Human Molecular Genetics, 2002, Vol. 11, No. 23 2961-2967
© 2002 Oxford University Press
Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C
T:A mutations
1Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK and 2Department of Pathology, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK.
Received July 26, 2002; Accepted September 3, 2002
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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We have recently demonstrated that inherited defects of the base excision repair gene MYH predispose to multiple colorectal adenomas and carcinoma. Three affected siblings from a single British family were identified as Y165C/G382D compound heterozygotes and both missense mutations were shown to be functionally compromised. Here, we report the identification of seven further unrelated patients with >100 colorectal adenomas (six with colorectal cancer) and biallelic germline mutations in MYH: four were homozygous for truncating mutations, two were homozygous for Y165C and one was a Y165C/G382D compound heterozygote. As predicted from studies of the bacterial and yeast orthologues of MYH, colorectal tumours from affected individuals displayed a significant excess of somatic G:C
T:A mutations in APC, as compared to sporadic ( 
2=242.96, P<10-20) or FAP-associated ( 2=194.85, P<10-20) colorectal tumours. The sequence immediately downstream of the somatic G:CT:A mutations was predominantly AA, irrespective of the nature of the germline MYH mutations. These findings confirm the role of MYH in colorectal adenoma and carcinoma predisposition. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Inherited factors are thought to play a major role in at least 15% of colorectal cancers (CRC), but established CRC predisposition genes account for only a minority of these (1). Familial adenomatous polyposis (FAP) (MIM 175100) is an autosomal dominant disorder associated with the development of hundreds or thousands of colorectal adenomas, some of which progress to cancer. It is caused by inherited mutations in the adenomatous polyposis coli (APC ) gene that acts as a gatekeeper regulating proliferation of colonic cells (2). Attenuated FAP (AFAP) is associated with smaller numbers of adenomas and is caused by mutations in the extreme 5' or 3' ends of APC or in the alternatively spliced region of exon 9 (2). Hereditary non-polyposis CRC (HNPCC; MIM 114500) is a distinct autosomal dominant disorder characterized by a family history of early-onset CRC and other cancers in the absence of florid polyposis. It is caused by inherited deficiencies in the mismatch repair (MMR) pathway (3).
Until recently, inherited deficiencies in the base excision repair (BER) pathway had not been causally linked with any human genetic disorder. The BER pathway plays a significant role in the repair of mutations caused by reactive oxygen species that are generated during aerobic metabolism (4). 8-oxo-7,8-dihydro2'deoxyguanosine (8-oxoG) is the most stable product of oxidative DNA damage (5) and readily mispairs with A residues (6), leading to G:CT:A mutations in repair-deficient bacteria and yeast (7–10). In Escherichia coli, three enzymes help protect cells against the mutagenic effects of guanine oxidation (8). MutM Glycosylase removes the oxidized base from 8-oxoG:C base pairs in duplex DNA, MutY glycosylase excises A residues misincorporated opposite unrepaired 8-oxoG during replication, and MutT, an 8-oxo-dGTPase, prevents the incorporation of 8-oxo-dGMP into nascent DNA. Homologues of mutM, MutY and mutT have been identified in human cells and termed OGG1 (11), MYH (12) and MTH1 (13), respectively. MYH interacts with proteins involved in long-patch BER (14) and is associated with the replication foci, suggesting a role in replication-coupled repair (15).
We previously studied a British Caucasian family with three affected siblings with multiple colorectal adenomas and carcinoma and excluded an inherited defect of the APC or MMR genes (16). We showed that the siblings were compound heterozygotes for the functionally compromised missense mutations Y165C and G382D in MYH. Colorectal tumours from these individuals exhibited a preponderance of somatic G:CT:A transversions. We now describe the identification of seven further unrelated patients with multiple colorectal adenomas (six with colorectal carcinoma) and biallelic germline MYH mutations, including four cases homozygous for truncating mutations. Colorectal tumours from these individuals exhibit a significant excess of somatic G:CT:A mutations, as compared to sporadic and FAP-associated tumours, confirming that biallelic mutations in MYH predispose to colorectal adenomas and carcinoma.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Biallelic germline mutations in MYH
We sequenced the entire open reading frame (ORF) of MYH in twenty-one unrelated patients with multiple colorectal adenomas with or without carcinoma. We identified seven patients with biallelic mutations (Figure 1, Table 1), six of whom were presumed to be homozygous for MYH variants since no wild type allele could be detected upon sequence analysis. One Pakistani case (MA27) was homozygous for the exon 3 nonsense mutation Y90X (270 C
A); two British Caucasian cases (MA22 and MA34) were homozygous for the exon 7 missense mutation Y165C (494 AG); one British Caucasian case (MA25) was compound heterozygous for Y165C/G382D (1145 GA); and three cases from different unrelated Indian families (MA20, MA24 and MA26) were homozygous for the exon 14 nonsense mutation E466X (1396 GT). All but one of the cases were sporadic, with no history of colorectal adenomas or carcinoma in first degree relatives. MA24 had two siblings affected by multiple colorectal adenomas, one of whom had CRC, but their samples were unavailable for analysis. No patients carried single mutant MYH alleles.
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The recurrent MYH variants Y90X (2 mutations, patient MA27) and Y165C (5 mutations, patients MA22, MA34 and MA25) were found in association with the G allele of the exon 12 polymorphism 972 C
G (H324Q) and E466X (6 mutations, patients MA20, MA24 and MA26) was always found in association with the C allele. Sequencing of the entire ORFs of OGG1 and MTH1 in the fourteen MYH negative cases, did not identify any likely pathogenic changes.
Phenotypes of patients with MYH mutations
All seven cases presented with symptoms and signs attributable to CRC or colorectal polyposis (diarrhoea, bleeding, anaemia, weight loss or abdominal pain) between 36 and 65 years of age. Six had over 100 separate macroscopic polyps (one had >400) and another had a cancer and 25 adenomas in only 22 cm of resected bowel. None had extracolonic signs of FAP or a history of other extracolonic tumours.
Identification of somatic G:CT:A mutations in colorectal tumours
Using denaturing high performance liquid chromatography (dHPLC) analysis, we tested for somatic mutations in the APC gene in 108 colorectal tumours from the seven patients with biallelic germline mutations of MYH (Table 2). We screened a region of APC spanning codons 653–1589 which encompassed the mutation cluster region (MCR, codons 1286–1513, ref. 17), a known hotspot for somatic mutations (2). In total, 50 somatic mutations were identified of which 49 (98%) were G:CT:A transversions creating nonsense codons (Figure 2, Table 2).
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We compared the proportion of somatic G:C
T:A transversion mutations in APC that were detected in colorectal tumours from patients with biallelic mutations of MYH, to a database of 503 reported somatic APC mutations from sporadic colorectal adenomas and carcinomas and 308 somatic mutations from FAP associated colorectal tumours (16). The excess of somatic G:CT:A transversions in patients with biallelic MYH mutations was highly significant (49/50 versus 49/503, 2=242.96, P<10-20; and 49/50 versus 30/308, 2=194.85, P<10-20, respectively).
Sequence surrounding the somatic G:CT:A mutations
Examination of the sequence context surrounding the 49 somatic G:CT:A mutations revealed that the two bases immediately 3' to the mutated G were almost always AA, irrespective of the nature of the germline MYH mutations (Table 2). The preponderance of G:CT:A mutations at GAA sequences is significant, since other sequences that could undergo G:CT:A mutation to stop codons are highly prevalent in the region of APC assayed for somatic mutations (83 GAA sites versus 67 non-GAA sites, 2=20.07, P=7.5x10-6).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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We have previously demonstrated that, in a single family, compound heterozygosity for the missense mutations Y165C and G382D in MYH was associated with multiple colorectal adenoma and carcinoma. Functional analysis of the equivalent mutations in E. coli MYH showed that these changes significantly compromised adenine glycosylase activities with both 8-oxoG:A and G:A substrates (16). In this study, we identified another patient compound heterozygous for Y165C/G382D and two patients homozygous for Y165C. More significantly, we also report the identification of four unrelated patients homozygous for nonsense mutations in MYH. The absence of any history of colorectal adenomas or carcinoma in the fourteen obligate heterozygote parents and the occurrence of similar phenotypes in two siblings of one index case, is consistent with transmission of colorectal polyposis due to MYH mutation as an autosomal recessive trait. Together with the highly significant excess of somatic G:C
T:A mutations in tumours from these patients, this data unequivocally confirms that biallelic inactivation of MYH predisposes to colorectal adenoma and carcinoma.
