Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Sep 1;76(17):5103-14.
doi: 10.1158/0008-5472.CAN-15-2980. Epub 2016 Apr 20.

Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

Gordon Fehringer  1 , Peter Kraft  2 , Paul D Pharoah  3 , Rosalind A Eeles  4 , Nilanjan Chatterjee  5 , Fredrick R Schumacher  6 , Joellen M Schildkraut  7 , Sara Lindström  2 , Paul Brennan  8 , Heike Bickeböller  9 , Richard S Houlston  4 , Maria Teresa Landi  5 , Neil Caporaso  5 , Angela Risch  10 , Ali Amin Al Olama  11 , Sonja I Berndt  5 , Edward L Giovannucci  2 , Henrik Grönberg  12 , Zsofia Kote-Jarai  4 , Jing Ma  13 , Kenneth Muir  14 , Meir J Stampfer  15 , Victoria L Stevens  16 , Fredrik Wiklund  12 , Walter C Willett  2 , Ellen L Goode  17 , Jennifer B Permuth  18 , Harvey A Risch  19 , Brett M Reid  18 , Stephane Bezieau  20 , Hermann Brenner  21 , Andrew T Chan  22 , Jenny Chang-Claude  23 , Thomas J Hudson  24 , Jonathan K Kocarnik  25 , Polly A Newcomb  25 , Robert E Schoen  26 , Martha L Slattery  27 , Emily White  25 , Muriel A Adank  28 , Habibul Ahsan  29 , Kristiina Aittomäki  30 , Laura Baglietto  31 , Carl Blomquist  30 , Federico Canzian  32 , Kamila Czene  12 , Isabel Dos-Santos-Silva  33 , A Heather Eliassen  34 , Jonine D Figueroa  5 , Dieter Flesch-Janys  35 , Olivia Fletcher  36 , Montserrat Garcia-Closas  5 , Mia M Gaudet  16 , Nichola Johnson  36 , Per Hall  12 , Aditi Hazra  15 , Rebecca Hein  37 , Albert Hofman  38 , John L Hopper  39 , Astrid Irwanto  40 , Mattias Johansson  41 , Rudolf Kaaks  23 , Muhammad G Kibriya  29 , Peter Lichtner  42 , Jianjun Liu  40 , Eiliv Lund  43 , Enes Makalic  39 , Alfons Meindl  44 , Bertram Müller-Myhsok  45 , Taru A Muranen  30 , Heli Nevanlinna  30 , Petra H Peeters  46 , Julian Peto  33 , Ross L Prentice  25 , Nazneen Rahman  47 , Maria Jose Sanchez  48 , Daniel F Schmidt  39 , Rita K Schmutzler  49 , Melissa C Southey  31 , Rulla Tamimi  15 , Ruth C Travis  50 , Clare Turnbull  47 , Andre G Uitterlinden  51 , Zhaoming Wang  5 , Alice S Whittemore  52 , Xiaohong R Yang  5 , Wei Zheng  53 , Daniel D Buchanan  31 , Graham Casey  6 , David V Conti  6 , Christopher K Edlund  6 , Steven Gallinger  1 , Robert W Haile  52 , Mark Jenkins  31 , Loïc Le Marchand  54 , Li Li  55 , Noralene M Lindor  56 , Stephanie L Schmit  6 , Stephen N Thibodeau  17 , Michael O Woods  57 , Thorunn Rafnar  58 , Julius Gudmundsson  58 , Simon N Stacey  58 , Kari Stefansson  58 , Patrick Sulem  58 , Y Ann Chen  18 , Jonathan P Tyrer  3 , David C Christiani  2 , Yongyue Wei  2 , Hongbing Shen  59 , Zhibin Hu  59 , Xiao-Ou Shu  53 , Kouya Shiraishi  60 , Atsushi Takahashi  61 , Yohan Bossé  62 , Ma'en Obeidat  63 , David Nickle  64 , Wim Timens  65 , Matthew L Freedman  66 , Qiyuan Li  67 , Daniela Seminara  5 , Stephen J Chanock  5 , Jian Gong  25 , Ulrike Peters  25 , Stephen B Gruber  6 , Christopher I Amos  68 , Thomas A Sellers  18 , Douglas F Easton  3 , David J Hunter  2 , Christopher A Haiman  6 , Brian E Henderson  6 , Rayjean J Hung  69 ; Ovarian Cancer Association Consortium (OCAC); PRACTICAL Consortium; Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON); Colorectal Transdisciplinary (CORECT) Study; African American Breast Cancer Consortium (AABC) and African Ancestry Prostate Cancer Consortium (AAPC)
Affiliations

Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

Gordon Fehringer et al. Cancer Res. .

Abstract

Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103-14. ©2016 AACR.

PubMed Disclaimer

Conflict of interest statement

of Potential Conflicts of Interest: Dr. David Nickle is a full time employee at Merck & Co. No potential conflicts of interest were disclosed by other authors.

Figures

Figure 1
Figure 1
Result for rs1057941. Forest plot showing per allele ORs for risk allele A (of A/G). Standard fixed effects meta-analysis (also indicated by dashed line), and subset meta-analysis results (two-sided, one-sided and positive and negative subset associations) are shown. Abbreviations - CRC: colorectal, ERNEG: estrogen receptor negative, Aggrsv: aggressive, Adeno: Adenocarcinoma.
Figure 2
Figure 2
Results for rs1057941 (A) Regional plot showing P values from overall meta-analysis at region 1q22 using GAME-ON/GECCO discovery set data. The top breast cancer hit (rs3814316) and top squamous cell carcinoma hit (rs4072037) are also highlighted. (B) Boxplots of gene expression levels in normal lung tissue for ADAM15 and THBS3 by study (Laval, UBC, Groningen).
Figure 3
Figure 3
Results for rs13016963: (A) Forest plot showing per allele ORs for risk allele G (of A/G). Standard fixed effects meta-analysis (also indicated by dashed line), and subset meta-analysis results (two-sided, one-sided and positive and negative subset associations) are shown. (B) Regional plot showing P values for GAME-ON prostate cancer GWAS at region 2q33.1 using GAME-ON/GECCO discovery set data. Peak is at ALS2CR12. (C) Boxplot of BZW1 gene expression levels in prostate tumor and normal tissue for rs1035142/rs13016963. rs1035142 is presented as a surrogate for rs13016963, with which it shows perfect LD in eQTL data. Abbreviations - CRC: colorectal, ERNEG: estrogen receptor negative, Aggrsv: aggressive, Adeno: Adenocarcinoma.
Figure 4
Figure 4
Results for rs62560775: (A) Forest plot showing per allele ORs for risk allele G (of A/G). Standard fixed effects meta-analysis (also indicated by dashed line), and subset meta-analysis results (two-sided, one-sided and positive and negative subset associations) are shown. (B) Regional plot showing P values for GAME-ON lung adenocarcinoma GWAS at region 9p21.3, using GAME-ON/GECCO discovery set data. Peak is at CDKN2B-AS1. Results for rs1011970: (C) Forest plot showing per allele ORs for risk allele T (of T/G). Standard fixed effects meta-analysis (also indicated by dashed line), and subset meta-analysis results (two-sided, one-sided and positive and negative subset associations) are shown. (D) Regional plot showing P values for GAME-ON prostate cancer GWAS at region 9p21.3, using GAME-ON/GECCO discovery set data. Peak is at CDKN2B-AS1. Abbreviations - CRC: colorectal, ERNEG: estrogen receptor negative, Aggrsv: aggressive, Adeno: Adenocarcinoma.
See this image and copyright information in PMC

Comment in

References

    1. Hindorff L, MacArthur J, Morales J, Junkins H, Hall P, Klemm A, et al. [Accessed 2014 13/10/2014];A Catalog of Published Genome-Wide Association Studies. < www.genome.gov/gwastudies>.
    1. Ghoussaini M, Song H, Koessler T, Al Olama AA, Kote-Jarai Z, Driver KE, et al. Multiple loci with different cancer specificities within the 8q24 gene desert. Journal of the National Cancer Institute. 2008;100:962–6. - PMC - PubMed
    1. Rafnar T, Sulem P, Stacey SN, Geller F, Gudmundsson J, Sigurdsson A, et al. Sequence variants at the TERT-CLPTM1L locus associate with many cancer types. Nature genetics. 2009;41:221–7. - PMC - PubMed
    1. Bhattacharjee S, Rajaraman P, Jacobs KB, Wheeler WA, Melin BS, Hartge P, et al. A subset-based approach improves power and interpretation for the combined analysis of genetic association studies of heterogeneous traits. American journal of human genetics. 2012;90:821–35. - PMC - PubMed
    1. Peters U, Jiao S, Schumacher FR, Hutter CM, Aragaki AK, Baron JA, et al. Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis. Gastroenterology. 2013;144:799–807. e24. - PMC - PubMed

Publication types

Grants and funding