Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy

Rizzolo, Piera; Silvestri, Valentina; Bucalo, Agostino; Zelli, Veronica; Valentini, Virginia; Catucci, Irene; Zanna, Ines; Masala, Giovanna; Bianchi, Simonetta; Spinelli, Alessandro Mauro; Tommasi, Stefania; Tibiletti, Maria Grazia; Russo, Antonio; Varesco, Liliana; Coppa, Anna; Calistri, Daniele; Cortesi, Laura; Viel, Alessandra; Bonanni, Bernardo; Azzollini, Jacopo; Manoukian, Siranoush; Montagna, Marco; Radice, Paolo; Palli, Domenico; Peterlongo, Paolo; Ottini, Laura

doi:10.3389/fonc.2018.00583

Cited by 28 publications

(27 citation statements)

References 52 publications

(56 reference statements)

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“…The MBC patient with biallelic MUTYH pathogenic variants had phenotypic manifestations of MUTYH ‐associated adenomatous polyposis (MAP), whereas none of the two MBC patients with APC c.3920T>A variant had phenotypic features associated with familial adenomatous polyposis (FAP) or had first‐degree FH of FAP (Table ). Monoallelic MUTYH pathogenic variants were also detected and reported in another study …”

Section: Resultssupporting

confidence: 64%

Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy

Rizzolo

Zelli

Silvestri

et al. 2019

Intl Journal of Cancer

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Breast cancer (BC) in men is rare and genetic predisposition is likely to play a relevant role in its etiology. Inherited mutations in BRCA1/2 account for about 13% of all cases and additional genes that may contribute to the missing heritability need to be investigated. In our study, a well‐characterized series of 523 male BC (MBC) patients from the Italian multicenter study on MBC, enriched for non‐BRCA1/2 MBC cases, was screened by a multigene custom panel of 50 cancer‐associated genes. The main clinical‐pathologic characteristics of MBC in pathogenic variant carriers and non‐carriers were also compared. BRCA1/2 pathogenic variants were detected in twenty patients, thus, a total of 503 non‐BRCA1/2 MBC patients were examined in our study. Twenty‐seven of the non‐BRCA1/2 MBC patients were carriers of germline pathogenic variants in other genes, including two APC p.Ile1307Lys variant carriers and one MUTYH biallelic variant carrier. PALB2 was the most frequently altered gene (1.2%) and PALB2 pathogenic variants were significantly associated with high risk of MBC. Non‐BRCA1/2 pathogenic variant carriers were more likely to have personal (p = 0.0005) and family (p = 0.007) history of cancer. Results of our study support a central role of PALB2 in MBC susceptibility and show a low impact of CHEK2 on MBC predisposition in the Italian population. Overall, our data indicate that a multigene testing approach may benefit from appropriately selected patients with implications for clinical management and counseling of MBC patients and their family members.

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Section: Resultssupporting

confidence: 64%

Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy

Rizzolo

Zelli

Silvestri

et al. 2019

Intl Journal of Cancer

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“…Six heterozygous MUTYH mutations, including p.Tyr179Cys, p.Gly396Asp and p.Pro405Leu (c.1214C > T, P405L), resulted in an association in families with both BC and CRC, but not polyposis[ 84 ] even if two years later an extensive case-control study did not confirm the association between MUTYH variants and BC, but did not exclude BC susceptibility[ 89 ]. An interesting result is the finding of one male with biallelic germline MUTYH pathogenic variants in a large cohort of males with BC[ 90 ]. In the same study, no biallelic MUTYH mutations been reported in women from large BC cohorts.…”

Section: Role Of Mutyh In Other Cancersmentioning

confidence: 99%

MUTYH: Not just polyposis

Curia

Catalano

Aceto

2020

WJCO

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MUTYH is a base excision repair enzyme, it plays a crucial role in the correction of DNA errors from guanine oxidation and may be considered a cell protective factor. In humans it is an adenine DNA glycosylase that removes adenine misincorporated in 7,8-dihydro-8-oxoguanine (8-oxoG) pairs, inducing G:C to T:A transversions. MUTYH functionally cooperates with OGG1 that eliminates 8-oxodG derived from excessive reactive oxygen species production. MUTYH mutations have been linked to MUTYH associated polyposis syndrome (MAP), an autosomal recessive disorder characterized by multiple colorectal adenomas. MAP patients show a greatly increased lifetime risk for gastrointestinal cancers. The cancer risk in mono-allelic carriers associated with one MUTYH mutant allele is controversial and it remains to be clarified whether the altered functions of this protein may have a pathophysiological involvement in other diseases besides familial gastrointestinal diseases. This review evaluates the role of MUTYH, focusing on current studies of human neoplastic and non-neoplastic diseases different to colon polyposis and colorectal cancer. This will provide novel insights into the understanding of the molecular basis underlying MUTYH -related pathogenesis. Furthermore, we describe the association between MUTYH single nucleotide polymorphisms (SNPs) and different cancer and non-cancer diseases. We address the utility to increase our knowledge regarding MUTYH in the light of recent advances in the literature with the aim of a better understanding of the potential for identifying new therapeutic targets. Considering the multiple functions and interactions of MUTYH protein, its involvement in pathologies based on oxidative stress damage could be hypothesized. Although the development of extraintestinal cancer in MUTYH heterozygotes is not completely defined, the risk for malignancies of the duodenum, ovary, and bladder is also increased as well as the onset of benign and malignant endocrine tumors. The presence of MUTYH pathogenic variants is an independent predictor of poor prognosis in sporadic gastric cancer and in salivary gland secretory carcinoma, while its inhibition has been shown to reduce the survival of pancreatic ductal adenocarcinoma cells. Furthermore, some MUTYH SNPs have been associated with lung, hepatocellular and cervical cancer risk. An additional role of MUTYH seems to contribute to the prevention of numerous other disorders with an inflammatory/degenerative basis, including neurological and ocular diseases. Finally, it is interesting to note that MUTYH could be a new therapeutic target and future studies will shed light on its specific functions in the prevention of diseases and in the improvement of the chemo-sensitivity of cancer cells.