The recurrent mutations Y90X, Y165C and E466X cannot be readily explained in terms of the well characterized mechanisms of hypermutagenesis and are associated with specific (and different) alleles of the polymorphism 972 CG in exon 12 of MYH. We therefore speculate that these mutations are not independent mutational events, but are likely to be derived from the same ancestral chromosomes. In total, we have identified four British families that are either homozygous for Y165C or compound heterozygous for Y165C/G382D, three Indian families that are homozygous for E466X and a single Pakistani family that is homozygous for Y90X. Specific mutations in MYH are likely to be identified in different ethnic populations, consistent with founder effects and diagnostic screening strategies will have to be optimized accordingly. A question still remains as to how frequently MYH mutations contribute to the phenotype of apparently sporadic AFAP/FAP and further analyses of patients from distinct geographical and ethnic populations will help to resolve this issue.
In a previous study of colorectal tumours from Y165C/G382D compound heterozygotes, we found that all somatic APC coding region G:CT:A mutations were followed by two adenine bases (16). In this study, we have confirmed that the sequence immediately downstream of somatic G:CT:A transversions is predominantly AA, irrespective of the nature of the germline mutations in MYH. Additional studies are therefore warranted to determine the basis of this sequence specificity, which may reflect susceptibility to guanine oxidation or defective recognition and/or repair by mutated MYH.
As in our previous study (16), we did not detect likely pathogenic variants in the BER genes OGG1 or MTH1, in cases with multiple colorectal adenomas and carcinoma. It is possible that these genes are less frequently mutated than MYH, but cause a similar phenotype (as is seen with the MSH6, MSH3 and MSH2 genes in HNPCC; ref. 3), or, the phenotype associated with inactivation of OGG1 or MTH1 may be unlike MYH-deficiency. It is also possible that mutations in OGG1 or MTH1 do not predispose to tumours in humans due to functional redundancy. Mouse models have provided only limited clues as to the function of these genes since Mth1-deficient mice display greater numbers of tumours in the lungs, liver and stomach compared to their wild-type littermates (18) and Ogg1-deficient mice do not exhibit an excess of tumours (19,20). Further studies in humans are therefore necessary to determine whether OGG1 or MTH1 play a role in CRC predisposition.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Samples
We analysed twenty-one unrelated index cases with multiple (>10) colorectal adenomas with or without colorectal cancer. No patients harboured truncating mutations in exon 4 or the alternatively spliced region of exon 9 of APC (normally associated with AFAP). DNA was prepared from venous blood samples and from colorectal adenoma and carcinoma tissue that had been micro-dissected from paraffin blocks. The nature of all tissues was verified histologically.
PCR amplification
We amplified exons 1–16 of MYH, 1–8 of OGG1 and 2–5 of MTH1 as 16, 11 and 4 fragments, as previously described (16). We amplified a 
2.8 kb segment of APC (between codons 653 and 1589) which encompassed the somatic mutation cluster region, as eighteen overlapping fragments. Primer sequences are available at http://www.uwcm.ac.uk/study/medicine/medical_genetics/research/tmg/projects/hmyh.html
Denaturing high performance liquid chromatography (dHPLC) analysis and fraction collection
dHPLC was carried out using the 3500HT WAVE nucleic acid fragment analysis system (Transgenomic, Crewe, UK). To enhance the formation of heteroduplexes prior to analysis, the PCR products were denatured at 94°C and reannealed by cooling to 50°C at a rate of 1°C per min. dHPLC was carried out at the melting temperatures predicted by Wavemaker (version 4.1) software (Transgenomic) with a 12% acetonitrile (ACN) gradient over 2.5 min (conditions are available at http://www.uwcm.ac.uk/study/medicine/medical_genetics/research/tmg/projects/myh2.html). Samples displaying aberrant dHPLC elution profiles were sequenced directly; those samples without clear sequence variations were reanalysed by isolating and sequencing dHPLC separated heteroduplexes. Fraction collection of heteroduplexes was carried out using a Transgenomic FCW-200 in-line fragment collector and products were eluted in 8% ACN.
Automated sequencing
Amplification products were purified using the PCR purification kit (Qiagen, Crawley, W. Sussex, UK) and automated sequencing was carried out using the Big Dye Terminator Cycle Sequencing kit (Applied Biosystems [ABI], Warrington, Cheshire, UK) according to the manufacturer's instructions. Sequencing reactions were purified by isopropanol precipitation and analysed on an ABI PRISM 3100 Genetic Analyser. Mutations were described according to the established nomenclature system (21).
Assays for sequence variants
All germline mutations in MYH and somatic mutations in APC were confirmed by sequencing at least two independent PCR products and/or dHPLC separated heteroduplexes, in forward and/or reverse directions. The germline mutations Y90X, G382D and E466X in MYH were further confirmed by restriction enzyme digestion (using RsaI, BglII and ApoI, respectively). The common polymorphism 972 CG (H324Q) in exon 12 of MYH was assayed by sequencing.
Somatic APC mutation database and statistical analysis
We have previously compiled a database of 503 somatic mutations observed in sporadic colorectal tumours and 308 somatic mutations observed in FAP and AFAP associated colorectal tumours (16). We carried out statistical analyses using the chi-squared test.
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ACKNOWLEDGEMENTS |
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We thank I. Tomlinson, D.N. Cooper and N. Thomas for helpful discussions, R. Butler for use of a fraction collector and N. Al-Tassan, J. Myring, S. Palmer-Smith and M. McDonald for assistance with sample preparation. This work was supported by the Knowledge Exploitation Fund (ELWA) and a CETIC (Centres of Expertise in Technology and Industrial Collaboration) award for the W.O.A.
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FOOTNOTES |
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* To whom correspondence should be addressed at: Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, United Kingdom. Tel: +44 2920742652; Fax: +44 2920746551; Email: cheadlejp{at}cardiff.ac.uk or sampson{at}cardiff.ac.uk
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Y. Tominaga, Y. Ushijima, D. Tsuchimoto, M. Mishima, M. Shirakawa, S. Hirano, K. Sakumi, and Y. Nakabeppu MUTYH prevents OGG1 or APEX1 from inappropriately processing its substrate or reaction product with its C-terminal domain Nucleic Acids Res., June 15, 2004; 32(10): 3198 - 3211. [Abstract] [Full Text] [PDF]
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B. Hao, H. Wang, K. Zhou, Y. Li, X. Chen, G. Zhou, Y. Zhu, X. Miao, W. Tan, Q. Wei, et al. Identification of Genetic Variants in Base Excision Repair Pathway and Their Associations with Risk of Esophageal Squamous Cell Carcinoma Cancer Res., June 15, 2004; 64(12): 4378 - 4384. [Abstract] [Full Text] [PDF]
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A. Ichinoe, M. Behmanesh, Y. Tominaga, Y. Ushijima, S. Hirano, Y. Sakai, D. Tsuchimoto, K. Sakumi, N. Wake, and Y. Nakabeppu Identification and characterization of two forms of mouse MUTYH proteins encoded by alternatively spliced transcripts Nucleic Acids Res., January 23, 2004; 32(2): 477 - 487. [Abstract] [Full Text] [PDF]
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A Plawski, J Lubinski, T Banasiewicz, J Paszkowski, D Lipinski, A Strembalska, G Kurzawski, T Byrski, S Zajaczek, D Hodorowicz-Zaniewska, et al. Novel germline mutations in the adenomatous polyposis coli gene in Polish families with familial adenomatous polyposis J. Med. Genet., January 1, 2004; 41(1): e11 - 11. [Full Text] [PDF]
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J. P. Cheadle and J. R. Sampson Exposing the MYtH about base excision repair and human inherited disease Hum. Mol. Genet., October 15, 2003; 12(90002): R159 - 165. [Abstract] [Full Text] [PDF]
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M. Kim, T. Huang, and J. H. Miller Competition between MutY and Mismatch Repair at A {middle dot} C Mispairs In Vivo J. Bacteriol., August 1, 2003; 185(15): 4626 - 4629. [Abstract] [Full Text] [PDF]
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J. P. Cheadle, S. Dolwani, and J. R. Sampson Inherited defects in the DNA glycosylase MYH cause multiple colorectal adenoma and carcinoma Carcinogenesis, July 1, 2003; 24(7): 1281 - 1282. [Full Text] [PDF]
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G. Marra and J. Jiricny Multiple Colorectal Adenomas -- Is Their Number Up? N. Engl. J. Med., February 27, 2003; 348(9): 845 - 847. [Full Text] [PDF]
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