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

NIHR BioResource Rare Diseases Consortium

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)3-18
Number of pages16
JournalAmerican journal of human genetics
Volume103
Issue number1
DOIs
Publication statusPublished - 5 Jul 2018

Cite this

@article{d789bf9ce70c430e932e537fc005fcd0,
title = "Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes",
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.",
keywords = "cancer-predisposition syndromes, genetic testing, inherited cancer genetics, whole-genome sequencing",
author = "James Whitworth and Smith, {Philip S.} and Martin, {Jose Ezequiel} and Hannah West and Andrea Luchetti and Faye Rodger and Graeme Clark and Keren Carss and Jonathan Stephens and Kathleen Stirrups and Chris Penkett and Rutendo Mapeta and Sofie Ashford and Karyn Megy and Hassan Shakeel and Munaza Ahmed and Julian Adlard and Julian Barwell and Carole Brewer and Casey, {Ruth T.} and Ruth Armstrong and Trevor Cole and Evans, {Dafydd Gareth} and Florentia Fostira and Lynn Greenhalgh and Helen Hanson and Alex Henderson and Jonathan Hoffman and Louise Izatt and Ajith Kumar and Ava Kwong and Fiona Lalloo and Ong, {Kai Ren} and Joan Paterson and Park, {Soo Mi} and Rakefet Chen-Shtoyerman and Claire Searle and Lucy Side and Skytte, {Anne Bine} and Katie Snape and Woodward, {Emma R.} and Timothy Aitman and Hana Alachkar and Sonia Ali and Louise Allen and David Allsup and {Huis in't Veld}, Anna and Kuijpers, {Taco W.} and Sergey Nejentsev and Noordegraaf, {Anton Vonk} and {NIHR BioResource Rare Diseases Consortium}",
year = "2018",
month = "7",
day = "5",
doi = "10.1016/j.ajhg.2018.04.013",
language = "English",
volume = "103",
pages = "3--18",
journal = "American journal of human genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "1",

}

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

In: American journal of human genetics, Vol. 103, No. 1, 05.07.2018, p. 3-18.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes

AU - Whitworth, James

AU - Smith, Philip S.

AU - Martin, Jose Ezequiel

AU - West, Hannah

AU - Luchetti, Andrea

AU - Rodger, Faye

AU - Clark, Graeme

AU - Carss, Keren

AU - Stephens, Jonathan

AU - Stirrups, Kathleen

AU - Penkett, Chris

AU - Mapeta, Rutendo

AU - Ashford, Sofie

AU - Megy, Karyn

AU - Shakeel, Hassan

AU - Ahmed, Munaza

AU - Adlard, Julian

AU - Barwell, Julian

AU - Brewer, Carole

AU - Casey, Ruth T.

AU - Armstrong, Ruth

AU - Cole, Trevor

AU - Evans, Dafydd Gareth

AU - Fostira, Florentia

AU - Greenhalgh, Lynn

AU - Hanson, Helen

AU - Henderson, Alex

AU - Hoffman, Jonathan

AU - Izatt, Louise

AU - Kumar, Ajith

AU - Kwong, Ava

AU - Lalloo, Fiona

AU - Ong, Kai Ren

AU - Paterson, Joan

AU - Park, Soo Mi

AU - Chen-Shtoyerman, Rakefet

AU - Searle, Claire

AU - Side, Lucy

AU - Skytte, Anne Bine

AU - Snape, Katie

AU - Woodward, Emma R.

AU - Aitman, Timothy

AU - Alachkar, Hana

AU - Ali, Sonia

AU - Allen, Louise

AU - Allsup, David

AU - Huis in't Veld, Anna

AU - Kuijpers, Taco W.

AU - Nejentsev, Sergey

AU - Noordegraaf, Anton Vonk

AU - NIHR BioResource Rare Diseases Consortium

PY - 2018/7/5

Y1 - 2018/7/5

N2 - 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.

AB - 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.

KW - cancer-predisposition syndromes

KW - genetic testing

KW - inherited cancer genetics

KW - whole-genome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85048339749&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2018.04.013

DO - 10.1016/j.ajhg.2018.04.013

M3 - Article

VL - 103

SP - 3

EP - 18

JO - American journal of human genetics

JF - American journal of human genetics

SN - 0002-9297

IS - 1

ER -