title: Monogenic and polygenic determinants of sarcoma risk: an international genetic study.
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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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.
authors: The Kinghorn Cancer Centre and Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors: Mandy L
authors: ML
authors: Ballinger
authors: Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors: David L
authors: DL
authors: Goode
authors: Department of Adult Medical Oncology, Centre Leon Berard, University Claude Bernard, Lyon, France.
authors: Isabelle
authors: I
authors: Ray-Coquard
authors: Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Department of Pathology, University of Melbourne, Melbourne, VIC, Australia; Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors: Paul A
authors: PA
authors: James
authors: Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors: Gillian
authors: G
authors: Mitchell
authors: Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors: Eveline
authors: E
authors: Niedermayr
authors: Department of Orthopedic Oncology, Tata Memorial Hospital, Mumbai, India.
authors: Ajay
authors: A
authors: Puri
authors: Division of Pediatric Hematology/Oncology, Department of Pediatrics, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors: Joshua D
authors: JD
authors: Schiffman
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia.
authors: Gillian S
authors: GS
authors: Dite
authors: The Kinghorn Cancer Centre and Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
authors: Arcadi
authors: A
authors: Cipponi
authors: Tisch Cancer Institute, Mount Sinai Medical Center, New York, NY, USA.
authors: Robert G
authors: RG
authors: Maki
authors: Sarcoma Department, Moffitt Cancer Center, Tampa, FL, USA.
authors: Andrew S
authors: AS
authors: Brohl
authors: Department of Tumor Biology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; Norwegian Cancer Genomics Consortium, Oslo, Norway.
authors: Ola
authors: O
authors: Myklebost
authors: Department of Tumor Biology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; Norwegian Cancer Genomics Consortium, Oslo, Norway.
authors: Eva W
authors: EW
authors: Stratford
authors: Department of Tumor Biology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; Norwegian Cancer Genomics Consortium, Oslo, Norway.
authors: Susanne
authors: S
authors: Lorenz
authors: Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, South Korea.
authors: Sung-Min
authors: SM
authors: Ahn
authors: Department of Oncology, Asan Medical Centre, Seoul, South Korea.
authors: Jin-Hee
authors: JH
authors: Ahn
authors: Department of Oncology, Asan Medical Centre, Seoul, South Korea.
authors: Jeong Eun
authors: JE
authors: Kim
authors: Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors: Sue
authors: S
authors: Shanley
authors: Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors: Victoria
authors: V
authors: Beshay
authors: Sarcoma Services, Department of Orthopaedics, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors: Robert Lor
authors: RL
authors: Randall
authors: Sarcoma Unit, The Royal Marsden NHS Foundation Trust, London, UK.
authors: Ian
authors: I
authors: Judson
authors: Sarcoma Unit, University College Hospital, London, UK.
authors: Beatrice
authors: B
authors: Seddon
authors: Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Department of Pathology, University of Melbourne, Melbourne, VIC, Australia; Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors: Ian G
authors: IG
authors: Campbell
authors: Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
authors: Mary-Anne
authors: MA
authors: Young
authors: Cancer Genetics Unit, ACTREC, Tata Memorial Centre, Mumbai, India.
authors: Rajiv
authors: R
authors: Sarin
authors: Department of Adult Medical Oncology, Centre Leon Berard, University Claude Bernard, Lyon, France.
authors: Jean-Yves
authors: JY
authors: Blay
authors: Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Commonwealth Scientific and Industrial Research Organisation (CSIRO), Sydney, Australia.
authors: Seán I
authors: SI
authors: O'Donoghue
authors: The Kinghorn Cancer Centre and Cancer Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia. Electronic address: d.thomas@garvan.org.au.
authors: David M
authors: DM
authors: Thomas
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D059472:Exome / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007390:International Agencies; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D010375:Pedigree; D011379:Prognosis; D012307:Risk Factors; D012463:Saliva / Q000737:chemistry*; D012509:Sarcoma / Q000097:blood / Q000235:genetics*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor