSH6 germline defect. The detailed characterisation of the clinical phenotype of this kindred contributes to the establishment of genotypephenotype correlations in HNPCC owing to mutations in specific mismatch repair genes. (J Med Genet 2001;38:318‐322)

  • atypical hnpcc owing to msh6 germline mutations analysis of a large dutch pedigree
    Journal of Medical Genetics, 2001
    Co-Authors: Anja Wagner, E J Meijersheijboer, W J F De Leeuw, Annette H J T Brockervriends, Yvonne M C Hendriks, Robert M.w. Hofstra, Hans Morreau, C M J Tops, E Bik, C Van Der Meer
    Abstract:

    Hereditary non-polyposis colorectal cancer (HNPCC) is the most common genetic susceptibility syndrome for colorectal cancer. HNPCC is most frequently caused by germline mutations in the DNA mismatch repair (MMR) genes MSH2 and MLH1. Recently, mutations in another MMR gene, MSH6 (also known as GTBP), have also been shown to result in HNPCC. Preliminary data indicate that the phenotype related to MSH6 mutations may differ from the classical HNPCC caused by defects in MSH2 and MLH1. Here, we describe an extended Dutch HNPCC family not fulfilling the Amsterdam Criteria II and resulting from a MSH6 mutation. Overall, the penetrance of colorectal cancer appears to be significantly decreased (p 80%). Endometrial cancer is a frequent manifestation among female carriers (six out of 13 malignant tumours). Transitional cell carcinoma of the urinary tract is also relatively common in both male and female carriers (10% of the carriers). Moreover, the mean age of onset of both colorectal cancer (MSH6 v MSH2/MLH1 = 55 years v 44/41 years) and endometrial carcinomas (MSH6 v MSH2/MLH1 = 55 years v 49/48 years) is delayed. As previously reported, we confirm that the pattern of microsatellite instability, in combination with immunohistochemical analysis, can predict the presence of a MSH6 germline defect. The detailed characterisation of the clinical phenotype of this kindred contributes to the establishment of genotype-phenotype correlations in HNPCC owing to mutations in specific mismatch repair genes.

Robert M.w. Hofstra - One of the best experts on this subject based on the ideXlab platform.

  • atypical hnpcc owing to msh6 germline mutations analysis of a large dutch pedigree
    Journal of Medical Genetics, 2001
    Co-Authors: Anja Wagner, E J Meijersheijboer, W J F De Leeuw, C Tops, Annette H J T Brockervriends, C Van Der Meer, Yvonne M C Hendriks, Robert M.w. Hofstra, Hans Morreau, Dick Lindhout
    Abstract:

    Hereditary non-polyposis colorectal cancer (HNPCC) is the most common genetic susceptibility syndrome for colorectal cancer. HNPCC is most frequently caused by germline mutations in the DNA mismatch repair (MMR) genes MSH2 and MLH1. Recently, mutations in another MMR gene, MSH6 (also known as GTBP), have also been shown to result in HNPCC. Preliminary data indicate that the phenotype related to MSH6 mutations may diVer from the classical HNPCC caused by defects in MSH2 and MLH1. Here, we describe an extended Dutch HNPCC family not fulfilling the Amsterdam Criteria II and resulting from a MSH6 mutation. Overall, the penetrance of colorectal cancer appears to be significantly decreased (p 80%). Endometrial cancer is a frequent manifestation among female carriers (six out of 13 malignant tumours). Transitional cell carcinoma of the urinary tract is also relatively common in both male and female carriers (10% of the carriers). Moreover, the mean age of onset of both colorectal cancer (MSH6 v MSH2/MLH1 = 55 years v 44/41 years) and endometrial carcinomas (MSH6 v MSH2/MLH1 =5 5 years v 49/48 years) is delayed. As previously reported, we confirm that the pattern of microsatellite instability, in combination with immunohistochemical analysis, can predict the presence of a MSH6 germline defect. The detailed characterisation of the clinical phenotype of this kindred contributes to the establishment of genotypephenotype correlations in HNPCC owing to mutations in specific mismatch repair genes. (J Med Genet 2001;38:318‐322)

  • atypical hnpcc owing to msh6 germline mutations analysis of a large dutch pedigree
    Journal of Medical Genetics, 2001
    Co-Authors: Anja Wagner, E J Meijersheijboer, W J F De Leeuw, Annette H J T Brockervriends, Yvonne M C Hendriks, Robert M.w. Hofstra, Hans Morreau, C M J Tops, E Bik, C Van Der Meer
    Abstract:

    Hereditary non-polyposis colorectal cancer (HNPCC) is the most common genetic susceptibility syndrome for colorectal cancer. HNPCC is most frequently caused by germline mutations in the DNA mismatch repair (MMR) genes MSH2 and MLH1. Recently, mutations in another MMR gene, MSH6 (also known as GTBP), have also been shown to result in HNPCC. Preliminary data indicate that the phenotype related to MSH6 mutations may differ from the classical HNPCC caused by defects in MSH2 and MLH1. Here, we describe an extended Dutch HNPCC family not fulfilling the Amsterdam Criteria II and resulting from a MSH6 mutation. Overall, the penetrance of colorectal cancer appears to be significantly decreased (p 80%). Endometrial cancer is a frequent manifestation among female carriers (six out of 13 malignant tumours). Transitional cell carcinoma of the urinary tract is also relatively common in both male and female carriers (10% of the carriers). Moreover, the mean age of onset of both colorectal cancer (MSH6 v MSH2/MLH1 = 55 years v 44/41 years) and endometrial carcinomas (MSH6 v MSH2/MLH1 = 55 years v 49/48 years) is delayed. As previously reported, we confirm that the pattern of microsatellite instability, in combination with immunohistochemical analysis, can predict the presence of a MSH6 germline defect. The detailed characterisation of the clinical phenotype of this kindred contributes to the establishment of genotype-phenotype correlations in HNPCC owing to mutations in specific mismatch repair genes.

  • association of hereditary nonpolyposis colorectal cancer related tumors displaying low microsatellite instability with msh6 germline mutations
    American Journal of Human Genetics, 1999
    Co-Authors: Ying Wu, Maran J W Berends, Rob G J Mensink, Harry Hollema, Charles H C M Buys, Rolf H. Sijmons, J H Kleibeuker, Claudia Kempinga, Robert M.w. Hofstra
    Abstract:

    Hereditary nonpolyposis colorectal cancer (HNPCC) (Amsterdam Criteria) is often caused by mutations in mismatch repair (MMR) genes, and tumors of patients with HNPCC show microsatellite instability (MSI-high phenotype). Germline mutations of MMR genes have rarely been found in families that have HNPCC or suspected HNPCC and that do not show microsatellite instability (MSI-low phenotype). Therefore, an MSI-high phenotype is often used as an inclusion criterion for mutation testing of MMR genes. Correction of base-base mismatches is the major function of MSH6. Since mismatches present with an MSI-low phenotype, we assumed that the phenotype in patients with HNPCC-related tumors might be associated with MSH6 germline mutations. We divided 36 patients with suspected HNPCC into an MSI-low group (n=18) and an MSI-high group (n=18), on the basis of the results of MSI testing. Additionally, three unrelated patients from Amsterdam families with MSI-low tumors were investigated. All patients were screened for MSH2, MLH1, and MSH6 mutations. Four presumably causative MSH6 mutations were detected in the patients (22%) who had suspected HNPCC and MSI-low tumors. Furthermore, we detected one frameshift mutation in one of the three patients with HNPCC and MSI-low tumors. In the MSI-high group, one MSH6 missense mutation was found, but the same patient also had an MLH1 mutation, which may explain the MSI-high phenotype. These results suggest that MSH6 may be involved in a substantial proportion of patients with HNPCC or suspected HNPCC and MSI-low tumors. Our data emphasize that an MSI-low phenotype cannot be considered an exclusion criterion for mutation testing of MMR genes in general.

  • dna mismatch repair gene mutations in 55 kindreds with verified or putative hereditary non polyposis colorectal cancer
    Human Molecular Genetics, 1996
    Co-Authors: Minna Nystromlahti, Robert M.w. Hofstra, Charles H C M Buys, Anuliisa Moisio, Jan Osinga, Jukkapekka Mecklin, Heikki Jarvinen, Jaakko Leisti, Albert De La Chapelle, Paivi Peltomaki
    Abstract:

    The DNA mismatch repair genes MSH2 and MLH1 have been shown to account for a major share of hereditary non-polyposis colorectal cancer (HNPCC). We searched for germline mutations in these genes in 35 HNPCC kindreds fulfilling the Amsterdam diagnostic Criteria and in a further 20 kindreds with an average of four affected members per family but not meeting the formal Criteria. We first screened for truncations by reverse transcriptase (RT)-PCR. If no mutation was found, we screened genomic DNA by a novel application of two-dimensional (2-D) DNA electrophoresis that allows the simultaneous study of all exons of each gene. All abnormalities were followed up by sequencing. Eight different pathogenic germline mutations were found, two in MSH2 and six in MLH1. We report three major conclusions. First, these mutations together accounted for 86% (30/35) of the kindreds meeting the Amsterdam Criteria, but only 30% (6/20) of the remaining kindreds, suggesting differences in etiology. Second, MLH1 was involved in >90% (34/36) of kindreds with a known predisposing mutation, suggesting that mutations in the MLH1 gene are responsible for most HNPCC kindreds in Finland. Third, our results indicate that the successive application of RT-PCR and 2-D DNA electrophoresis is a sensitive and efficient method for mutation screening in typical HNPCC.

Hans F. A. Vasen - One of the best experts on this subject based on the ideXlab platform.

  • increased mutyh mutation frequency among dutch families with breast cancer and colorectal cancer
    Breast Cancer Research and Treatment, 2010
    Co-Authors: Marijke Wasielewski, Marjan M. Weiss, Carli M. J. Tops, Maartje Nielsen, Hans F. A. Vasen, Astrid A Out, Joyce Vermeulen, Ans M W Van Den Ouweland, Juul T Wijnen, Jan G M Klijn
    Abstract:

    Homozygous and compound heterozygous MUTYH mutations predispose for MUTYH-associated polyposis (MAP). The clinical phenotype of MAP is characterised by the multiple colorectal adenomas and colorectal carcinoma. We previously found that female MAP patients may also have an increased risk for breast cancer. Yet, the involvement of MUTYH mutations in families with both breast cancer and colorectal cancer is unclear. Here, we have genotyped the MUTYH p.Tyr179Cys, p.Gly396Asp and p.Pro405Leu founder mutations in 153 Dutch families with breast cancer patients and colorectal cancer patients. Families were classified as polyposis, revised Amsterdam Criteria positive (FCRC-AMS positive), revised Amsterdam Criteria negative (FCRC-AMS negative), hereditary breast and colorectal cancer (HBCC) and non-HBCC breast cancer families. As anticipated, biallelic MUTYH mutations were identified among 13% of 15 polyposis families, which was significantly increased compared to the absence of biallelic MUTYH mutations in the population (P = 0.0001). Importantly, six heterozygous MUTYH mutations were identified among non-polyposis families with breast and colorectal cancer. These mutations were identified specifically in FCRC-AMS negative and in HBCC breast cancer families (11% of 28 families and 4% of 74 families, respectively; P = 0.02 for both groups combined vs. controls). Importantly, the 11% MUTYH frequency among FCRC-AMS negative families was almost fivefold higher than the reported frequencies for FCRC-AMS negative families unselected for the presence of breast cancer patients (P = 0.03). Together, our results indicate that heterozygous MUTYH mutations are associated with families that include both breast cancer patients and colorectal cancer patients, independent of which tumour type is more prevalent in the family.

  • high risk of endometrial cancer in colorectal cancer kindred is pathognomonic for mmr mutation carriers
    Familial Cancer, 2009
    Co-Authors: Eli Marie Grindedal, Hans F. A. Vasen, Astrid Stormorken, Ignacio Blanco, Lovise Maehle, Neal Clark, Sara Gonzalez, Gabriel Capella, J Burn, Pal Moller
    Abstract:

    Endometrial cancer is frequent in MMR-mutation carriers. Estimates of annual incidence rates have, however, been based on retrospective studies. The purpose of our study was to prospectively assess the incidence rates of endometrial cancer in women either having a mutation in one of the four MMR genes MLH1, MSH2, MSH6 or PMS2 (Mut+) or belonging to families meeting the revised Amsterdam Criteria in which no MMR mutation was detected (Ams+). Eight out of 80 Mut+ (10%) contracted invasive endometrial cancer compared to 1/171 (0.6%) of the Ams+ (P = 0.0006). The annual incidence rate after first control was 2.5% in Mut+ and 0.2% in Ams+. Two of the 8 Mut+ women (25%) had synchronous gynaecological tumours. The numbers included did not allow for firm conclusions, but the results are in keeping with the notion that the inherited colon-endometrial cancer syndrome may be restricted to carriers of MMR mutations.

