Duodenal carcinoma in MUTYH-associated polyposis

Centre for Human and Clinical Genetics, LUMC, Leiden, the Netherlands.
Journal of Clinical Pathology (Impact Factor: 2.92). 11/2006; 59(11):1212-5. DOI: 10.1136/jcp.2005.031757
Source: PubMed


Bi-allelic germline mutations in the MUTYH gene give rise to multiple adenomas and an increased incidence of colorectal cancer. In addition, duodenal adenomas and other extra-colonic manifestations have been described in MUTYH-associated polyposis (MAP) patients. We describe two patients with bi-allelic MUTYH gene mutations with duodenal carcinoma. The tumour in Patient A was detected during evaluation of non-specific abdominal complaints. Patient B was already diagnosed with tens of adenomas and a colon carcinoma, when a duodenal neoplasm was detected. The identification of somatic G>T mutations in codon 12 of the K-RAS2 gene provides evidence that the duodenal lesions were induced by MUTYH deficiency. Studies in larger series of MAP patients are needed to investigate the risk of upper-gastro-intestinal malignancies and to determine further guidelines for endoscopical surveillance.

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Available from: Maartje Nielsen
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    • "Codon 12 and 13 of the KRAS2 gene and the Mutation Cluster Region (codons 1286–1513) of the APC gene were analyzed as described previously. [23] Primer pairs were designed for the coding regions and exon-intron boundaries of p53 exons 5–8 and SMAD4 exons 3–13. Primer details are available from the authors upon request. "
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    ABSTRACT: Background MUTYH-associated polyposis (MAP) is a recessively inherited disorder which predisposes biallelic carriers for a high risk of polyposis and colorectal carcinoma (CRC). Since about one third of the biallelic MAP patients in population based CRC series has no adenomas, this study aimed to identify specific clinicopathological characteristics of MAP CRCs and compare these with reported data on sporadic and Lynch CRCs. Methods From 44 MAP patients who developed ≥ 1 CRCs, 42 of 58 tumours were analyzed histologically and 35 immunohistochemically for p53 and beta-catenin. Cell densities of CD3, CD8, CD57, and granzyme B positive lymphocytes were determined. KRAS2, the mutation cluster region (MCR) of APC, p53, and SMAD4 were analyzed for somatic mutations. Results MAP CRCs frequently localized to the proximal colon (69%, 40/58), were mucinous in 21% (9/42), and had a conspicuous Crohn's like infiltrate reaction in 33% (13/40); all of these parameters occurred at a higher rate than reported for sporadic CRCs. Tumour infiltrating lymphocytes (TILs) were also highly prevalent in MAP CRCs. Somatic APC MCR mutations occurred in 14% (5/36) while 64% (23/36) had KRAS2 mutations (22/23 c.34G>T). G>T tranversions were found in p53 and SMAD4, although the relative frequency compared to other mutations was low. Conclusion MAP CRCs show some similarities to micro-satellite unstable cancers, with a preferential proximal location, a high rate of mucinous histotype and increased presence of TILs. These features should direct the practicing pathologist towards a MAP aetiology of CRC as an alternative for a mismatch repair deficient cause. High frequent G>T transversions in APC and KRAS2 (mutated in early tumour development) but not in P53 and SMAD4 (implicated in tumour progression) might indicate a predominant MUTYH effect in early carcinogenesis.
    Full-text · Article · Jun 2009 · BMC Cancer
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    • "Apart from the availability of reliable data our study has a number of further limitations. First, we did not include the occurrence of duodenal adenomas and duodenal cancer which has been reported in a few MAP cases [40] and which is likely to improve the cost-effectiveness of genetic testing in MAP families. At present, there is not enough information to include this in our cost-effectiveness analysis. "
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    ABSTRACT: MUTYH associated polyposis (MAP) is an autosomal recessive inherited disorder. Carriers of bi-allelic MUTYH germline mutations have a risk of approximately 60% to develop colorectal carcinoma (CRC). In the general population about 1.5% is a heterozygous MUTYH mutation carrier. Children of MAP patients have an increased risk of inheriting two MUTYH mutations compared to the general population, implicating an increased risk for developing CRC. Using data from the literature and Dutch MAP patients (n = 40), we constructed a Markov model to perform a societal cost-utility analysis of genetic screening in MAP families. Genetic screening was done by testing the spouse first and, in case of a heterozygous spouse, also testing of the children. The cost of genetic screening of families of MAP patients, when compared to no genetic screening, was estimated at 25,000 euros per quality-adjusted life year (QALY). The presence of Fecal Occult Blood testing (FOBT) population screening only slightly increased this cost-utility ratio to 25,500 euros per QALY. For a MUTYH heterozygote index-patient, the ratio was 51,500 euros per QALY. The results of our analysis were sensitive to several of the parameters in the model, including the cost assumed for molecular genetic testing. The costs per QALY of genetic screening in families of MAP patients are acceptable according to international standards. Therefore, genetic testing of spouses and/or children should be discussed with and offered to counselees.
    Full-text · Article · Feb 2007 · BMC Medical Genetics
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    ABSTRACT: Each year, approximately eleven thousand new colorectal cancer (CRC) patients are registered in the Netherlands. Half of these patients will eventually die of this disease. Consequently, it is of great importance to identify individuals with an increased risk for CRC. In this thesis, we evaluate the use of molecular pathology for identifying individuals with an increased risk for CRC based on their genetic makeup, and for generating insight into the tumorigenesis of familial CRC. We conclude that molecular pathology has a high potential for playing an active role in identifying individuals with CRC predisposing syndromes in a diagnostic setting as well as in studying tumorigenesis of CRC in a research setting. Tests which are readily applicable and straightforward, are now extensively used in our daily molecular pathology diagnostics. In the research setting, molecular pathology will be an important player in study the contribution to an increased CRC risk of the susceptibility alleles that are being identified. Furthermore, we now argue that the distinct tumor profiles that we found are convincing examples that molecular pathology approaches are also crucial in the characterization and elucidation of unresolved familial causes of CRC.
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