Skip to main content
Erschienen in: Familial Cancer 4/2011

01.12.2011

Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals

verfasst von: Mev Dominguez Valentin, Felipe Carneiro da Silva, Erika Maria Monteiro dos Santos, Bianca Garcia Lisboa, Ligia Petrolini de Oliveira, Fabio de Oliveira Ferreira, Israel Gomy, Wilson Toshihiko Nakagawa, Samuel Aguiar Junior, Mariana Redal, Carlos Vaccaro, Adriana Della Valle, Carlos Sarroca, Dirce Maria Carraro, Benedito Mauro Rossi

Erschienen in: Familial Cancer | Ausgabe 4/2011

Einloggen, um Zugang zu erhalten

Abstract

Lynch syndrome (LS) is an autosomal dominant syndrome that predisposes individuals to development of cancers early in life. These cancers are mainly the following: colorectal, endometrial, ovarian, small intestine, stomach and urinary tract cancers. LS is caused by germline mutations in DNA mismatch repair genes (MMR), mostly MLH1 and MSH2, which are responsible for more than 85% of known germline mutations. To search for germline mutations in MLH1 and MSH2 genes in 123 unrelated South American suspected LS patients (Bethesda or Amsterdam Criteria) DNA was obtained from peripheral blood, and PCR was performed followed by direct sequencing in both directions of all exons and intron–exon junctions regions of the MLH1 and MSH2 genes. MLH1 or MSH2 pathogenic mutations were found in 28.45% (34/123) of the individuals, where 25/57 (43.85%) fulfilled Amsterdam I, II and 9/66 (13.63%) the Bethesda criteria. The mutations found in both genes were as follows: nonsense (35.3%), frameshift (26.47%), splicing (23.52%), and missense (9%). Thirteen alterations (35.14%) were described for the first time. The data reported in this study add new information about MLH1 and MSH2 gene mutations and contribute to better characterize LS in Brazil, Uruguay and Argentina. The high rate of novel mutations demonstrates the importance of defining MLH1 and MSH2 mutations in distinct LS populations.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Talseth-Palmer BA, McPhillips M, Groombridge C, Spigelman A, Scott RJ (2010) MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer. Hered Cancer Clin Pract 8:5PubMedCrossRef Talseth-Palmer BA, McPhillips M, Groombridge C, Spigelman A, Scott RJ (2010) MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer. Hered Cancer Clin Pract 8:5PubMedCrossRef
2.
Zurück zum Zitat Lynch HT, Shaw T, Lynch J, Grady W (2005) Histórico do câncer colorretal hereditário sem polipose: Síndrome de Lynch. In: Rossi B, Nakagawa W, Ferreira F, Aguiar Junior S, Lopes A (eds) Câncer de cólon, reto e ânus. Lemar/Tecmedd, pp 575–593 Lynch HT, Shaw T, Lynch J, Grady W (2005) Histórico do câncer colorretal hereditário sem polipose: Síndrome de Lynch. In: Rossi B, Nakagawa W, Ferreira F, Aguiar Junior S, Lopes A (eds) Câncer de cólon, reto e ânus. Lemar/Tecmedd, pp 575–593
3.
Zurück zum Zitat Chialina SG, Fornes C, Landi C, de la Vega Elena CD, Nicolorich MV, Dourisboure RJ, Solano A, Solis EA (2006) Microsatellite instability analysis in hereditary non-polyposis colon cancer using the Bethesda consensus panel of microsatellite markers in the absence of proband normal tissue. BMC Med Genet 7:1–5CrossRef Chialina SG, Fornes C, Landi C, de la Vega Elena CD, Nicolorich MV, Dourisboure RJ, Solano A, Solis EA (2006) Microsatellite instability analysis in hereditary non-polyposis colon cancer using the Bethesda consensus panel of microsatellite markers in the absence of proband normal tissue. BMC Med Genet 7:1–5CrossRef
4.