  • mutations predisposing to hereditary nonpolyposis colorectal cancer database and results of a collaborative study
    Gastroenterology, 1997
    Co-Authors: Paivi Peltomaki, Hans F. A. Vasen
    Abstract:

    Abstract BACKGROUND & AIMS: Germline mutations in four DNA mismatch repair genes are known to cause susceptibility to hereditary nonpolyposis colorectal cancer (HNPCC). The rapidly increasing information about these mutations needs to be collected and appropriately stored to facilitate further studies on the biological and clinical significance of the findings. METHODS: The International Collaborative Group on HNPCC has established a database of DNA mismatch repair gene mutations and polymorphisms. In this report, 126 predisposing mutations were analyzed. RESULTS: A majority of the mutations affected either the Mut L homologue (MLH) 1 (n = 75) or the Mut S homologue (MSH) 2 (n = 48) and were quite evenly distributed, with some clustering in MSH2 exon 12 and MLH1 exon 16. Most MSH2 mutations consisted of frameshift (60%) or nonsense changes (23%), whereas MLH1 was mainly affected by frameshift (40%) or missense alterations (31%). Although most mutations were unique, a few common recurring mutations were identified. Of the families studied (n = 202), 82% met the Amsterdam Criteria and 15% did not; the general mutation profile was similar in both groups. CONCLUSIONS: The construction of mutation profiles will facilitate the development of diagnostic strategies in HNPCC. (Gastroenterology 1997 Oct;113(4):1146-58)

  • hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam Criteria show extremely low frequency of mismatch repair gene mutations
    American Journal of Human Genetics, 1997
    Co-Authors: Juul T Wijnen, Hans F. A. Vasen, Meera P Khan, Heleen M Van Der Klift, Adri Mulder, Inge Van Leeuwencornelisse, Bert Bakker, Monique Losekoot, Pal Moller, Riccardo Fodde
    Abstract:

    Summary Hereditary nonpolyposis colorectal cancer (HNPCC) is a common autosomal dominant cancer-susceptibility condition characterized by early onset colorectal cancer. Germ-line mutations in one of four DNA mismatch repair (MMR) genes, hMSH2, hMLH1, hPMS1 , or hPMS2 , are known to cause HNPCC. Although many mutations in these genes have been found in HNPCC kindreds complying with the so-called Amsterdam Criteria, little is known about the involvement of these genes in families not satisfying these Criteria but showing clear-cut familial clustering of colorectal cancer and other cancers. Here, we applied denaturing gradient-gel electrophoresis to screen for hMSH2 and hMLH1 mutations in two sets of HNPCC families, one set comprising families strictly complying with the Amsterdam Criteria and another set in which at least one of the Criteria was not satisfied. Interestingly, hMSH2 and hMLH1 mutations were found in 49% of the kindreds fully complying with the Amsterdam Criteria, whereas a disease-causing mutation could be identified in only 8% of the families in which the Criteria were not satisfied fully. In correspondence with these findings, 4 of 6 colorectal tumors from patients belonging to kindreds meeting the Criteria showed microsat-ellite instability, whereas only 3 of 11 tumors from the other set of families demonstrated this instability. Although the number of tumors included in the study admittedly is small, the frequencies of mutations in the MMR genes show obvious differences between the two clinical sets of families. These results also emphasize the practical importance of the Amsterdam Criteria, which provide a valid clinical subdivision between families, on the basis of their chance of carrying an hMSH2 or an hMLH1 mutation, and which bear important consequences for genetic testing and counseling and for the management of colorectal cancer families.

Micaela Mathiak - One of the best experts on this subject based on the ideXlab platform.

