Abstract
MYH associated polyposis is a hereditary syndrome responsible for early colorectal cancer with a distinct genetic pathway from the Familial Adenomatous Polyposis or the Hereditary Non Polyposis Colorectal Cancer syndrome. We have studied a family with three members bearing a biallelic mutation in MYH at c.1185_1186dup. One patient who developed colon cancer had loss of expression of MLH1 on tumoral tissue and microsatellite instability (MSI) phenotype. Analysis of MLH1 based on his blood sample revealed no germline mutation or large genomic deletion. No methylation of the promoter was identified in tumoral DNA. No transversion mutations were identified in APC or KRAS in tumor DNA of this patient. Loss of expression of MLH1 was due to a transversion in intron 7 at position +5 (c.588 + 5G > T) leading to a complete deletion of exon 7 at the RNA level. This observation demonstrates that MLH1 can be a target of MYH transversions leading to MSI phenotype.
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References
Cunningham JM, Christensen ER, Tester DJ, Kim CY, Roche PC, Burgart LJ et al (1998) Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res 58:3455–3460
Parc Y, Gueroult S, Mourra N, Serfaty L, Flejou JF, Tiret E et al (2004) Prognostic significance of microsatellite instability determined by immunohistochemical staining of MSH2 and MLH1 in sporadic T3N0M0 colon cancer. Gut 53:371–375
Al-Tassan N, Chmiel NH, Maynard J et al (2002) Inherited variants of MYH associated with somatic G:C → T:A mutations in colorectal tumors. Nat Genet 30(2):227–232
Stone JG, Robertson D, Houlston RS (2001) Immunohistochemistry for MSH2, MHL1: a method for identifying mismatch repair deficient colorectal cancer. J Clin Pathol 54(6):484–487
Colebatch A, Hitchins M, Williams R, Meagher A, Hawkins NJ, Ward RL (2006) The role of MYH and microsatellite instability in the development of sporadic colorectal cancer. Br J Cancer 95(9):1239–1243
Kane MF, Loda M, Gaida GM et al (1997) Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 57(5):808–811
Herman JG, Umar A, Polyak K et al (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 95(12):6870–6875
Deng G, Bell I, Crawley S et al (2004) BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clin Cancer Res 10(1 Pt 1):191–195
Domingo E, Laiho P, Ollikainen M et al (2004) BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J Med Genet 41(9):664–668
Grabowski M, Mueller-Koch Y, Grasbon-Frodl E et al (2005) Deletions account for 17% of pathogenic germline alterations in MLH1, MSH2 in hereditary nonpolyposis colorectal cancer (HNPCC) families. Genet Test 9(2):138–146
Slupphaug G, Kavli B, Krokan HE (2003) The interacting pathways for prevention and repair of oxidative DNA damage. Mutat Res 531(1–2):231–251
Lefevre JH, Rodrigue CM, Mourra N et al (2006) Implication of MYH in colorectal polyposis. Ann Surg 244(6):874–880
Lipton L, Halford SE, Johnson V et al (2003) Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway. Cancer Res 63(22):7595–7599
Wolf B, Gruber S, Henglmueller S et al (2006) Efficiency of the revised Bethesda guidelines (2003) for the detection of mutations in mismatch repair genes in Austrian HNPCC patients. Int J Cancer 118(6):1465–1470
Pagenstecher C, Wehner M, Friedl W et al (2006) Aberrant splicing in MLH1 and MSH2 due to exonic and intronic variants. Hum Genet 119(1–2):9–22
Hemminki A, Peltomaki P, Mecklin JP et al (1994) Loss of the wild type MLH1 gene is a feature of hereditary nonpolyposis colorectal cancer. Nat Genet 8(4):405–410
Tuupanen S, Karhu A, Jarvinen H, Mecklin JP, Launonen V, Aaltonen LA (2007) No evidence for dual role of loss of heterozygosity in hereditary non-polyposis colorectal cancer. Oncogene 26(17):2513–2517
Zhang J, Lindroos A, Ollila S et al (2006) Gene conversion is a frequent mechanism of inactivation of the wild-type allele in cancers from MLH1/MSH2 deletion carriers. Cancer Res 66(2):659–664
Borrego S, Wright FA, Fernandez RM et al (2003) A founding locus within the RET proto-oncogene may account for a large proportion of apparently sporadic Hirschsprung disease and a subset of cases of sporadic medullary thyroid carcinoma. Am J Hum Genet 72(1):88–100
Gu Y, Parker A, Wilson TM, Bai H, Chang DY, Lu AL (2002) Human MutY homolog, a DNA glycosylase involved in base excision repair, physically and functionally interacts with mismatch repair proteins human MutS homolog 2/human MutS homolog 6. J Biol Chem 277(13):11135–11142
Colussi C, Parlanti E, Degan P et al (2002) The mammalian mismatch repair pathway removes DNA 8-oxodGMP incorporated from the oxidized dNTP pool. Curr Biol 12(11):912–918
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Lefevre, J.H., Colas, C., Coulet, F. et al. MYH biallelic mutation can inactivate the two genetic pathways of colorectal cancer by APC or MLH1 transversions. Familial Cancer 9, 589–594 (2010). https://doi.org/10.1007/s10689-010-9367-0
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DOI: https://doi.org/10.1007/s10689-010-9367-0