Filling the gap: A thorough investigation for the genetic diagnosis of unsolved polyposis patients with monoallelic <i>MUTYH</i> pathogenic variants

Dell’Elice, Anastasia; Cini, Giulia; Fornasarig, Mara; Armelao, Franco; Barana, D.; Bianchi, Francesca; Cavalchini, Guido C Casalis; Maffè, Antonella; Mammi, Isabella; Pedroni, Monica; Sorrentini, I.; Tibiletti, M. G.; Maestro, Roberta; Quaia, Michele; Viel, Alessandra

doi:10.1002/mgg3.1831

Cited by 4 publications

(2 citation statements)

References 30 publications

(37 reference statements)

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“…Mammalian MutY homologue (MUTYH) encodes a DNA glycosylase involved in base excision repair during DNA replication and damage repair. PVs/LPVs in MUTYH are associated with autosomal recessive colorectal adenomatous polyposis, but interestingly, monoallelic variants on this gene have been reported by both our and other groups as being associated with cancer predisposition in several patients [30,31]. An interesting case in the present study is represented by the detection of a MUTYH c.734G>A variant in one female patient with a personal history of breast cancer diagnosed at the age of 44 years, previously tested for BRCA1/2 variants at another institute and found to be negative.…”

Section: Discussionmentioning

confidence: 72%

Detection of Germline Mutations in a Cohort of 250 Relatives of Mutation Carriers in Multigene Panel: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2

Di Rado,

Giansante,

Cicirelli

et al. 2023

Cancers

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Background: Several hereditary–familial syndromes associated with various types of tumors have been identified to date, evidencing that hereditary cancers caused by germline mutations account for 5–10% of all tumors. Advances in genetic technology and the implementation of Next-Generation Sequencing (NGS) have accelerated the discovery of several susceptibility cancer genes, allowing for the detection of cancer-predisposing mutations in a larger number of cases. The aim of this study is to highlight how the application of an NGS-multigene panel to a group of oncological patients subsequently leads to improvement in the identification of carriers of healthy pathogenic variants/likely pathogenic variants (PVs/LPVs) and prevention of the disease in these cases. Methods: Starting from a total of 110 cancer patients carrying PVs/LPVs in genes involved in cancer susceptibility detected via a customized NGS panel of 27 cancer-associated genes, we enrolled 250 healthy collateral family members from January 2020 to July 2022. The specific PVs/LPVs identified in each proband were tested in healthy collateral family members via Sanger sequencing. Results: A total of 131 out of the 250 cases (52%) were not carriers of the mutation detected in the affected relative, while 119 were carriers. Of these, 81/250 patients carried PVs/LPVs on BRCA1/2 (33%), 35/250 harbored PVs/LPVs on other genes beyond BRCA1 and BRCA2 (14%), and 3/250 (1%) were PVs/LPVs carriers both on BRCA1/2 and on another susceptibility gene. Conclusion: Our results show that the analysis of BRCA1/2 genes would have only resulted in a missed diagnosis in a number of cases and in the lack of prevention of the disease in a considerable percentage of healthy carriers with a genetic mutation (14%).

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Section: Discussionmentioning

confidence: 72%

Detection of Germline Mutations in a Cohort of 250 Relatives of Mutation Carriers in Multigene Panel: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2

Di Rado,

Giansante,

Cicirelli

et al. 2023

Cancers

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“…Interestingly, our study showed that 94% of MUTYH carriers had a heterozygous variant. PVs/LPVs in MUTYH are associated with colorectal adenomatous polyposis autosomal recessive, while recent literature data revealed the association between monoallelic MUTYH variants and several type of cancer (Dell'Elice et al, 2021). BC, PC and OC, together with colon and prostate cancer, are the major tumors linked to clinical familiar history, as well as the major BRCA-associated cancers (Daly et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Clinical usefulness of NGS multi-gene panel testing in hereditary cancer analysis

et al. 2023

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Introduction: A considerable number of families with pedigrees suggestive of a Mendelian form of Breast Cancer (BC), Ovarian Cancer (OC), or Pancreatic Cancer (PC) do not show detectable BRCA1/2 mutations after genetic testing. The use of multi-gene hereditary cancer panels increases the possibility to identify individuals with cancer predisposing gene variants. Our study was aimed to evaluate the increase in the detection rate of pathogenic mutations in BC, OC, and PC patients when using a multi-gene panel.Methods: 546 patients affected by BC (423), PC (64), or OC (59) entered the study from January 2020 to December 2021. For BC patients, inclusion criteria were i) positive cancer family background, ii) early onset, and iii) triple negative BC. PC patients were enrolled when affected by metastatic cancer, while OC patients were all submitted to genetic testing without selection. The patients were tested using a Next-Generation Sequencing (NGS) panel containing 25 genes in addition to BRCA1/2.Results: Forty-four out of 546 patients (8%) carried germline pathogenic/likely pathogenic variants (PV/LPV) on BRCA1/2 genes, and 46 (8%) presented PV or LPV in other susceptibility genes.Discussion: Our findings demonstrate the utility of expanded panel testing in patients with suspected hereditary cancer syndromes, since this approach increased the mutation detection rate of 15% in PC, 8% in BC and 5% in OC cases. In absence of multi-gene panel analysis, a considerable percentage of mutations would have been lost.

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Filling the gap: A thorough investigation for the genetic diagnosis of unsolved polyposis patients with monoallelic MUTYH pathogenic variants

Dell’Elice

Cini

Fornasarig

et al. 2021

Molec Gen & Gen Med

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Filling the gap: A thorough investigation for the genetic diagnosis of unsolved polyposis patients with monoallelic MUTYH pathogenic variants

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 4 publications

References 30 publications

Detection of Germline Mutations in a Cohort of 250 Relatives of Mutation Carriers in Multigene Panel: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2

Detection of Germline Mutations in a Cohort of 250 Relatives of Mutation Carriers in Multigene Panel: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2

Clinical usefulness of NGS multi-gene panel testing in hereditary cancer analysis

Filling the gap: A thorough investigation for the genetic diagnosis of unsolved polyposis patients with monoallelic MUTYH pathogenic variants

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