Zurück zum Zitat Vasen HF, Mecklin JP, Khan PM, Lynch HT (1991) The international collaborative group on hereditary non-polyposis colorectal cancer (ICG-HNPCC). Dis Colon Rectum 34:424–425PubMedCrossRef Vasen HF, Mecklin JP, Khan PM, Lynch HT (1991) The international collaborative group on hereditary non-polyposis colorectal cancer (ICG-HNPCC). Dis Colon Rectum 34:424–425PubMedCrossRef
5.
Zurück zum Zitat Vasen HF, Watson P, Mecklin JP, Lynch HT (1999) New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 116:1453–1456PubMedCrossRef Vasen HF, Watson P, Mecklin JP, Lynch HT (1999) New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 116:1453–1456PubMedCrossRef
6.
Zurück zum Zitat Rodriguez-Bigas MA, Boland CR, Hamilton SR et al (1997) A national cancer institute workshop on hereditary nonpolyposis colorectal cancer syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 89:1758–1762PubMedCrossRef Rodriguez-Bigas MA, Boland CR, Hamilton SR et al (1997) A national cancer institute workshop on hereditary nonpolyposis colorectal cancer syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 89:1758–1762PubMedCrossRef
7.
Zurück zum Zitat Umar A, Boland CR, Terdiman JP et al (2004) Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268PubMedCrossRef Umar A, Boland CR, Terdiman JP et al (2004) Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268PubMedCrossRef
8.
Zurück zum Zitat Yap HL, Chieng WS, Lim JR et al (2009) Recurring MLH1 deleterious mutations in unrelated Chinese Lynch syndrome families in Singapore. Fam Cancer 8:85–94PubMedCrossRef Yap HL, Chieng WS, Lim JR et al (2009) Recurring MLH1 deleterious mutations in unrelated Chinese Lynch syndrome families in Singapore. Fam Cancer 8:85–94PubMedCrossRef
9.
Zurück zum Zitat Da Silva FC, Dominguez MV, Ferreira FO et al (2009) Mismatch repair genes in Lynch syndrome: a review. São Paulo Med J 127:46–51PubMedCrossRef Da Silva FC, Dominguez MV, Ferreira FO et al (2009) Mismatch repair genes in Lynch syndrome: a review. São Paulo Med J 127:46–51PubMedCrossRef
10.
Zurück zum Zitat Ou J, Niessen RC, Lützen A et al (2007) Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes. Hum Mutat 28:1047–1054PubMedCrossRef Ou J, Niessen RC, Lützen A et al (2007) Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes. Hum Mutat 28:1047–1054PubMedCrossRef
11.
Zurück zum Zitat Ou J, Niessen RC, Vonk J et al (2008) A database to support the interpretation of human mismatch repair gene variants. Hum Mutat 29:1337–1341PubMedCrossRef Ou J, Niessen RC, Vonk J et al (2008) A database to support the interpretation of human mismatch repair gene variants. Hum Mutat 29:1337–1341PubMedCrossRef
12.
Zurück zum Zitat Couch FJ, Rasmussen LJ, Hofstra R et al (2008) Assessment of functional effects of unclassified genetic variants. Hum Mutat 29:1314–1326PubMedCrossRef Couch FJ, Rasmussen LJ, Hofstra R et al (2008) Assessment of functional effects of unclassified genetic variants. Hum Mutat 29:1314–1326PubMedCrossRef
13.
Zurück zum Zitat Baudi F, Fersini G, Lavecchia A et al (2005) A novel missense germline mutation in exon 2 of the hMSH2 gene in a HNPCC family from Southern Italy. Cancer Lett 223:285–291PubMedCrossRef Baudi F, Fersini G, Lavecchia A et al (2005) A novel missense germline mutation in exon 2 of the hMSH2 gene in a HNPCC family from Southern Italy. Cancer Lett 223:285–291PubMedCrossRef
14.
Zurück zum Zitat Dominguez MV, Bastos EP, Santos EM et al (2008) Two new MLH1 germline mutations in Brazilian Lynch syndrome families. Int J Colorectal Dis 23:1263–1264PubMedCrossRef Dominguez MV, Bastos EP, Santos EM et al (2008) Two new MLH1 germline mutations in Brazilian Lynch syndrome families. Int J Colorectal Dis 23:1263–1264PubMedCrossRef
15.
