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Article: Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes

TitleComprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes
Authors
Issue Date2018
PublisherCell Press. The Journal's web site is located at http://www.cell.com/AJHG/
Citation
American Journal of Human Genetics, 2018, v. 103, p. 3-18 How to Cite?
AbstractMultiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.
Persistent Identifierhttp://hdl.handle.net/10722/265153
ISSN
2019 Impact Factor: 10.502
2015 SCImago Journal Rankings: 8.769
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorWhitworth, J-
dc.contributor.authorSmith, PS-
dc.contributor.authorMartin, JE-
dc.contributor.authorCarss, K-
dc.contributor.authorStephens, J-
dc.contributor.authorStirrups, K-
dc.contributor.authorPenkett, C-
dc.contributor.authorMapeta, R-
dc.contributor.authorAshford, S-
dc.contributor.authorMegy, K-
dc.contributor.authorShakeel, H-
dc.contributor.authorCasey, RT-
dc.contributor.authorGreenhalgh, L-
dc.contributor.authorHanson, H-
dc.contributor.authorHenderson, A-
dc.contributor.authorHoffman, J-
dc.contributor.authorIzatt, L-
dc.contributor.authorKumar, A-
dc.contributor.authorKwong, A-
dc.date.accessioned2018-11-20T02:01:12Z-
dc.date.available2018-11-20T02:01:12Z-
dc.date.issued2018-
dc.identifier.citationAmerican Journal of Human Genetics, 2018, v. 103, p. 3-18-
dc.identifier.issn0002-9297-
dc.identifier.urihttp://hdl.handle.net/10722/265153-
dc.description.abstractMultiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.-
dc.languageeng-
dc.publisherCell Press. The Journal's web site is located at http://www.cell.com/AJHG/-
dc.relation.ispartofAmerican Journal of Human Genetics-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleComprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes-
dc.typeArticle-
dc.identifier.emailKwong, A: avakwong@hku.hk-
dc.identifier.authorityKwong, A=rp01734-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1016/j.ajhg.2018.04.013-
dc.identifier.scopuseid_2-s2.0-85048339749-
dc.identifier.hkuros295924-
dc.identifier.volume103-
dc.identifier.spage3-
dc.identifier.epage18-
dc.identifier.isiWOS:000438168800001-
dc.publisher.placeUnited States-

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