Monogenic and polygenic determinants of sarcoma risk: an international genetic study

Mandy L. Ballinger, David L. Goode, Isabelle Ray-Coquard, Paul A. James, Gillian Mitchell, Eveline Niedermayr, Ajay Puri, Joshua D. Schiffman, Gillian S. Dite, Arcadi Cipponi, Robert G. Maki, Andrew S. Brohl, Ola Myklebost, Eva W. Stratford, Susanne Lorenz, Sung Min Ahn, Jin Hee Ahn, Jeong Eun Kim, Sue Shanley, Victoria BeshayR Randall, Ian Judson, Beatrice Seddon, Ian G. Campbell, Mary Anne Young, Rajiv Sarin, Jean Yves Blay, Seán I. O'Donoghue, David M. Thomas

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Background Sarcomas are rare, phenotypically heterogeneous cancers that disproportionately affect the young. Outside rare syndromes, the nature, extent, and clinical significance of their genetic origins are not known. We aimed to investigate the genetic basis for bone and soft-tissue sarcoma seen in routine clinical practice. Methods In this genetic study, we included 1162 patients with sarcoma from four cohorts (the International Sarcoma Kindred Study [ISKS], 966 probands; Project GENESIS, 48 probands; Asan Bio-Resource Center, 138 probands; and kConFab, ten probands), who were older than 15 years at the time of consent and had a histologically confirmed diagnosis of sarcoma, recruited from specialist sarcoma clinics without regard to family history. Detailed clinical, pathological, and pedigree information was collected, and cancer diagnoses in probands and relatives were independently verified. Targeted exon sequencing using blood (n=1114) or saliva (n=48) samples was done on 72 genes (selected due to associations with increased cancer risk) and rare variants were stratified into classes approximating the International Agency for Research on Cancer (IARC) clinical classification for genetic variation. We did a case-control rare variant burden analysis using 6545 Caucasian controls included from three cohorts (ISKS, 235 controls; LifePool, 2010 controls; and National Heart, Lung, and Blood Institute Exome Sequencing Project [ESP], 4300 controls). Findings The median age at cancer diagnosis in 1162 sarcoma probands was 46 years (IQR 29–58), 170 (15%) of 1162 probands had multiple primary cancers, and 155 (17%) of 911 families with informative pedigrees fitted recognisable cancer syndromes. Using a case-control rare variant burden analysis, 638 (55%) of 1162 sarcoma probands bore an excess of pathogenic germline variants (combined odds ratio [OR] 1·43, 95% CI 1·24–1·64, p<0·0001), with 227 known or expected pathogenic variants occurring in 217 individuals. All classes of pathogenic variants (known, expected, or predicted) were associated with earlier age of cancer onset. In addition to TP53, ATM, ATR, and BRCA2, an unexpected excess of functionally pathogenic variants was seen in ERCC2. Probands were more likely than controls to have multiple pathogenic variants compared with the combined control cohort group and the LifePool control cohort (OR 2·22, 95% CI 1·57–3·14, p=1·2 × 10−6) and the cumulative burden of multiple variants correlated with earlier age at cancer diagnosis (Mantel-Cox log-rank test for trend, p=0·0032). 66 of 1162 probands carried notifiable variants following expert clinical review (those recognised to be clinically significant to health and about which patients should be advised), whereas 293 (25%) probands carried variants with potential therapeutic significance. Interpretation About half of patients with sarcoma have putatively pathogenic monogenic and polygenic variation in known and novel cancer genes, with implications for risk management and treatment. Funding Rainbows for Kate Foundation, Johanna Sewell Research Foundation, Australian National Health and Medical Research Council, Cancer Australia, Sarcoma UK, National Cancer Institute, Liddy Shriver Sarcoma Initiative.

Original languageEnglish (US)
Pages (from-to)1261-1271
Number of pages11
JournalThe Lancet Oncology
Volume17
Issue number9
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

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Sarcoma
Neoplasms
Pedigree
Odds Ratio
Exome
National Heart, Lung, and Blood Institute (U.S.)
International Agencies
National Cancer Institute (U.S.)
Neoplasm Genes
Health
Risk Management
Age of Onset
Saliva
Research
Biomedical Research
Exons
Bone and Bones
Control Groups

ASJC Scopus subject areas

  • Oncology

Cite this

Ballinger, M. L., Goode, D. L., Ray-Coquard, I., James, P. A., Mitchell, G., Niedermayr, E., ... Thomas, D. M. (2016). Monogenic and polygenic determinants of sarcoma risk: an international genetic study. The Lancet Oncology, 17(9), 1261-1271. https://doi.org/10.1016/S1470-2045(16)30147-4

Monogenic and polygenic determinants of sarcoma risk : an international genetic study. / Ballinger, Mandy L.; Goode, David L.; Ray-Coquard, Isabelle; James, Paul A.; Mitchell, Gillian; Niedermayr, Eveline; Puri, Ajay; Schiffman, Joshua D.; Dite, Gillian S.; Cipponi, Arcadi; Maki, Robert G.; Brohl, Andrew S.; Myklebost, Ola; Stratford, Eva W.; Lorenz, Susanne; Ahn, Sung Min; Ahn, Jin Hee; Kim, Jeong Eun; Shanley, Sue; Beshay, Victoria; Randall, R; Judson, Ian; Seddon, Beatrice; Campbell, Ian G.; Young, Mary Anne; Sarin, Rajiv; Blay, Jean Yves; O'Donoghue, Seán I.; Thomas, David M.

In: The Lancet Oncology, Vol. 17, No. 9, 01.09.2016, p. 1261-1271.

Research output: Contribution to journalArticle

Ballinger, ML, Goode, DL, Ray-Coquard, I, James, PA, Mitchell, G, Niedermayr, E, Puri, A, Schiffman, JD, Dite, GS, Cipponi, A, Maki, RG, Brohl, AS, Myklebost, O, Stratford, EW, Lorenz, S, Ahn, SM, Ahn, JH, Kim, JE, Shanley, S, Beshay, V, Randall, R, Judson, I, Seddon, B, Campbell, IG, Young, MA, Sarin, R, Blay, JY, O'Donoghue, SI & Thomas, DM 2016, 'Monogenic and polygenic determinants of sarcoma risk: an international genetic study', The Lancet Oncology, vol. 17, no. 9, pp. 1261-1271. https://doi.org/10.1016/S1470-2045(16)30147-4
Ballinger ML, Goode DL, Ray-Coquard I, James PA, Mitchell G, Niedermayr E et al. Monogenic and polygenic determinants of sarcoma risk: an international genetic study. The Lancet Oncology. 2016 Sep 1;17(9):1261-1271. https://doi.org/10.1016/S1470-2045(16)30147-4
Ballinger, Mandy L. ; Goode, David L. ; Ray-Coquard, Isabelle ; James, Paul A. ; Mitchell, Gillian ; Niedermayr, Eveline ; Puri, Ajay ; Schiffman, Joshua D. ; Dite, Gillian S. ; Cipponi, Arcadi ; Maki, Robert G. ; Brohl, Andrew S. ; Myklebost, Ola ; Stratford, Eva W. ; Lorenz, Susanne ; Ahn, Sung Min ; Ahn, Jin Hee ; Kim, Jeong Eun ; Shanley, Sue ; Beshay, Victoria ; Randall, R ; Judson, Ian ; Seddon, Beatrice ; Campbell, Ian G. ; Young, Mary Anne ; Sarin, Rajiv ; Blay, Jean Yves ; O'Donoghue, Seán I. ; Thomas, David M. / Monogenic and polygenic determinants of sarcoma risk : an international genetic study. In: The Lancet Oncology. 2016 ; Vol. 17, No. 9. pp. 1261-1271.
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abstract = "Background Sarcomas are rare, phenotypically heterogeneous cancers that disproportionately affect the young. Outside rare syndromes, the nature, extent, and clinical significance of their genetic origins are not known. We aimed to investigate the genetic basis for bone and soft-tissue sarcoma seen in routine clinical practice. Methods In this genetic study, we included 1162 patients with sarcoma from four cohorts (the International Sarcoma Kindred Study [ISKS], 966 probands; Project GENESIS, 48 probands; Asan Bio-Resource Center, 138 probands; and kConFab, ten probands), who were older than 15 years at the time of consent and had a histologically confirmed diagnosis of sarcoma, recruited from specialist sarcoma clinics without regard to family history. Detailed clinical, pathological, and pedigree information was collected, and cancer diagnoses in probands and relatives were independently verified. Targeted exon sequencing using blood (n=1114) or saliva (n=48) samples was done on 72 genes (selected due to associations with increased cancer risk) and rare variants were stratified into classes approximating the International Agency for Research on Cancer (IARC) clinical classification for genetic variation. We did a case-control rare variant burden analysis using 6545 Caucasian controls included from three cohorts (ISKS, 235 controls; LifePool, 2010 controls; and National Heart, Lung, and Blood Institute Exome Sequencing Project [ESP], 4300 controls). Findings The median age at cancer diagnosis in 1162 sarcoma probands was 46 years (IQR 29–58), 170 (15{\%}) of 1162 probands had multiple primary cancers, and 155 (17{\%}) of 911 families with informative pedigrees fitted recognisable cancer syndromes. Using a case-control rare variant burden analysis, 638 (55{\%}) of 1162 sarcoma probands bore an excess of pathogenic germline variants (combined odds ratio [OR] 1·43, 95{\%} CI 1·24–1·64, p<0·0001), with 227 known or expected pathogenic variants occurring in 217 individuals. All classes of pathogenic variants (known, expected, or predicted) were associated with earlier age of cancer onset. In addition to TP53, ATM, ATR, and BRCA2, an unexpected excess of functionally pathogenic variants was seen in ERCC2. Probands were more likely than controls to have multiple pathogenic variants compared with the combined control cohort group and the LifePool control cohort (OR 2·22, 95{\%} CI 1·57–3·14, p=1·2 × 10−6) and the cumulative burden of multiple variants correlated with earlier age at cancer diagnosis (Mantel-Cox log-rank test for trend, p=0·0032). 66 of 1162 probands carried notifiable variants following expert clinical review (those recognised to be clinically significant to health and about which patients should be advised), whereas 293 (25{\%}) probands carried variants with potential therapeutic significance. Interpretation About half of patients with sarcoma have putatively pathogenic monogenic and polygenic variation in known and novel cancer genes, with implications for risk management and treatment. Funding Rainbows for Kate Foundation, Johanna Sewell Research Foundation, Australian National Health and Medical Research Council, Cancer Australia, Sarcoma UK, National Cancer Institute, Liddy Shriver Sarcoma Initiative.",
author = "Ballinger, {Mandy L.} and Goode, {David L.} and Isabelle Ray-Coquard and James, {Paul A.} and Gillian Mitchell and Eveline Niedermayr and Ajay Puri and Schiffman, {Joshua D.} and Dite, {Gillian S.} and Arcadi Cipponi and Maki, {Robert G.} and Brohl, {Andrew S.} and Ola Myklebost and Stratford, {Eva W.} and Susanne Lorenz and Ahn, {Sung Min} and Ahn, {Jin Hee} and Kim, {Jeong Eun} and Sue Shanley and Victoria Beshay and R Randall and Ian Judson and Beatrice Seddon and Campbell, {Ian G.} and Young, {Mary Anne} and Rajiv Sarin and Blay, {Jean Yves} and O'Donoghue, {Se{\'a}n I.} and Thomas, {David M.}",
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TY - JOUR

