MUTYH-associated polyposis (MAP)

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Abstract

The human mutY homologue (MUTYH) gene is responsible for inheritable polyposis and colorectal cancer. This review discusses the molecular genetic aspects of the MUTYH gene and protein, the clinical impact of mono- and biallelic MUTYH mutations and histological aspects of the MUTYH tumors. Furthermore, the relationship between MUTYH and the mismatch repair genes in colorectal cancer (CRC) families is examined. Finally, the role of other base excision repair genes in polyposis and CRC patients is discussed.

Introduction

Colorectal adenomas are a common manifestation in the general population, primarily at an older age, and are thought to be the requisite precursor for colorectal cancer (CRC) [1]. In addition to adenoma size and grade of dysplasia, the chance of malignancy among these lesions grows with larger numbers of adenomas [2]. When adenomas or other polyps are numerous or manifest at a relatively young age, an inheritable form of polyposis should be considered.

MUTYH-associated polyposis (MAP) (OMIM #608456) is the most recent reported CRC and polyposis syndrome. It was discovered in 2002 by a Welsh research group [3]. An earlier identified other polyposis and CRC syndrome is familial adenomatous polyposis (FAP), caused by mutations in the adenomatous polyposis coli (APC) gene. Lynch syndrome, or hereditary non-polyposis colorectal carcinoma (HNPCC), is a tumor predisposition syndrome associated with colorectal and endometrial cancer and several other extracolonic malignancies, caused by mutations in the ‘mismatch repair’ (MMR) genes, predominantly MLH1, MSH2, MSH6 and PMS2. Less prevalent syndromes are Peutz–Jeghers (caused by mutations in LKB1), juvenile polyposis (SMAD4, BMPR1A, ENG-genes), hereditary mixed polyposis (BMPR1A-gene), and hyperplastic polyposis syndrome (HPS) [4].

Intriguingly, the latter are all dominantly inherited syndromes (except HPS, inheritance and gene unknown); MAP is the first known polyposis syndrome with a recessive mode of inheritance. Mutations in both MUTYH genes predispose patients to the development of polyps. The disease is, in principal, restricted to one generation; see Section 4 for more clinical details. Since its discovery, multiple international research groups have investigated the consequences of mono- and biallelic mutations in the MUTYH gene in humans, bacteria and other species. Several aspects of the natural history and pathophysiology of MAP have been elucidated and a possible CRC risk in MUTYH heterozygotes has been analyzed in large case–control studies.

MUTYH has been shown to cooperate with other proteins involved in DNA repair, such as MSH6. MUTYH might act as a causative factor or modifier in Lynch syndrome families. Furthermore, it has been suggested that other base excision repair genes might be involved in the development of adenomas and CRC.

Section snippets

Methods

The computerized PubMed database was searched for the literature published from 1980 to August 2009, looking for publications that concern MYH, hMYH, MutY homolog or MUTYH. Additional relevant articles were identified by reviewing the references of retrieved publications. Proceedings of the Meeting of the International Society for Gastrointestinal Hereditary Tumors (InSiGHT) 2009 in Dusseldorf were also included; see the website for more information http://www.insight2009.info/.

Functional studies and the mutation spectrum

In 1988, the mutY gene was cloned in Escherichia coli [5]. The equivalent gene, which was identified from human HeLa cells, was described in 1991 [6] and named MYH. Later, the name MYH was replaced by MUTYH because MYH was already in use for another group of genes: the myosin heavy chain genes. The role of the MUTYH gene in polyposis was discovered in a family of 3 siblings in 2002 by Al Tassan et al. In 11 tumors of these siblings, a significantly greater proportion of G:C to T:A transversions

Clinical presentation and guidelines for surveillance and molecular genetic testing

Over 500 MAP patients have been reported thus far [19], [25], [26], [28], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77] [InSiGHT 2009]. Most biallelic MUTYH carriers have between 10 and a few hundred polyps, only two MAP cases with more than 500 polyps have been reported so far (Table 1) [56], [74]. Also, a number of MAP patients with CRC

MUTYH and extracolonic lesions

Since oxidative stress is a common manifestation, it can be expected that a defective MUTYH gene leads to cancers and tumors external to the colon as well. Indeed, in MUTYH knockout mice, tumors are found in the small intestine [90]. Mice deficient for both MUTYH and APC (APCmin/+) have tumors in the small intestine, breast and lung [91]. In double MUTYH and OGG1 knockout mice ovarian tumors and lymphomas were found [92].

Recently, extraintestinal lesions were systematically evaluated in a

MAP carcinoma, molecular and histological characteristics

One can expect specific molecular and histological characteristics for MAP carcinoma because they follow, at least in part, a different genetic pathway than that followed by sporadic tumors. A dysfunctional MUTYH protein is expected to generate specifically somatic G > T transversions in other genes. In fact, G > T transversions in the APC gene in polyps of a Welsh family led to the initial discovery of the MUTYH gene.

Heterozygous MUTYH mutations and CRC

There has been much debate regarding whether monoallelic (heterozygous) mutation carriers also have a higher risk for developing colorectal cancer, possibly at a later age. The carrier rate for MUTYH monoallelic mutations in controls is 1.5–2.0% for all mutations [67] [Farrington InSiGHT] and, more specifically, 1.1–1.6% for p.G396D, 0.4–0.6% for p.Y179C, [Farrington InSiGHT] and less than 0.1% for other mutations [67]. The risk for CRC in these MUTYH heterozygotes would arise from a second

Synergy between MUTYH and the mismatch repair system

The occurrence of sebaceous gland tumors and other Lynch syndrome-associated tumors (ovarian, bladder and endometrial) in MAP patients points to a phenotypic overlap with Lynch syndrome.

In Lynch syndrome patients with proven pathogenic MMR mutations (mainly MLH1 and MSH2), no overrepresentation of mono- or biallelic MUTYH mutations has been found [49], [136], arguing against a modifying effect of MUTYH. Furthermore, in CRC families without mismatch repair mutations (Amsterdam positive HNPCC

Other genes involved in base excision repair (BER) machinery

A number of other enzymes (OGG1, NTH1, NUDT1, NEIL1, 2 and 3) are involved in BER and oxidative DNA damage and represent candidate predisposition genes for colorectal carcinoma and polyposis [148], [149]. Until now however, no clear association between pathogenic mutations in these associated genes and CRC development has been found, also not in combination with mutations in MUTYH [3], [62], [64], [129], [139], [150], [151]. In a review on OGG1, it was concluded that although functional and

Conclusions

Most biallelic MUTYH patients described to date developed between 10 and 500 polyps. In addition, a number of MAP patients have been described with CRC and none or only a few polyps. The CRC risk in MAP patients is about 43% at age 60 and the life-time risk is assumed to be close to 100% in the absence of timely surveillance. The lifetime risk for duodenal cancer is about 4% and a significantly increased incidence has been shown for ovarian, bladder and skin cancers (SIR 5.7, SIR 7.2 and

Conflict of interest statement

There are no conflicts of interest.

Reviewer

Randall W. Burt, M.D., University of Utah, Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT 84112-5550, United States.

Mrs. Maartje Nielsen is a medical doctor and currently working as a trainee in clinical genetics department of the Leiden University Medical Center She is currently completing her Ph.D. degree Research on MUTYH-associated polyposis. She has published on clinical, pathological as well as economical aspects of MAP and other polyposis syndromes.

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  • Cited by (0)

    Mrs. Maartje Nielsen is a medical doctor and currently working as a trainee in clinical genetics department of the Leiden University Medical Center She is currently completing her Ph.D. degree Research on MUTYH-associated polyposis. She has published on clinical, pathological as well as economical aspects of MAP and other polyposis syndromes.

    Prof. Hans Morreau is a pathologist at the Leiden University Medical Center. Molecular and genetic tumor pathology is one of his core activities. He has a focus on inheritable forms of cancers, specifically of the GE tract and endocrine cancer. In 1992, he defended his Ph.D. thesis entitled: “Structural and Functional Analysis of Lysosomal Beta-galactosidase and its Relation to the Protective Protein”. His research is aiming at the identification of genetic mechanisms underlying familial colorectal cancer, and molecular pathology in general. Recently he was invited to update the latest version of the WHO Classification of Tumours of the Digestive System Series with a MAP chapter.

    Prof Hans F.A. Vasen is since 1984 internist and since 1985 medical director of The Netherlands Foundation for the Detection of Hereditary Tumours and staff member at the Department of Gastroenterology at the Leiden University Medical Center. He established a large register of families with an inherited predisposition for cancer in The Netherlands. In 1989, he wrote a Ph.D. thesis entitled: “Screening for Hereditary Cancer”. The main interest of Vasen is identification of families at risk for hereditary cancer, development of surveillance protocols and translating the results from molecular genetic studies into clinical practice. He published more than 200 articles in peer-reviewed journals and 35 chapters in books. Since 2000, he is editor-in-chief of Familial Cancer.

    Dr. Frederik J. Hes is currently working as a clinical geneticist at the department of clinical Genetics at the Leiden University Medical Center. In 2000, he wrote a Ph.D. thesis entitled: “Von Hippel-Lindau disease: clinical and genetic investigations in the Netherlands” at the University Medical Center in Utrecht. The research in which he is involved focuses on improving the identification and management of patients with tumor syndromes. His main interests are colorectal cancer syndromes (polyposis) and endocrine tumors (paragangliomas). Furthermore, he is one of the initiators of a European collaboration which resulted in the publication of several large studies on MUTYH-associated polyposis.

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