TY - JOUR
T1 - Quantifying the genetic correlation between multiple cancer types
AU - Lindström, Sara
AU - Finucane, Hilary
AU - Bulik-Sullivan, Brendan
AU - Schumacher, Fredrick R.
AU - Amos, Christopher I.
AU - Hung, Rayjean J.
AU - Rand, Kristin
AU - Gruber, Stephen B.
AU - Conti, David
AU - Permuth, Jennifer B.
AU - Lin, Hui Yi
AU - Goode, Ellen L.
AU - Sellers, Thomas A.
AU - Amundadottir, Laufey T.
AU - Stolzenberg-Solomon, Rachael
AU - Klein, Alison
AU - Petersen, Gloria
AU - Risch, Harvey
AU - Wolpin, Brian
AU - Hsu, Li
AU - Huyghe, Jeroen R.
AU - Chang-Claude, Jenny
AU - Chan, Andrew
AU - Berndt, Sonja
AU - Eeles, Rosalind
AU - Easton, Douglas
AU - Haiman, Christopher A.
AU - Hunter, David J.
AU - Neale, Benjamin
AU - Price, Alkes L.
AU - Kraft, Peter
N1 - Funding Information:
CCFR: This work was supported by grant UM1 CA167551 from the National Cancer Institute and through cooperative agreements with the following CCFR centers: Ontario Familial Colorectal Cancer Registry (U01/U24 CA074783) and Seattle Colorectal Cancer Family Registry (U01/U24 CA074794).
Funding Information:
This work was supported by the Genetic Associations and Mechanisms in Oncology Network, GAME-ON (http://epi.grants.cancer.gov/gameon/), which includes the following consortia: CORECT (grant number U19 CA148107); DRIVE (U19 CA148065); ELLIPSE (grant number U19 CA148537); FOCI (U19 CA148112); TRICL (U19 CA148127). This work was also supported by NIH grants CA194393, CA173785 and CA189532. R. Eeles is supported by NIHR funding to the Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden NHS Foundation Trust. HKF is supported by the Fannie and John Hertz Foundation.
Funding Information:
GECCO was supported by National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088; U01 CA164930). Genotyping/Sequencing services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the NIH to The Johns Hopkins University, contract number HHSN268201200008I.
Funding Information:
DACHS: German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS: NIH (R01 CA48998 to M.L. Slattery).
Funding Information:
ASTERISK: A Hospital Clinical Research Program (PHRC-BRD09/C) from the University Hospital Center of Nantes (CHU de Nantes) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Franc¸aises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC). COLO2&3: NIH (R01 CA60987).
Funding Information:
The Colon CFR GWAS was supported by funding from the National Cancer Institute, NIH (U01 CA122839 and R01 CA143237 to Graham Casey). The content of this manuscript does not necessarily reflect the views or policies of the National CancerInstitute oranyofthecollaboratingcentersintheColon Cancer Family Registry (CCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CCFR.
Funding Information:
HPFS is supported by the NIH (P01 CA055075, UM1 CA167552, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003), NHS and NHS II by the NIH (R01 CA137178, P01 CA087969, UM1 CA186107, UM1 CA176726, R01 CA67262, R01 CA151993, R01 CA49449, R35 CA197735, K07 CA190673, and P50 CA127003), and PHS by the NIH (R01 CA042182). MEC: NIH (R37 CA54281, P01 CA033619, and R01 CA63464).
Funding Information:
PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. In addition, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS (Yeager, M and colleagues Genome-wide association study of prostate cancer identifies a second risk locus at 8q24 [Nat Genet 2007 May;39(5):645–9], CGEMS pancreatic cancer scan (PanScan; Amundadottir and colleagues, Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer; [Nat Genet. 2009 Sep;41(9):986–90], and Petersen and colleagues [A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet. 2010 Mar;42(3):224–8], and the Lung Cancer and Smoking study [Landi and colleagues, A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma; Am J Hum Genet 2009 Nov;85 (5):679–91]. The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http://cgems.can cer.gov/data/) accession numbers phs000207.v1.p1 and phs000206.v3.p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093. v2.p2. Funding for the Lung Cancer and Smoking study was provided by NIH, Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. PMH: NIH (R01 CA076366 to P.A. Newcomb). VITAL: NIH (K05 CA154337).