T1 - Monogenic and polygenic determinants of sarcoma risk

T2 - an international genetic study

AU - Ballinger, Mandy L.

AU - Goode, David L.

AU - Ray-Coquard, Isabelle

AU - James, Paul A.

AU - Mitchell, Gillian

AU - Niedermayr, Eveline

AU - Puri, Ajay

AU - Schiffman, Joshua D.

AU - Dite, Gillian S.

AU - Cipponi, Arcadi

AU - Maki, Robert G.

AU - Brohl, Andrew S.

AU - Myklebost, Ola

AU - Stratford, Eva W.

AU - Lorenz, Susanne

AU - Ahn, Sung Min

AU - Ahn, Jin Hee

AU - Kim, Jeong Eun

AU - Shanley, Sue

AU - Beshay, Victoria

AU - Randall, R

AU - Judson, Ian

AU - Seddon, Beatrice

AU - Campbell, Ian G.

AU - Young, Mary Anne

AU - Sarin, Rajiv

AU - Blay, Jean Yves

AU - O'Donoghue, Seán I.

AU - Thomas, David M.

PY - 2016/9/1

Y1 - 2016/9/1

N2 - Background Sarcomas are rare, phenotypically heterogeneous cancers that disproportionately affect the young. Outside rare syndromes, the nature, extent, and clinical significance of their genetic origins are not known. We aimed to investigate the genetic basis for bone and soft-tissue sarcoma seen in routine clinical practice. Methods In this genetic study, we included 1162 patients with sarcoma from four cohorts (the International Sarcoma Kindred Study [ISKS], 966 probands; Project GENESIS, 48 probands; Asan Bio-Resource Center, 138 probands; and kConFab, ten probands), who were older than 15 years at the time of consent and had a histologically confirmed diagnosis of sarcoma, recruited from specialist sarcoma clinics without regard to family history. Detailed clinical, pathological, and pedigree information was collected, and cancer diagnoses in probands and relatives were independently verified. Targeted exon sequencing using blood (n=1114) or saliva (n=48) samples was done on 72 genes (selected due to associations with increased cancer risk) and rare variants were stratified into classes approximating the International Agency for Research on Cancer (IARC) clinical classification for genetic variation. We did a case-control rare variant burden analysis using 6545 Caucasian controls included from three cohorts (ISKS, 235 controls; LifePool, 2010 controls; and National Heart, Lung, and Blood Institute Exome Sequencing Project [ESP], 4300 controls). Findings The median age at cancer diagnosis in 1162 sarcoma probands was 46 years (IQR 29–58), 170 (15%) of 1162 probands had multiple primary cancers, and 155 (17%) of 911 families with informative pedigrees fitted recognisable cancer syndromes. Using a case-control rare variant burden analysis, 638 (55%) of 1162 sarcoma probands bore an excess of pathogenic germline variants (combined odds ratio [OR] 1·43, 95% CI 1·24–1·64, p<0·0001), with 227 known or expected pathogenic variants occurring in 217 individuals. All classes of pathogenic variants (known, expected, or predicted) were associated with earlier age of cancer onset. In addition to TP53, ATM, ATR, and BRCA2, an unexpected excess of functionally pathogenic variants was seen in ERCC2. Probands were more likely than controls to have multiple pathogenic variants compared with the combined control cohort group and the LifePool control cohort (OR 2·22, 95% CI 1·57–3·14, p=1·2 × 10−6) and the cumulative burden of multiple variants correlated with earlier age at cancer diagnosis (Mantel-Cox log-rank test for trend, p=0·0032). 66 of 1162 probands carried notifiable variants following expert clinical review (those recognised to be clinically significant to health and about which patients should be advised), whereas 293 (25%) probands carried variants with potential therapeutic significance. Interpretation About half of patients with sarcoma have putatively pathogenic monogenic and polygenic variation in known and novel cancer genes, with implications for risk management and treatment. Funding Rainbows for Kate Foundation, Johanna Sewell Research Foundation, Australian National Health and Medical Research Council, Cancer Australia, Sarcoma UK, National Cancer Institute, Liddy Shriver Sarcoma Initiative.