  • spectrum and frequencies of mutations in msh2 and mlh1 identified in 1 721 german families suspected of hereditary nonpolyposis colorectal cancer
    International Journal of Cancer, 2005
    Co-Authors: Elisabeth Mangold, Christoph Engel, Waltraut Friedl, Micaela Mathiak, Constanze Pagenstecher, Reinhard Buettner, Markus Loeffler, Elke Holinskifeder, Yvonne Mullerkoch, Gisela Keller
    Abstract:

    Mutations in DNA MMR genes, mainly MSH2 and MLH1, account for the majority of HNPCC, an autosomal dominant predisposition to colorectal cancer and other malignancies. The evaluation of many questions regarding HNPCC requires clinically and genetically well-characterized HNPCC patient cohorts of reasonable size. One main focus of this multicenter study is the evaluation of the mutation spectrum and mutation frequencies in a large HNPCC cohort in Germany; 1,721 unrelated patients, mainly of German descent, who met the Bethesda Criteria were included in the study. In tumor samples of 1,377 patients, microsatellite analysis was successfully performed and the results were applied to select patients eligible for mutation analysis. In the patients meeting the strict Amsterdam Criteria (AC) for HNPCC, 72% of the tumors exhibited high microsatellite instability (MSI-H) while only 37% of the tumors from patients fulfilling the less stringent Criteria showed MSI-H; 454 index patients (406 MSI-H and 48 meeting the AC of whom no tumor samples were available) were screened for small mutations. In 134 index patients, a pathogenic MSH2 mutation, and in 118 patients, a pathogenic MLH1 mutation was identified (overall detection rate for pathogenic mutations 56%). One hundred sixty distinct mutations were detected, of which 86 are novel mutations. Noteworthy is that 2 mutations were over-represented in our patient series: MSH2,c.942+3A>T and MLH1,c.1489_1490insC, which account for 11% and 18% of the MSH2 and MLH1 mutations, respectively. A subset of 238 patients was screened for large genomic deletions. In 24 (10%) patients, a deletion was found. In 72 patients, only unspecified variants were found. Our findings demonstrate that preselection by microsatellite analysis substantially raises mutation detection rates in patients not meeting the AC. As a mutation detection strategy for German HNPCC patients, we recommend to start with screening for large genomic deletions and to continue by screening for common mutations in exon 5 of MSH2 and exon 13 of MLH1 before searching for small mutations in the remaining exons. © 2005 Wiley-Liss, Inc.

  • spectrum and frequencies of mutations in msh2 and mlh1 identified in 1 721 german families suspected of hereditary nonpolyposis colorectal cancer
    International Journal of Cancer, 2005
    Co-Authors: Elisabeth Mangold, Christoph Engel, Waltraut Friedl, Micaela Mathiak, Constanze Pagenstecher, Reinhard Buettner, Markus Loeffler, Elke Holinskifeder, Yvonne Mullerkoch, Gisela Keller
    Abstract:

    Mutations in DNA MMR genes, mainly MSH2 and MLH1, account for the majority of HNPCC, an autosomal dominant predisposition to colorectal cancer and other malignancies. The evaluation of many questions regarding HNPCC requires clinically and genetically well-characterized HNPCC patient cohorts of reasonable size. One main focus of this multicenter study is the evaluation of the mutation spectrum and mutation frequencies in a large HNPCC cohort in Germany; 1,721 unrelated patients, mainly of German descent, who met the Bethesda Criteria were included in the study. In tumor samples of 1,377 patients, microsatellite analysis was successfully performed and the results were applied to select patients eligible for mutation analysis. In the patients meeting the strict Amsterdam Criteria (AC) for HNPCC, 72% of the tumors exhibited high microsatellite instability (MSI-H) while only 37% of the tumors from patients fulfilling the less stringent Criteria showed MSI-H; 454 index patients (406 MSI-H and 48 meeting the AC of whom no tumor samples were available) were screened for small mutations. In 134 index patients, a pathogenic MSH2 mutation, and in 118 patients, a pathogenic MLH1 mutation was identified (overall detection rate for pathogenic mutations 56%). One hundred sixty distinct mutations were detected, of which 86 are novel mutations. Noteworthy is that 2 mutations were over-represented in our patient series: MSH2,c.942+3A>T and MLH1,c.1489_1490insC, which account for 11% and 18% of the MSH2 and MLH1 mutations, respectively. A subset of 238 patients was screened for large genomic deletions. In 24 (10%) patients, a deletion was found. In 72 patients, only unspecified variants were found. Our findings demonstrate that preselection by microsatellite analysis substantially raises mutation detection rates in patients not meeting the AC. As a mutation detection strategy for German HNPCC patients, we recommend to start with screening for large genomic deletions and to continue by screening for common mutations in exon 5 of MSH2 and exon 13 of MLH1 before searching for small mutations in the remaining exons.