Funding Information:
OFCCR: NIH, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see previous CCFR section. Additional funding toward genetic analyses of OFCCR includes the Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation.
Funding Information:
WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute,NIH,U.S.DepartmentofHealthandHumanServicesthroughcontracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C.
Funding Information:
PanScan is supported by the Intramural Research Program of the NIH, National Cancer Institute.
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - Background: Many cancers share specific genetic risk factors, including both rare high-penetrance mutations and common SNPs identified through genome-wide association studies (GWAS). However, little is known about the overall shared heritability across cancers. Quantifying the extent to which two distinct cancers share genetic origin will give insights to shared biological mechanisms underlying cancer and inform design for future genetic association studies. Methods: In this study, we estimated the pair-wise genetic correlation between six cancer types (breast, colorectal, lung, ovarian, pancreatic, and prostate) using cancer-specific GWAS summary statistics data based on 66,958 case and 70,665 control subjects of European ancestry. We also estimated genetic correlations between cancers and 14 noncancer diseases and traits. Results: After adjusting for 15 pair-wise genetic correlation tests between cancers, we found significant (P < 0.003) genetic correlations between pancreatic and colorectal cancer (rg = 0.55, P = 0.003), lung and colorectal cancer (rg = 0.31, P = 0.001). We also found suggestive genetic correlations between lung and breast cancer (rg = 0.27, P = 0.009), and colorectal and breast cancer (rg = 0.22, P = 0.01). In contrast, we found no evidence that prostate cancer shared an appreciable proportion of heritability with other cancers. After adjusting for 84 tests studying genetic correlations between cancer types and other traits (Bonferroni-corrected P value: 0.0006), only the genetic correlation between lung cancer and smoking remained significant (rg = 0.41, P = 1.03 × 10-6). We also observed nominally significant genetic correlations between body mass index and all cancers except ovarian cancer. Conclusions: Our results highlight novel genetic correlations and lend support to previous observational studies that have observed links between cancers and risk factors. Impact: This study demonstrates modest genetic correlations between cancers; in particular, breast, colorectal, and lung cancer share some degree of genetic basis.
AB - Background: Many cancers share specific genetic risk factors, including both rare high-penetrance mutations and common SNPs identified through genome-wide association studies (GWAS). However, little is known about the overall shared heritability across cancers. Quantifying the extent to which two distinct cancers share genetic origin will give insights to shared biological mechanisms underlying cancer and inform design for future genetic association studies. Methods: In this study, we estimated the pair-wise genetic correlation between six cancer types (breast, colorectal, lung, ovarian, pancreatic, and prostate) using cancer-specific GWAS summary statistics data based on 66,958 case and 70,665 control subjects of European ancestry. We also estimated genetic correlations between cancers and 14 noncancer diseases and traits. Results: After adjusting for 15 pair-wise genetic correlation tests between cancers, we found significant (P < 0.003) genetic correlations between pancreatic and colorectal cancer (rg = 0.55, P = 0.003), lung and colorectal cancer (rg = 0.31, P = 0.001). We also found suggestive genetic correlations between lung and breast cancer (rg = 0.27, P = 0.009), and colorectal and breast cancer (rg = 0.22, P = 0.01). In contrast, we found no evidence that prostate cancer shared an appreciable proportion of heritability with other cancers. After adjusting for 84 tests studying genetic correlations between cancer types and other traits (Bonferroni-corrected P value: 0.0006), only the genetic correlation between lung cancer and smoking remained significant (rg = 0.41, P = 1.03 × 10-6). We also observed nominally significant genetic correlations between body mass index and all cancers except ovarian cancer. Conclusions: Our results highlight novel genetic correlations and lend support to previous observational studies that have observed links between cancers and risk factors. Impact: This study demonstrates modest genetic correlations between cancers; in particular, breast, colorectal, and lung cancer share some degree of genetic basis.
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U2 - 10.1158/1055-9965.EPI-17-0211
DO - 10.1158/1055-9965.EPI-17-0211
M3 - Article
C2 - 28637796
AN - SCOPUS:85028912366
VL - 26
SP - 1427
EP - 1435
JO - Cancer Epidemiology Biomarkers and Prevention
JF - Cancer Epidemiology Biomarkers and Prevention
SN - 1055-9965
IS - 9
ER -