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 - NIHR BioResource Rare Diseases Consortium
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 - Ambegaonkar, Gautum
AU - Anderson, Julie
AU - Greene, Daniel
AU - Turro, Ernest
N1 - Publisher Copyright:
© 2018 The Authors
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
C2 - 29909963
AN - SCOPUS:85048339749
SN - 0002-9297
VL - 103
SP - 3
EP - 18
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -