Endometrial cancer may be part of the MUTYH-associated polyposis cancer spectrum

Villy, Marie‐Charlotte; Masliah‐Planchon, Julien; Bruno, Benedetto; Beaulaton, Clément; Vincent‐Salomon, Anne; Stoppa‐Lyonnet, Dominique; Colas, Chrystelle

doi:10.1016/j.ejmg.2021.104385

Cited by 9 publications

(6 citation statements)

References 18 publications

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“…While the early onset of endometrial cancer has been associated with Lynch syndrome (59), this patient's tumours were microsatellite stable and thus could not be the result of Lynch syndrome. The third case report described excess G:C>T:A transversions and the presence of the c.34G>T p.(Gly12Cys) variant in the KRAS gene in the endometrial cancer of a MAP patient (60). These observations could mean that there is a link between MAP and endometrial cancer, but investigations on a larger scale are required to fully validate this relationship (59).…”

Section: Extraintestinal Manifestationsmentioning

confidence: 99%

Phenotype correlations with pathogenic DNA variants in theMUTYHgene

Thet,

Plazzer,

Capella

et al. 2024

Preprint

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MUTYH-associated polyposis (MAP) is an autosomal recessive disorder where the inheritance of constitutional biallelic pathogenicMUTYHvariants predisposes a person to the development of adenomas and colorectal cancer (CRC). It is also associated with extracolonic and extraintestinal manifestations that may overlap with the phenotype of familial adenomatous polyposis (FAP). Currently, there are discrepancies in the literature regarding whether certain phenotypes are truly associated with MAP. This narrative review aims to explore the phenotypic spectrum of MAP to better characterise the MAP phenotype. A literature search was conducted to identify articles reporting on MAP-specific phenotypes. Clinical data from 2109 MAP patients identified from the literature showed that 1123 patients (53.2%) had CRC. Some patients with CRC had no associated adenomas, suggesting that adenomas are not an obligatory component of MAP. Carriers of the two missense founder variants, and possibly truncating variants, had an increased cancer risk when compared to those who carry other pathogenic variants. It has been suggested that somatic G:C>T:A transversions are a mutational signature of MAP, and could be used as a biomarker in screening and identifying patients with atypical MAP, or in associating certain phenotypes with MAP. The extracolonic and extraintestinal manifestations that have been associated with MAP include duodenal adenomas, duodenal cancer, fundic gland polyps, gastric cancer, ovarian cancer, bladder cancer and skin cancer. The association of breast cancer and endometrial cancer with MAP remains disputed. Desmoids and Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPEs) are rarely reported in MAP, but have long been seen in FAP patients, and thus could act as a distinguishing feature between the two. This collection of MAP phenotypes will assist in the assessment of pathogenicMUTYHvariants using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) Variant Interpretation Guidelines, and ultimately improve patient care.

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Section: Extraintestinal Manifestationsmentioning

confidence: 99%

Phenotype correlations with pathogenic DNA variants in theMUTYHgene

Thet,

Plazzer,

Capella

et al. 2024

Preprint

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“…Biallelic germline pathogenic variants in MUTYH have been associated with a type of adenomatous polyposis affecting the colon and duodenum, known as MUTYH ‐associated polyposis (MAP) 3 . This condition follows an autosomal recessive hereditary pattern (OMIM: 608456) and is linked to an elevated susceptibility to colorectal cancer 2,3 ; while there is speculation about an increased risk of other cancers beyond the digestive system, such as ovarian, endometrial and breast cancers, the pathogenic connection remains unclear 4,5 …”

Section: Figurementioning

confidence: 99%

“…3 This condition follows an autosomal recessive hereditary pattern (OMIM: 608456) and is linked to an elevated susceptibility to colorectal cancer 2,3 ; while there is speculation about an increased risk of other cancers beyond the digestive system, such as ovarian, endometrial and breast cancers, the pathogenic connection remains unclear. 4,5 Villy et al described a case of medulloblastoma (MB) in a patient with MAP. 6 The patient affected by MB molecular subgroup WNT carried the homozygous pathogenic variant c.1227_1228dup, p.…”

mentioning

confidence: 99%

A second case report of medulloblastoma in a patient carrying biallelic pathogenic MUTYH germline variants

Cipri,

Del Baldo,

Carai

et al. 2024

Neuropathology Appl Neurobio

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“…This condition is an autosomal recessive disease (OMIM: 608456) associated with an increased risk of colorectal cancer 2,3 . Predisposition to extra‐digestive tumours including ovarian, endometrial and breast cancers is suspected but remains unclear 4–7 . In these patients, MUTYH deficiency leads to an excess of unrepaired G:C → T:A transversions in digestive lesions, defining a new mutational signature called single base substitution signature 36 (SBS36) 8,9 …”

Section: Introductionmentioning

confidence: 99%

First report of medulloblastoma in a patient with MUTYH‐associated polyposis

Villy,

Warcoin,

Filser

et al. 2023

Neuropathology Appl Neurobio

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AimsThe mutY DNA glycosylase encoded by the MUTYH gene prevents G:C → T:A transversions through the base excision repair DNA repair system. Germline biallelic pathogenic variants in MUTYH cause an adenomatous polyposis called MUTYH‐associated polyposis (MAP), an autosomal recessive disease (OMIM: 608456), with an increased risk of colorectal cancer. Digestive lesions in this context show an excess of G:C → T:A transversions, individualising a specific mutational signature associated with MUTYH deficiency called signature SBS36. Predisposition to other tumours in patients with germline biallelic pathogenic variants in MUTYH is suspected but remains unclear. We report the first case of medulloblastoma in a patient with MAP, carrying the homozygous pathogenic variant c.1227_1228dup, p.(Glu410Glyfs*43) in MUTYH.MethodsWhole exome sequencing was performed on the medulloblastoma to enlighten single nucleotide variants of interest, microsatellite status and mutational signature. The objective was to determine the involvement of MUTYH deficiency in the oncogenesis of this medulloblastoma.ResultsThe medulloblastoma has the mutational signature SBS36 and driver pathogenic variants in CTNNB1, PTCH1 and KDM6A corresponding to G:C → T:A transversions, suggesting a role of MUTYH deficiency in oncogenesis.ConclusionsTherefore, medulloblastoma could be a rare manifestation associated with germline biallelic pathogenic variants in MUTYH.

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Endometrial cancer may be part of the MUTYH-associated polyposis cancer spectrum

Cited by 9 publications

References 18 publications

Phenotype correlations with pathogenic DNA variants in theMUTYHgene

Phenotype correlations with pathogenic DNA variants in theMUTYHgene

A second case report of medulloblastoma in a patient carrying biallelic pathogenic MUTYH germline variants

First report of medulloblastoma in a patient with MUTYH‐associated polyposis

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