Genome-wide association study identifies tumor anatomical site-specific risk variants for colorectal cancer survival

Julia D Labadie^{1

2}, Sevtap Savas^{3

4}, Tabitha A Harrison¹, Barb Banbury¹, Yuhan Huang^{1

2}, Daniel D Buchanan^{5

6

7}, Peter T Campbell⁸, Steven J Gallinger⁹, Graham G Giles^{5

10

11}, Marc J Gunter¹², Michael Hoffmeister¹³, Li Hsu¹, Mark A Jenkins⁵, Yi Lin¹, Shuji Ogino^{14

15

16

17}, Amanda I Phipps^{1

2}, Martha L Slattery¹⁸, Robert S Steinfelder¹, Wei Sun¹, Bethany Van Guelpen^{19

20}, Xinwei Hua^{1

2}, Jane C Figuieredo^{21

22}, Rish K Pai²³, Rami Nassir²⁴, Lihong Qi²⁵, Andrew T Chan^{26

27

28

29}, Ulrike Peters^{1

2}, Polly A Newcomb^{30

31}

Affiliations

¹ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
² Department of Epidemiology, University of Washington, Seattle, WA, USA.
³ Discipline of Genetics, Faculty of Medicine, Memorial University, St. John's, NL, Canada.
⁴ Discipline of Oncology, Faculty of Medicine, Memorial University, St. John's, NL, Canada.
⁵ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
⁶ Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia.
⁷ Genetic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, VIC, Australia.
⁸ Department of Population Science, American Cancer Society, Atlanta, GA, USA.
⁹ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
¹⁰ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
¹¹ Medicine, School of Clinical Sciences at Monash Health, Monash University, VIC, Australia.
¹² Nutrition and Metabolism Section, International Agency for Research On Cancer, World Health Organization, Lyon, France.
¹³ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁴ Program in Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁵ Cancer Immunology Program, Dana-Farber Harvard Cancer Center, Boston, MA, USA.
¹⁶ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁷ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁸ Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA.
¹⁹ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
²⁰ Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
²¹ Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
²² Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
²³ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
²⁴ Department of Pathology, School of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
²⁵ Department of Public Health Sciences, University of California Davis, Davis, CA, USA.
²⁶ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²⁷ Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
²⁸ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²⁹ Broad Institute of Harvard and MIT, Cambridge, MA, USA.
³⁰ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. pnewcomb@fredhutch.org.
³¹ Department of Epidemiology, University of Washington, Seattle, WA, USA. pnewcomb@fredhutch.org.

PMID: 34996992
PMCID: PMC8741984
DOI: 10.1038/s41598-021-03945-x

Comparative Study

Genome-wide association study identifies tumor anatomical site-specific risk variants for colorectal cancer survival

Julia D Labadie et al. Sci Rep. 2022.

. 2022 Jan 7;12(1):127.

doi: 10.1038/s41598-021-03945-x.

Authors

Affiliations

¹ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
² Department of Epidemiology, University of Washington, Seattle, WA, USA.
³ Discipline of Genetics, Faculty of Medicine, Memorial University, St. John's, NL, Canada.
⁴ Discipline of Oncology, Faculty of Medicine, Memorial University, St. John's, NL, Canada.
⁵ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
⁶ Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia.
⁷ Genetic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, VIC, Australia.
⁸ Department of Population Science, American Cancer Society, Atlanta, GA, USA.
⁹ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
¹⁰ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
¹¹ Medicine, School of Clinical Sciences at Monash Health, Monash University, VIC, Australia.
¹² Nutrition and Metabolism Section, International Agency for Research On Cancer, World Health Organization, Lyon, France.
¹³ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁴ Program in Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁵ Cancer Immunology Program, Dana-Farber Harvard Cancer Center, Boston, MA, USA.
¹⁶ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁷ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁸ Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA.
¹⁹ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
²⁰ Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
²¹ Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
²² Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
²³ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
²⁴ Department of Pathology, School of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
²⁵ Department of Public Health Sciences, University of California Davis, Davis, CA, USA.
²⁶ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²⁷ Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
²⁸ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²⁹ Broad Institute of Harvard and MIT, Cambridge, MA, USA.
³⁰ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. pnewcomb@fredhutch.org.
³¹ Department of Epidemiology, University of Washington, Seattle, WA, USA. pnewcomb@fredhutch.org.

PMID: 34996992
PMCID: PMC8741984
DOI: 10.1038/s41598-021-03945-x

Abstract

Identification of new genetic markers may improve the prediction of colorectal cancer prognosis. Our objective was to examine genome-wide associations of germline genetic variants with disease-specific survival in an analysis of 16,964 cases of colorectal cancer. We analyzed genotype and colorectal cancer-specific survival data from a consortium of 15 studies. Approximately 7.5 million SNPs were examined under the log-additive model using Cox proportional hazards models, adjusting for clinical factors and principal components. Additionally, we ran secondary analyses stratifying by tumor site and disease stage. We used a genome-wide p-value threshold of 5 × 10^-8 to assess statistical significance. No variants were statistically significantly associated with disease-specific survival in the full case analysis or in the stage-stratified analyses. Three SNPs were statistically significantly associated with disease-specific survival for cases with tumors located in the distal colon (rs698022, HR = 1.48, CI 1.30-1.69, p = 8.47 × 10^-9) and the proximal colon (rs189655236, HR = 2.14, 95% CI 1.65-2.77, p = 9.19 × 10^-9 and rs144717887, HR = 2.01, 95% CI 1.57-2.58, p = 3.14 × 10^-8), whereas no associations were detected for rectal tumors. Findings from this large genome-wide association study highlight the potential for anatomical-site-stratified genome-wide studies to identify germline genetic risk variants associated with colorectal cancer-specific survival. Larger sample sizes and further replication efforts are needed to more fully interpret these findings.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Figure 1**
Manhattan plot of -log₁₀ p-values by genomic position for the genome-wide analysis of colorectal cancer survival in 16,964 cases. The red line indicates genome-wide significance threshold (p = 5 × 10^–8).

**Figure 2**
Manhattan plots of -log₁₀ p-values by genomic position for the genome-wide analysis of colorectal cancer survival stratified by tumor site. (A) proximal colon tumor-specific in 6,214 cases, (B) distal colon tumor-specific in 4,881 cases, (C) rectal tumor-specific in 4,749 cases. The red line indicates genome-wide significance threshold (p = 5 × 10^–8).

See this image and copyright information in PMC

References

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Genome-wide association study identifies tumor anatomical site-specific risk variants for colorectal cancer survival

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Genome-wide association study identifies tumor anatomical site-specific risk variants for colorectal cancer survival

Authors

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Abstract

Conflict of interest statement

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