Zurück zum Zitat Greenblatt MS, Brody LC, Foulkes WD et al (2008) Locus-specific database and recommendations to strengthen their contribution to the classification of variants in cancer susceptibility genes. Hum Mutat 29:1273–1281PubMedCrossRef Greenblatt MS, Brody LC, Foulkes WD et al (2008) Locus-specific database and recommendations to strengthen their contribution to the classification of variants in cancer susceptibility genes. Hum Mutat 29:1273–1281PubMedCrossRef
16.
Zurück zum Zitat Tunca B, Pedroni M, Cecener G et al (2010) Analysis of mismatch repair gene mutations in Turkish HNPCC patients. Fam Cancer 9(3):365–376PubMedCrossRef Tunca B, Pedroni M, Cecener G et al (2010) Analysis of mismatch repair gene mutations in Turkish HNPCC patients. Fam Cancer 9(3):365–376PubMedCrossRef
17.
Zurück zum Zitat Mangold E, Pagenstecher C, Friedl W et al (2005) Tumours from MSH2 mutation carriers show loss of MSH2 expression but many tumours from MLH1 mutation carriers exhibit weak positive MLH1 staining. J Pathol 207:385–395PubMedCrossRef Mangold E, Pagenstecher C, Friedl W et al (2005) Tumours from MSH2 mutation carriers show loss of MSH2 expression but many tumours from MLH1 mutation carriers exhibit weak positive MLH1 staining. J Pathol 207:385–395PubMedCrossRef
18.
Zurück zum Zitat Martínez-Bouzas C, Beristain E, Ojembarrena E et al (2009) A study on MSH2 and MLH1 mutations in hereditary nonpolyposis colorectal cancer families from the Basque Country, describing four new germline mutations. Fam Cancer 8:533–539PubMedCrossRef Martínez-Bouzas C, Beristain E, Ojembarrena E et al (2009) A study on MSH2 and MLH1 mutations in hereditary nonpolyposis colorectal cancer families from the Basque Country, describing four new germline mutations. Fam Cancer 8:533–539PubMedCrossRef
19.
Zurück zum Zitat Tang R, Hsiung C, Wang JY et al (2009) Germ line MLH1 and MSH2 mutations in Taiwanese Lynch syndrome families: characterization of a founder genomic mutation in the MLH1 gene. Clin Genet 75:334–345PubMedCrossRef Tang R, Hsiung C, Wang JY et al (2009) Germ line MLH1 and MSH2 mutations in Taiwanese Lynch syndrome families: characterization of a founder genomic mutation in the MLH1 gene. Clin Genet 75:334–345PubMedCrossRef
20.
Zurück zum Zitat Pineda M, González S, Lázaro C et al (2010) Detection of genetic alterations in hereditary colorectal cancer screening. Mutat Res 693(1–2):19–31PubMed Pineda M, González S, Lázaro C et al (2010) Detection of genetic alterations in hereditary colorectal cancer screening. Mutat Res 693(1–2):19–31PubMed
21.
Zurück zum Zitat Perera T, Wijesuriya RE, Suraweera PH et al (2008) Prevalence of colorectal cancer and survival in patients from the Gampaha District, North Colombo region. Ceylon Med J 53:17–21PubMedCrossRef Perera T, Wijesuriya RE, Suraweera PH et al (2008) Prevalence of colorectal cancer and survival in patients from the Gampaha District, North Colombo region. Ceylon Med J 53:17–21PubMedCrossRef
22.
Zurück zum Zitat Nyström-Lahti M, Wu Y, Moisio AL et al (1996) DNA mismatch repair gene mutations in 55 kindreds with verified or putative hereditary non-polyposis colorectal cancer. Hum Mol Genet 5:763–769PubMedCrossRef Nyström-Lahti M, Wu Y, Moisio AL et al (1996) DNA mismatch repair gene mutations in 55 kindreds with verified or putative hereditary non-polyposis colorectal cancer. Hum Mol Genet 5:763–769PubMedCrossRef
24.
Zurück zum Zitat Rossi BM, Lopes A, Oliveira Ferreira F et al (2002) hMLH1 and hMSH2 gene mutation in Brazilian families with suspected hereditary nonpolyposis colorectal cancer. Ann Surg Oncol 9:555–561PubMed Rossi BM, Lopes A, Oliveira Ferreira F et al (2002) hMLH1 and hMSH2 gene mutation in Brazilian families with suspected hereditary nonpolyposis colorectal cancer. Ann Surg Oncol 9:555–561PubMed