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“…U heterozygotů patogenní mutace MUTYH genu je popsáno asi 2krát zvý šené riziko rozvoje kolorektálního karci nomu (colorectal cancer -CRC) od 45 let (OR 1,5-2,1), které odpovídá riziku CRC u prvostupňových příbuzných pa cienta se sporadickým časným CRC [41]. Ně kte ré studie uvádějí také 2krát zvýšené riziko karcinomu prsu, především ve specifických populacích (židovská, holandská) [42], v italské populaci do konce i u mužů [43]. Mírně zvýšená nad běžné populační riziko jsou i rizika roz voje dalších nádorových onemocnění (dělohy, žaludku, jater), sumárně jsou však tato rizika stále spíše nízká, bez spe ciálních doporučení stran preventivního sledování [44].…”

Section: Atmunclassified

Risks of Solid Tumors in Heterozygous Carriers of Recessive Syndromes

Koudová¹,

Puchmajerová²

2019

Klin Onkol

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Centrum lékařské genetiky a reprodukční medicíny GENNET, Praha SouhrnRozšířené panelové testování dědičných nádorových dispozic metodou masivně paralelního sek venování vede k nálezu heterozygotních patogenních variant v genech pro autozomálně recesivně dědičné nádorové syndromy. Ke stanovení míry rizika rozvoje solidních nádorů a vhodné dispenza rizace pro heterozygoty nejsou u většiny těchto genů v současnosti k dispozici klinická guidelines ani není definován postup pro další genetické vyšetření v rodině a u jejich partnerů. Naším cílem bylo na základě současných poznatků vytvořit "české guidelines" pro tyto případy. V předkládané práci uvádíme přehled vybraných genů pro autozomálně recesivně dědičné nádorové syndromy, rozdělený do dvou skupin -geny pro Fanconiho anémii a geny pro ostatní autozomálně recesivně dědičné nádorové syndromy. V každé části je vytvořena souhrnná tabulka, která obsahuje frekvenci heterozygotů mutace daného genu v populaci, riziko nádorů u heterozygotů a návrh dispenzarizace a doporučení pro predikce v rodině a ke genetickému vyšetření partnerů heterozygotů. Prediktivní vyšetření je vhodné provádět tam, kde je u heterozygotů zvýšené riziko nádorových onemocnění a/ nebo je předpoklad další reprodukce a vyšší frekvence heterozygotů v populaci, tedy i zvýšeného rizika autozomálně recesivního syndromu pro děti nosiče mutace. Uvedené návrhy a doporučení vycházejí ze současných poznatků a v budoucnosti je bude potřeba dále korigovat dle přibývajících znalostí o stávajících nebo dalších, dosud neprozkoumaných, genech. Klíčová slovadědičné nádorové syndromy -autozomálně recesivní dědičnost -heterozygot -mutace -ri ziko nádorů -prediktivní testování SummaryExpanded gene panel test ing for hereditary cancer predispositions us ing massive parallel sequenc ing can identify heterozygous pathogenic variants of genes that cause autosomal recessive inheri ted cancer syndromes. There are no clinical guidelines regard ing assessment of the risk of develop ing solid tumors or for develop ing appropriate surveillance strategies for heterozygotes for most of these genes, nor is there delineation with respect to the management for genetic testing of relatives and partners. Based on current knowledge, our aim was to create "Czech guidelines" for these cases. Here, we present an overview of the selected genes for autosomal recessive inherited tumor syndromes. The genes were divided into two groups: genes caus ing Fanconi anemia and genes caus ing other autosomal recessive inherited tumor syndromes. A summary table was crea ted for each group. The table shows the population frequency of heterozygotes, the cancer risk for heterozygotes, the proposed surveillance strategy, and recommendations for family prediction and genetic test ing of partners. Predictive testing should be performed in the case of heterozygotes that have an increased risk of cancer and/or as prerequisite to further reproduction of heterozygo tes for a given gene with significant population frequency (this allows an estimation of the risk of a...

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Contribution of MUTYH Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy

Cited by 28 publications

References 52 publications

Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy

Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy

MUTYH: Not just polyposis

Risks of Solid Tumors in Heterozygous Carriers of Recessive Syndromes

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