Expanded Extracolonic Tumor Spectrum in MUTYH-Associated Polyposis

Vogt, Stefanie; Jones, Natalie; Christian, Daria; Engel, Christoph; Nielsen, Maartje; Kaufmann, Astrid; Steinke, Verena; Vasen, Hans F. A.; Propping, Peter; Sampson, Julian R.; Hes, Frederik J.; Aretz, Stefan

doi:10.1053/j.gastro.2009.08.052

Cited by 302 publications

(248 citation statements)

References 55 publications

Supporting

Mentioning

224

Contrasting

Unclassified

Order By: Relevance

“…The mutation prevalence of 4.4% in our study replicates a similar prevalence estimate from participants in our Middle East Cancer Consortium study of colorectal cancer (unpublished Abbreviations: G396D, glycine-to-aspartic acid substitution at codon 396; MutYH, mutY homolog gene; SD, standard deviation; Y179C, tyrosine-to-cysteine substitution at codon 179. 9,11,13 did demonstrate an association with breast cancer in special populations with familial cancer 9 or polyposis. 11,13 It is interesting to note that no interaction was noted between family history status and the breast cancer risk of mutations in MutYH in our study.…”

Section: Discussionmentioning

confidence: 89%

“…9,11,13 did demonstrate an association with breast cancer in special populations with familial cancer 9 or polyposis. 11,13 It is interesting to note that no interaction was noted between family history status and the breast cancer risk of mutations in MutYH in our study. One explanation may be that a significant proportion of cases with a family history who have wild-type MutYH may be carriers of mutations in other genes, such as the breast …”

Section: Discussionmentioning

confidence: 89%

“…7 It is known that mutations in mismatch-repair genes increase susceptibility to cancer in organs other than the colon, but former data published regarding a possible association between MutYH mutations and breast cancer risk are conflicting. [8][9][10][11][12][13][14] We studied the prevalence of the 2 commonly described founder mutations in MutYH, a glycine-to-aspartic acid substitution at codon 396 (G396D) and a tyrosine-to-cysteine substitution at codon 179 (Y179C), in a case-control study of breast cancer that was restricted to Sephardi Jews in whom we noted a high prevalence of these mutations (unpublished results).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

MutYH mutation carriers have increased breast cancer risk

Rennert

Lejbkowicz

Cohen

et al. 2011

Cancer

View full text Add to dashboard Cite

BACKGROUND: Variants of the mutY homolog gene MutYH, a DNA repair gene, are associated with increased risk of colorectal cancer; however, it remains unclear whether these variants also are associated with the risk of other cancers. The authors studied the risk of breast cancer associated with MutYH variants in a unique ethnic group of Sephardi Jews in Israel with a high prevalence of MutYH mutations. METHODS: The study participants were 930 Sephardi Jewish women of North African origin who were recruited into the population-based case-control Breast Cancer in Northern Israel Study (BCINIS) either as breast cancer cases or as healthy controls. All participants contributed a blood sample and completed an interview. Two MutYH variants, a glycine-to-aspartic acid substitution at codon 396 (G396D) and a tyrosine-to-cysteine substitution at codon 179 (Y179C), were studied. RESULTS: In the Sephardi Jews, among the healthy controls, 20 women (3.7%) were homozygote or heterozygote carriers of the G396D variant, and 4 women (0.7%) were heterozygote carriers of the Y179C variant. Breast cancer cases had a 6.7% prevalence of G396D, yielding a significantly elevated risk estimate for breast cancer (odds ratio, 1.86; 95% confidence interval, 1.02-3.39; P ¼ .039). The tumors detected in carriers with MutYH variants were similar in characteristics to those without MutYH variants, as was the age at diagnosis. CONCLUSIONS: Carriers of variants in MutYH, although not very common, may have an increased risk of breast cancer in Jews of North African origin. Identification of such carriers and special surveillance protocols may be warranted. Cancer 2012;118:1989-

show abstract

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

MutYH mutation carriers have increased breast cancer risk

Rennert

Lejbkowicz

Cohen

et al. 2011

Cancer

View full text Add to dashboard Cite

show abstract

“…7,8 Interestingly, three further cancer diagnoses were reported in this family including CRC and breast cancer, which are compatible with a recessive mode of inheritance and the clinical phenotype of MAP. [23][24][25] Biallelic MUTYH mutations were detected in the brother and might also have induced the tumourigenesis in the cousins (not investigated). Heterozygous MUTYH mutations were not identified in the remaining 84 index patients, for which somatic mutations or further germline pathomechanisms, for example, large genomic rearrangements such as inversions in the MMR genes have to be considered.…”

Section: Discussionmentioning

confidence: 99%

Biallelic MUTYH mutations can mimic Lynch syndrome

et al. 2014

View full text Add to dashboard Cite

The hallmarks of Lynch syndrome (LS) include a positive family history of colorectal cancer (CRC), germline mutations in the DNA mismatch repair (MMR) genes, tumours with high microsatellite instability (MSI-H) and loss of MMR protein expression. However, in B10-15% of clinically suspected LS cases, MMR mutation analyses cannot explain MSI-H and abnormal immunohistochemistry (IHC) results. The highly variable phenotype of MUTYH-associated polyposis (MAP) can overlap with the LS phenotype, but is inherited recessively. We analysed the MUTYH gene in 85 'unresolved' patients with tumours showing IHC MMR-deficiency without detectable germline mutation. Biallelic p.(Tyr179Cys) MUTYH germline mutations were found in one patient (frequency 1.18%) with CRC, urothelial carcinoma and a sebaceous gland carcinoma. LS was suspected due to a positive family history of CRC and because of MSI-H and MSH2-MSH6 deficiency on IHC in the sebaceous gland carcinoma. Sequencing of this tumour revealed two somatic MSH2 mutations, thus explaining MSI-H and IHC results, and mimicking LS-like histopathology. This is the first report of two somatic MSH2 mutations leading to an MSI-H tumour lacking MSH2-MSH6 protein expression in a patient with MAP. In addition to typical transversion mutations in KRAS and APC, MAP can also induce tumourigenesis via the MSI-pathway.

show abstract

“…7,12 Phenotypic overlap with Lynch syndrome/ HNPCC has also been reported. 13 The frequency of biallelic MUTYH mutations is low (0.3-1.7%) in population-based and early-onset CRC cohorts and in patients with a low number of adenomas (o10) at any age, without an overt family history (and no carcinoma). For these cases, currently no general recommendations regarding MUTYH mutation analysis exist.…”

Section: Negative Clinical Predictive Value (Probability Not To Develmentioning

confidence: 99%