25.
Zurück zum Zitat Sarroca C, Valle AD, Fresco R et al (2005) Frequency of hereditary non-polyposis colorectal cancer among Uruguayan patients with colorectal cancer. Clin Genet 68:80–87PubMedCrossRef Sarroca C, Valle AD, Fresco R et al (2005) Frequency of hereditary non-polyposis colorectal cancer among Uruguayan patients with colorectal cancer. Clin Genet 68:80–87PubMedCrossRef
26.
Zurück zum Zitat Giraldo A, Gómez A, Salguero G et al (2005) MLH1 and MSH2 mutations in Colombian families with hereditary nonpolyposis colorectal cancer (Lynch syndrome)- description of four novel mutations. Fam Cancer 4:285–290PubMedCrossRef Giraldo A, Gómez A, Salguero G et al (2005) MLH1 and MSH2 mutations in Colombian families with hereditary nonpolyposis colorectal cancer (Lynch syndrome)- description of four novel mutations. Fam Cancer 4:285–290PubMedCrossRef
27.
Zurück zum Zitat Olilla S, Bebek DD, Jiricny J et al (2008) Mechanisms of pathogenicity in Human MSH2 missense mutants. Hum Mutat 29:1355–1363CrossRef Olilla S, Bebek DD, Jiricny J et al (2008) Mechanisms of pathogenicity in Human MSH2 missense mutants. Hum Mutat 29:1355–1363CrossRef
28.
Zurück zum Zitat Lastella P, Surdo NC, Resta N et al (2006) In silico and in vivo splicing analysis of MLH1 and MSH2 missense mutations shows exon- and tissue-specific effects. BMC Genomics 7:243PubMedCrossRef Lastella P, Surdo NC, Resta N et al (2006) In silico and in vivo splicing analysis of MLH1 and MSH2 missense mutations shows exon- and tissue-specific effects. BMC Genomics 7:243PubMedCrossRef
29.
Zurück zum Zitat Peltomäki P, Vasen HFA (1997) The international collaborative group on hereditary nonpolyposis colorectal cancer. Mutations predisposing to hereditary nonpolyposis colorectal cancer: Database and results of a collaborative study. Gastroenterology 113:1146–1158PubMedCrossRef Peltomäki P, Vasen HFA (1997) The international collaborative group on hereditary nonpolyposis colorectal cancer. Mutations predisposing to hereditary nonpolyposis colorectal cancer: Database and results of a collaborative study. Gastroenterology 113:1146–1158PubMedCrossRef
30.
Zurück zum Zitat Apessos A, Mihalatos M, Danielidis I et al (2005) hMSH2 is the most commonly mutated MMR gene in a cohort of Greek HNPCC patients. Br J Cancer 92:396–404PubMed Apessos A, Mihalatos M, Danielidis I et al (2005) hMSH2 is the most commonly mutated MMR gene in a cohort of Greek HNPCC patients. Br J Cancer 92:396–404PubMed
31.
Zurück zum Zitat Sjöblom T, Jones S, Wood LD et al (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314:268–274PubMedCrossRef Sjöblom T, Jones S, Wood LD et al (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314:268–274PubMedCrossRef
33.
Zurück zum Zitat Rouleau E, Lefol C, Bourdon V et al (2009) Quantitative PCR high-resolution melting (qPCR-HRM) curve analysis, a new approach to simultaneously screen point mutations and large rearrangements: application to MLH1 germline mutations in Lynch syndrome. Hum Mutat 30:867–875PubMedCrossRef Rouleau E, Lefol C, Bourdon V et al (2009) Quantitative PCR high-resolution melting (qPCR-HRM) curve analysis, a new approach to simultaneously screen point mutations and large rearrangements: application to MLH1 germline mutations in Lynch syndrome. Hum Mutat 30:867–875PubMedCrossRef
34.
Zurück zum Zitat Isidro G, Veiga I, Matos P et al (2000) Four novel MSH2/MLH1 gene mutations in Portuguese HNPCC families. Hum Mutat 15:116PubMedCrossRef Isidro G, Veiga I, Matos P et al (2000) Four novel MSH2/MLH1 gene mutations in Portuguese HNPCC families. Hum Mutat 15:116PubMedCrossRef
35.
