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

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 c...

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Vydáno v:The lancet oncology Ročník 17; číslo 9; s. 1261 - 1271
Hlavní autoři: 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, Robert Lor, Judson, Ian, Seddon, Beatrice, Campbell, Ian G, Young, Mary-Anne, Sarin, Rajiv, Blay, Jean-Yves, O'Donoghue, Seán I, Thomas, David M
Médium: Journal Article
Jazyk:angličtina
Vydáno: England Elsevier Ltd 01.09.2016
Elsevier Limited
Témata:
Adolescent
Adult
Age
Aged
Aged, 80 and over
Biomarkers, Tumor - blood
Biomarkers, Tumor - genetics
Breast cancer
Case-Control Studies
Cell cycle
Child
Child, Preschool
Classification
Disease
Exome - genetics
Family medical history
Female
Follow-Up Studies
Genes
Genetic diversity
Genomes
Genotype & phenotype
Health risk assessment
Hematology, Oncology and Palliative Medicine
High-Throughput Nucleotide Sequencing - methods
Humans
Infant
Infant, Newborn
International Agencies
Male
Mammography
Medical research
Middle Aged
Mutation
Mutation - genetics
Neoplasm Staging
Pedigree
Population
Prognosis
Risk Factors
Saliva
Saliva - chemistry
Sarcoma
Sarcoma - blood
Sarcoma - genetics
Studies
Young Adult
ISSN:1470-2045, 1474-5488, 1474-5488
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Shrnutí: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. 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). 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. 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. 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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ISSN:1470-2045
1474-5488
1474-5488
DOI:10.1016/S1470-2045(16)30147-4