  • hereditary nonpolyposis colorectal cancer frequent occurrence of large genomic deletions in msh2 and mlh1 genes
    International Journal of Cancer, 2003
    Co-Authors: Yaping Wang, Waltraut Friedl, Christof Lamberti, Matthias Jungck, Micaela Mathiak, Constanze Pagenstecher, Peter Propping, Elisabeth Mangold
    Abstract:

    Hereditary nonpolyposis colorectal cancer (HNPCC) is often caused by a deficiency in DNA mismatch repair. By using conventional methods of mutation analysis, point mutations in the DNA mismatch repair genes MSH2 and MLH1 have been detected in up to 64% of patients suspected of HNPCC. However, large genomic deletions cannot be detected by these methods. In our study, we applied a semiquantitative multiplex PCR to detect the proportion of large deletions in patients meeting the Bethesda Criteria whose tumours exhibited microsatellite instability (MSI). Of 368 unrelated patients, 180 exhibited MSI. In these patients, 68 disease-causing point mutations (38%) had previously been detected in the MSH2 and MLH1 genes by SSCP, heteroduplex analysis or DHPLC followed by direct sequencing. The remaining 112 patients (including 24 patients with rare missense or other unclarified variants) were examined for large deletions. We identified deletions in 19 patients (10.6%); 11/19 (58%) deletions were located in MSH2 and 8/19 (42%) in MLH1, respectively. The size of deletions ranged from 1 exon to a deletion of a whole gene. Five breakpoints of deletions were sequenced; Alu-repetitive elements were involved in all of them. In patients meeting the Amsterdam Criteria the proportion of large deletions was 12.6%. A similar proportion of deletions was found in the group of patients with a positive family history for colorectal cancer and MSI tumours, not meeting the Amsterdam Criteria. The results of our study suggest that large genomic deletions in both MSH2 and MLH1 genes play a considerable role in the pathogenesis of HNPCC and should be part of the routine HNPCC mutation detection protocols.

  • muir torre phenotype has a frequency of dna mismatch repair gene mutations similar to that in hereditary nonpolyposis colorectal cancer families defined by the Amsterdam Criteria
    American Journal of Human Genetics, 1998
    Co-Authors: Roland Kruse, Yaping Wang, Christof Lamberti, Matthias Jungck, Micaela Mathiak, Arno Rutten, Hamid Reza Hosseinymalayeri, Corina Ruelfs, Thomas Ruzicka, Wolfgang Hartschuh
    Abstract:

    Muir-Torre syndrome (MTS) is an autosomal dominant disease defined by the coincidence of at least one sebaceous skin tumor and one internal malignancy. About half of MTS patients are affected by colorectal cancer. In a subgroup of MTS patients the disease has an underlying DNA mismatch-repair (MMR) defect and thus is allelic to hereditary nonpolyposis colorectal cancer (HNPCC). The purpose of this study was to examine to what extent germ-line mutations in DNA MMR genes are the underlying cause of the MTS phenotype. We ascertained 16 MTS patients with sebaceous skin tumors and colorectal cancer, and we examined their skin and visceral tumors for microsatellite instability. All the patients exhibited high genomic instability in at least one tumor. The search for germ-line mutations in the hMSH2 and hMLH1 genes in 13 of the MTS patients revealed truncating mutations in 9 (69%): eight mutations in the hMSH2 gene and one in the hMLH1 gene. This is the first systematic search for germ-line mutations in patients ascertained on the basis of sebaceous skin tumors. Our results indicate that (1) MTS patients exhibit significantly more mutations in the hMSH2 gene than in the hMLH1 gene; and (2) the subpopulation of MTS patients who are also affected by colorectal cancer, irrespective of family history and age at onset of tumors, may have a likelihood for an underlying DNA MMR defect similar to that for patients with a family history fulfilling the strict clinical Criteria for HNPCC.

Jonathan P Terdiman - One of the best experts on this subject based on the ideXlab platform.