Zurück zum Zitat Lage PA, Albuquerque C, Sousa RG et al (2004) Association of colonic and endometrial carcinomas in Portuguese families with hereditary nonpolyposis colorectal carcinoma significantly increases the probability of detecting a pathogenic mutation in mismatch repair genes, primarily the MSH2 gene. Cancer 101:172–177PubMedCrossRef Lage PA, Albuquerque C, Sousa RG et al (2004) Association of colonic and endometrial carcinomas in Portuguese families with hereditary nonpolyposis colorectal carcinoma significantly increases the probability of detecting a pathogenic mutation in mismatch repair genes, primarily the MSH2 gene. Cancer 101:172–177PubMedCrossRef
36.
Zurück zum Zitat Ewald J, Rodrigue CM, Mourra N et al (2007) Immunohistochemical staining for mismatch repair proteins, and its relevance in the diagnosis of hereditary non-polyposis colorectal cancer. British J surg 94:1020–1027CrossRef Ewald J, Rodrigue CM, Mourra N et al (2007) Immunohistochemical staining for mismatch repair proteins, and its relevance in the diagnosis of hereditary non-polyposis colorectal cancer. British J surg 94:1020–1027CrossRef
37.
Zurück zum Zitat Terdiman JP, Levin TR, Allen BA et al (2002) Hereditary nonpolyposis colorectal cancer in young colorectal cancer patients: high-risk clinic versus population-based registry. Gastroenterology 122:940–947PubMedCrossRef Terdiman JP, Levin TR, Allen BA et al (2002) Hereditary nonpolyposis colorectal cancer in young colorectal cancer patients: high-risk clinic versus population-based registry. Gastroenterology 122:940–947PubMedCrossRef
38.
Zurück zum Zitat Rodrigues FC, Kawasaki-Oyama RS, Fo JF et al (2003) Analysis of CDKN1A polymorphisms: markers of cancer susceptibility? Cancer Genet Cytogenet 142:92–98PubMedCrossRef Rodrigues FC, Kawasaki-Oyama RS, Fo JF et al (2003) Analysis of CDKN1A polymorphisms: markers of cancer susceptibility? Cancer Genet Cytogenet 142:92–98PubMedCrossRef
39.
Zurück zum Zitat Martinez SL, Kolodner RD (2010) Functional analysis of human mismatch repair gene mutations identifies weak alleles and polymorphisms capable of polygenic interactions. PNAS 107:5070–5075PubMedCrossRef Martinez SL, Kolodner RD (2010) Functional analysis of human mismatch repair gene mutations identifies weak alleles and polymorphisms capable of polygenic interactions. PNAS 107:5070–5075PubMedCrossRef
40.
Zurück zum Zitat Kámory E, Tanyi M, Kolacsek O et al (2006) Two germline alterations in mismatch repair genes found in a HNPCC patient with poor family history. Pathol Oncol Res 12:228–233PubMedCrossRef Kámory E, Tanyi M, Kolacsek O et al (2006) Two germline alterations in mismatch repair genes found in a HNPCC patient with poor family history. Pathol Oncol Res 12:228–233PubMedCrossRef
41.
Zurück zum Zitat Wimmer K, Etzler J (2008) Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Hum Genet 124:105–122PubMedCrossRef Wimmer K, Etzler J (2008) Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Hum Genet 124:105–122PubMedCrossRef
Metadaten
Titel
Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals
verfasst von
Mev Dominguez Valentin
Felipe Carneiro da Silva
Erika Maria Monteiro dos Santos
Bianca Garcia Lisboa
Ligia Petrolini de Oliveira
Fabio de Oliveira Ferreira
Israel Gomy
Wilson Toshihiko Nakagawa
Samuel Aguiar Junior
Mariana Redal
Carlos Vaccaro
Adriana Della Valle
Carlos Sarroca
Dirce Maria Carraro
Benedito Mauro Rossi
Publikationsdatum
01.12.2011
Verlag
Springer Netherlands
Erschienen in
Familial Cancer / Ausgabe 4/2011
Print ISSN: 1389-9600
Elektronische ISSN: 1573-7292
DOI
https://doi.org/10.1007/s10689-011-9461-y

Weitere Artikel der Ausgabe 4/2011

Familial Cancer 4/2011 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.