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

2.50
Hdl Handle:
http://hdl.handle.net/11287/620753
Title:
Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.
Authors:
Whitworth, J. [et al]; Brewer, Carole
Abstract:
Multiple 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.
Citation:
Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes. 2018, 103 (1):3-18 Am. J. Hum. Genet.
Publisher:
Cell Press
Journal:
American journal of human genetics
Issue Date:
5-Jul-2018
URI:
http://hdl.handle.net/11287/620753
DOI:
10.1016/j.ajhg.2018.04.013
PubMed ID:
29909963
Additional Links:
https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(18)30160-5
Note:
This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.
Type:
Journal Article
Language:
en
ISSN:
1537-6605
Appears in Collections:
Clinical Genetics (Peninsula Genetics); 2018 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorWhitworth, J. [et al]en
dc.contributor.authorBrewer, Caroleen
dc.date.accessioned2018-07-10T11:55:08Z-
dc.date.available2018-07-10T11:55:08Z-
dc.date.issued2018-07-05-
dc.identifier.citationComprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes. 2018, 103 (1):3-18 Am. J. Hum. Genet.en
dc.identifier.issn1537-6605-
dc.identifier.pmid29909963-
dc.identifier.doi10.1016/j.ajhg.2018.04.013-
dc.identifier.urihttp://hdl.handle.net/11287/620753-
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.en
dc.language.isoenen
dc.publisherCell Pressen
dc.relation.urlhttps://linkinghub.elsevier.com/retrieve/pii/S0002-9297(18)30160-5en
dc.rightsArchived with thanks to American journal of human genetics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).en
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleComprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.en
dc.typeJournal Articleen
dc.identifier.journalAmerican journal of human geneticsen
dc.description.noteThis article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.en
dc.type.versionPublisheden

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