  • gynecologic cancer as a sentinel cancer for women with hereditary nonpolyposis colorectal cancer syndrome
    Obstetrics & Gynecology, 2005
    Co-Authors: Mai Dinh, Leemay Chen, Sapna Syngal, Wendy Kohlmann, Patrice Watson, Jane Green, Prathap Bandipalliam, Brian Allen, Peggy Conrad, Jonathan P Terdiman
    Abstract:

    OBJECTIVE: Women with hereditary nonpolyposis colorectal cancer syndrome have a 40 - 60% lifetime risk for colon cancer, a 40 - 60% lifetime risk for endometrial cancer, and a 12% lifetime risk for ovarian cancer. A number ofwomen with hereditary nonpolyposis colorectal cancer syndrome will have more than one cancer in their lifetime. The purpose of this study was to estimate whether women with hereditary nonpolyposis colorectal cancer syndrome who develop 2 primary cancers present with gynecologic or colon cancer as their sentinel cancer. METHODS: Women whose families fulfilled Amsterdam Criteria for hereditary nonpolyposis colorectal cancer syndrome and who developed 2 primary colorectal/gynecologic cancers in their lifetime were identified from 5 large hereditary nonpolyposis colorectal cancer syndrome registries. Information on age at cancer diagnoses and which cancer (colon cancer or endometrial cancer/ovarian cancer) developed first was obtained. RESULTS: A total of 117 women with dual primary cancers from 223 Amsterdam families were identified. In 16 women, colon cancer and endometrial cancer/ovarian cancer were diagnosed simultaneously. Of the remaining 101 women, 52 (51%) women had an endometrial or ovarian cancer diagnosed first. Forty-nine (49%) women had a colon cancer diagnosed first. For women who developed endometrial cancer/ovarian cancer first, mean age at diagnosis of endometrial cancer/ovarian cancer was 44. For women who developed colon cancer first, the mean age at diagnosis of colon cancer was 40. CONCLUSION: In this large series of women with hereditary nonpolyposis colorectal cancer syndrome who developed 2 primary colorectal/gynecologic cancers, endometrial cancer/ovarian cancer was the sentinel cancer, preceding the development of colon cancer, in half of the cases. Therefore, gynecologists and gynecologic oncologists play a pivotal role in the identification of women with hereditary nonpolyposis colorectal cancer syndrome.

  • efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testing
    Gastroenterology, 2001
    Co-Authors: Jonathan P Terdiman, Peggy Conrad, James R Gum, Glenn Miller, Vivian Weinberg, Suzanne C Crawley, Theodore R Levin, Cynthia Reeves, Anna Schmitt, Michael Hepburn
    Abstract:

    Abstract Background & Aims: The optimal strategy for the detection of hereditary nonpolyposis colorectal cancer (HNPCC) gene carriers remains uncertain. We evaluated whether microsatellite instability (MSI) analysis or MSH2 and MLH1 protein immunostaining of tumors will screen individuals efficiently for germline MSH2 and MLH1 testing. Methods: We performed a case-series study of 114 eligible families enrolled in our high-risk colorectal cancer (CRC) registry. Medical history data were collected on probands and relatives. MSI analysis was performed on proband tumors, and MSH2 and MLH1 protein immunostaining was assessed. Denaturing gradient gel electrophoresis was used to identify germline MSH2 or MLH1 mutations in probands found to have tumors with high-frequency MSI. Results: Tumor tissue and adequate clinical data were available in 109 of the 114 families. Amsterdam Criteria and Bethesda guidelines were met by 23% and 70% of the families, respectively. High-frequency MSI was identified in the proband tumors in 47 of the 109 families (43%). Germline MSH2 and MLH1 gene testing was carried out in the probands of 32 of 47 families with MSI-H tumors. Mutations were detected in 16 families (9 in MSH2 and 7 in MLH1 ) and sequence variants of uncertain significance in 5 families (1 in MSH2 and 4 in MLH1 ). Germline mutations or sequence variants of uncertain significance were detected in 15 of 19 (79%) of our Amsterdam families and in 6 of 13 (46%) of our non-Amsterdam families with MSI-H tumors. MSH2 and MLH1 protein immunostaining was assessed in 38 of the 47 MSI-H tumors. Unequivocal loss of hMLH1 expression was found in 20 tumors and loss of MSH2 expression in 9 tumors. Corresponding loss of protein expression was seen in 17 of 18 (94%) of tumors from probands with germline mutations or variants. Conclusions: The detection of high-frequency MSI or the loss of MSH2 or MLH1 immunostaining in CRCs are both useful Criteria for selecting high-risk patients who should be tested for germline mutations in MSH2 or MLH1 . GASTROENTEROLOGY 2001;120:21-30