AB - Background Sarcomas are rare, phenotypically heterogeneous cancers that disproportionately affect the young. Outside rare syndromes, the nature, extent, and clinical significance of their genetic origins are not known. We aimed to investigate the genetic basis for bone and soft-tissue sarcoma seen in routine clinical practice. Methods In this genetic study, we included 1162 patients with sarcoma from four cohorts (the International Sarcoma Kindred Study [ISKS], 966 probands; Project GENESIS, 48 probands; Asan Bio-Resource Center, 138 probands; and kConFab, ten probands), who were older than 15 years at the time of consent and had a histologically confirmed diagnosis of sarcoma, recruited from specialist sarcoma clinics without regard to family history. Detailed clinical, pathological, and pedigree information was collected, and cancer diagnoses in probands and relatives were independently verified. Targeted exon sequencing using blood (n=1114) or saliva (n=48) samples was done on 72 genes (selected due to associations with increased cancer risk) and rare variants were stratified into classes approximating the International Agency for Research on Cancer (IARC) clinical classification for genetic variation. We did a case-control rare variant burden analysis using 6545 Caucasian controls included from three cohorts (ISKS, 235 controls; LifePool, 2010 controls; and National Heart, Lung, and Blood Institute Exome Sequencing Project [ESP], 4300 controls). Findings The median age at cancer diagnosis in 1162 sarcoma probands was 46 years (IQR 29–58), 170 (15%) of 1162 probands had multiple primary cancers, and 155 (17%) of 911 families with informative pedigrees fitted recognisable cancer syndromes. Using a case-control rare variant burden analysis, 638 (55%) of 1162 sarcoma probands bore an excess of pathogenic germline variants (combined odds ratio [OR] 1·43, 95% CI 1·24–1·64, p<0·0001), with 227 known or expected pathogenic variants occurring in 217 individuals. All classes of pathogenic variants (known, expected, or predicted) were associated with earlier age of cancer onset. In addition to TP53, ATM, ATR, and BRCA2, an unexpected excess of functionally pathogenic variants was seen in ERCC2. Probands were more likely than controls to have multiple pathogenic variants compared with the combined control cohort group and the LifePool control cohort (OR 2·22, 95% CI 1·57–3·14, p=1·2 × 10−6) and the cumulative burden of multiple variants correlated with earlier age at cancer diagnosis (Mantel-Cox log-rank test for trend, p=0·0032). 66 of 1162 probands carried notifiable variants following expert clinical review (those recognised to be clinically significant to health and about which patients should be advised), whereas 293 (25%) probands carried variants with potential therapeutic significance. Interpretation About half of patients with sarcoma have putatively pathogenic monogenic and polygenic variation in known and novel cancer genes, with implications for risk management and treatment. Funding Rainbows for Kate Foundation, Johanna Sewell Research Foundation, Australian National Health and Medical Research Council, Cancer Australia, Sarcoma UK, National Cancer Institute, Liddy Shriver Sarcoma Initiative.

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