. 2022 Jun 17;12(1):10207.

doi: 10.1038/s41598-022-14408-2.

Association between germline variants and somatic mutations in colorectal cancer

Richard Barfield¹, Conghui Qu², Robert S Steinfelder², Chenjie Zeng³, Tabitha A Harrison², Stefanie Brezina⁴, Daniel D Buchanan^{5

6

7}, Peter T Campbell⁸, Graham Casey⁹, Steven Gallinger¹⁰, Marios Giannakis^{11

12}, Stephen B Gruber¹³, Andrea Gsur⁴, Li Hsu^{2

14}, Jeroen R Huyghe², Victor Moreno^{15

16

17

18}, Polly A Newcomb^{2

19}, Shuji Ogino^{12

20

21

22}, Amanda I Phipps^{2

23}, Martha L Slattery²⁴, Stephen N Thibodeau²⁵, Quang M Trinh²⁶, Amanda E Toland²⁷, Thomas J Hudson²⁶, Wei Sun^{2

14

28}, Syed H Zaidi²⁶, Ulrike Peters^{29

30}

Affiliations

¹ Department of Biostatistics and Bioinformatics, Duke University, 11028A Hock Plaza, 2424 Erwin Road Suite 1106, Durham, NC, 27705, USA. richard.barfield@duke.edu.
² Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
³ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁴ Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
⁵ Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.
⁶ University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, 3010, Australia.
⁷ Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, VIC, Australia.
⁸ Department of Epidemiology and Population Science, Albert Einstein College of Medicine, Bronx, NY, USA.
⁹ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
¹⁰ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
¹² The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹³ Department of Medical Oncology and Therapeuytic, University of Southern California, Los Angeles, CA, USA.
¹⁴ Department of Biostatistics, University of Washington, Seattle, WA, USA.
¹⁵ Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
¹⁶ CIBER Epidemiología Y Salud Pública (CIBERESP), Madrid, Spain.
¹⁷ Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
¹⁸ ONCOBEL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
¹⁹ School of Public Health, University of Washington, Seattle, WA, USA.
²⁰ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²¹ Cancer Immunology Program, Dana-Farber Harvard Cancer Center, Boston, MA, USA.
²² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²³ Department of Epidemiology, Fred Hutchinson Cancer Research Center, University of Washington, 1100 Fairview Ave N, Mail Stop M4-B402, Seattle, WA, 98109, USA.
²⁴ Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
²⁵ Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
²⁶ Ontario Institute for Cancer Research, Toronto, ON, Canada.
²⁷ Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
²⁸ Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA.
²⁹ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. upeters@fredhutch.org.
³⁰ Department of Epidemiology, Fred Hutchinson Cancer Research Center, University of Washington, 1100 Fairview Ave N, Mail Stop M4-B402, Seattle, WA, 98109, USA. upeters@fredhutch.org.

PMID: 35715570
PMCID: PMC9205954
DOI: 10.1038/s41598-022-14408-2

Association between germline variants and somatic mutations in colorectal cancer

Richard Barfield et al. Sci Rep. 2022.

. 2022 Jun 17;12(1):10207.

doi: 10.1038/s41598-022-14408-2.

Authors

Affiliations

¹ Department of Biostatistics and Bioinformatics, Duke University, 11028A Hock Plaza, 2424 Erwin Road Suite 1106, Durham, NC, 27705, USA. richard.barfield@duke.edu.
² Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
³ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁴ Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
⁵ Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.
⁶ University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, 3010, Australia.
⁷ Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, VIC, Australia.
⁸ Department of Epidemiology and Population Science, Albert Einstein College of Medicine, Bronx, NY, USA.
⁹ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
¹⁰ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
¹² The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹³ Department of Medical Oncology and Therapeuytic, University of Southern California, Los Angeles, CA, USA.
¹⁴ Department of Biostatistics, University of Washington, Seattle, WA, USA.
¹⁵ Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
¹⁶ CIBER Epidemiología Y Salud Pública (CIBERESP), Madrid, Spain.
¹⁷ Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
¹⁸ ONCOBEL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
¹⁹ School of Public Health, University of Washington, Seattle, WA, USA.
²⁰ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²¹ Cancer Immunology Program, Dana-Farber Harvard Cancer Center, Boston, MA, USA.
²² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²³ Department of Epidemiology, Fred Hutchinson Cancer Research Center, University of Washington, 1100 Fairview Ave N, Mail Stop M4-B402, Seattle, WA, 98109, USA.
²⁴ Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
²⁵ Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
²⁶ Ontario Institute for Cancer Research, Toronto, ON, Canada.
²⁷ Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
²⁸ Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA.
²⁹ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. upeters@fredhutch.org.
³⁰ Department of Epidemiology, Fred Hutchinson Cancer Research Center, University of Washington, 1100 Fairview Ave N, Mail Stop M4-B402, Seattle, WA, 98109, USA. upeters@fredhutch.org.

PMID: 35715570
PMCID: PMC9205954
DOI: 10.1038/s41598-022-14408-2

Abstract

Colorectal cancer (CRC) is a heterogeneous disease with evidence of distinct tumor types that develop through different somatically altered pathways. To better understand the impact of the host genome on somatically mutated genes and pathways, we assessed associations of germline variations with somatic events via two complementary approaches. We first analyzed the association between individual germline genetic variants and the presence of non-silent somatic mutations in genes in 1375 CRC cases with genome-wide SNPs data and a tumor sequencing panel targeting 205 genes. In the second analysis, we tested if germline variants located within previously identified regions of somatic allelic imbalance were associated with overall CRC risk using summary statistics from a recent large scale GWAS (n≃125 k CRC cases and controls). The first analysis revealed that a variant (rs78963230) located within a CNA region associated with TLR3 was also associated with a non-silent mutation within gene FBXW7. In the secondary analysis, the variant rs2302274 located in CDX1/PDGFRB frequently gained/lost in colorectal tumors was associated with overall CRC risk (OR = 0.96, p = 7.50e-7). In summary, we demonstrate that an integrative analysis of somatic and germline variation can lead to new insights about CRC.

PubMed Disclaimer

Conflict of interest statement

Marios Giannakis receives research funds from Merck, Bristol-Myers Squibb, Servier, and Janssen unrelated to this research. Other authors have declared that no competing interests exist.

Figures

**Figure 1**
Description of study and pipeline of analysis.

**Figure 2**
Modified Manhattan plot of areas that overlap with CNA regions and their respective association with CRC risk.

**Figure 3**
LocusZoom plot of SORBS2 region. Highlighted region shows the CNA region called by Palin et al.

See this image and copyright information in PMC

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Association between germline variants and somatic mutations in colorectal cancer

Affiliations

Association between germline variants and somatic mutations in colorectal cancer

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