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Epidemiology

Abstract 1286: Targeted deep sequencing of colorectal tumor tissues to study associations of tumor subtypes with germline genetic, lifestyle, and environmental risk factors

Syed H. Zaidi, Wei Sun, Jeroen Huyghe, Catherine S. Grasso, Quang Trinh, Charles Connolly, Amy French, Jasmine Mu, Marios Giannakis, Eve Shinbrot, Ivan Borozan, Michael J. Quist, Hermann Brenner, Daniel Buchanan, Peter Campbell, Andrew Chan, Jenny Chang-Claude, Vincent Ferretti, Charles Fuchs, Andrea Gsur, Marc Gunter, Tabitha Harrison, Michael Hoffmeister, Wen-Yi Huang, Paul Krzyzanowski, Stephen Lee, Mathieu Lemire, Jessica Miller, Danielle Pasternack, Cherie Teney, Elaine Mardis, Polly Newcomb, Lincoln Stein, Lee Timms, David Wheeler, Christina Yung, Niha Zubair, Levi Garraway, Shuji Ogino, Li Hsu, Steven Gallinger, Stephen Thibodeau, Thomas Hudson and Ulrike Peters
Syed H. Zaidi
Ontario Institute for Cancer Research, Toronto, Ontario, Canada;
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Wei Sun
Fred Hutchinson Cancer Research Center, Seattle, WA;
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Jeroen Huyghe
Fred Hutchinson Cancer Research Center, Seattle, WA;
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Catherine S. Grasso
Fred Hutchinson Cancer Research Center, Seattle, WA;
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Quang Trinh
Ontario Institute for Cancer Research, Toronto, Ontario, Canada;
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Charles Connolly
Fred Hutchinson Cancer Research Center, Seattle, WA;
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Amy French
Mayo Clinic, Rochester, MN;
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Jasmine Mu
Broad Institute, Cambridge, MA;
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Marios Giannakis
Dana-Farber Cancer Institute, Boston, MA;
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Eve Shinbrot
Baylor College of Medicine, Houston, TX;
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Ivan Borozan
Ontario Institute for Cancer Research, Toronto, Ontario, Canada;
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Michael J. Quist
Fred Hutchinson Cancer Research Center, Seattle, WA;
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Hermann Brenner
German Cancer Research Center (DKFZ), Germany;
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Daniel Buchanan
The University of Melbourne, Australia;
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Peter Campbell
American Cancer Society, Atlanta, GA;
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Andrew Chan
Massachusetts General Hospital, Boston, MA;
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Jenny Chang-Claude
German Cancer Research Center (DKFZ), Germany;
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Vincent Ferretti
Ontario Institute for Cancer Research, Toronto, Ontario, Canada;
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Charles Fuchs
Dana-Farber Cancer Institute, Boston, MA;
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Andrea Gsur
Medical University of Vienna, Austria;
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Marc Gunter
International Agency for Research on Cancer, France;
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Tabitha Harrison
Fred Hutchinson Cancer Research Center, Seattle, WA;
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Michael Hoffmeister
German Cancer Research Center (DKFZ), Germany;
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Wen-Yi Huang
National Cancer Institute, NIH, DHHS, Bethesda, MD;
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Paul Krzyzanowski
Ontario Institute for Cancer Research, Toronto, Ontario, Canada;
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Stephen Lee
Ontario Institute for Cancer Research, Toronto, Ontario, Canada;
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Mathieu Lemire
Ontario Institute for Cancer Research, Toronto, Ontario, Canada;
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Jessica Miller
Ontario Institute for Cancer Research, Toronto, Ontario, Canada;
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Danielle Pasternack
Ontario Institute for Cancer Research, Toronto, Ontario, Canada;
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Cherie Teney
Ontario Institute for Cancer Research, Toronto, Ontario, Canada;
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Elaine Mardis
Washington University School of Medicine, St. Louis, MO;
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Polly Newcomb
Fred Hutchinson Cancer Research Center, Seattle, WA;
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Lincoln Stein
Ontario Institute for Cancer Research, Toronto, Ontario, Canada;
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Lee Timms
Ontario Institute for Cancer Research, Toronto, Ontario, Canada;
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David Wheeler
Baylor College of Medicine, Houston, TX;
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Christina Yung
Ontario Institute for Cancer Research, Toronto, Ontario, Canada;
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Niha Zubair
Fred Hutchinson Cancer Research Center, Seattle, WA;
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Levi Garraway
Dana-Farber Cancer Institute, Boston, MA;
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Shuji Ogino
Harvard Medical School, Boston, MA.
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Li Hsu
Fred Hutchinson Cancer Research Center, Seattle, WA;
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Steven Gallinger
Ontario Institute for Cancer Research, Toronto, Ontario, Canada;
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Stephen Thibodeau
Mayo Clinic, Rochester, MN;
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Thomas Hudson
Ontario Institute for Cancer Research, Toronto, Ontario, Canada;
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Ulrike Peters
Fred Hutchinson Cancer Research Center, Seattle, WA;
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DOI: 10.1158/1538-7445.AM2017-1286 Published July 2017
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Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC

Abstract

The Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) in collaboration with the Colorectal Cancer Family Registry (CCFR) aims to identify genetic variants and environmental risk factors that impact colorectal cancer (CRC). Over 30 studies from North America, Europe, and Australia participate in GECCO. These studies have collected clinical, epidemiological, and survival data, as well as blood and tumor biospecimens, for over 80,000 CRC cases and controls.

The current study aims to conduct targeted deep sequencing of tumors and matching normal DNA to identify recurrent and novel somatic and germline variants in 4,200 CRC cases. To achieve this goal, an AmpliSeq targeted sequencing panel of 1.12 Mbp was constructed to sequence the coding regions of 190 significantly mutated genes identified from whole exome sequencing datasets generated by the Nurses’ Health Study and Health Professional’s Follow-up Study, and The Cancer Genome Atlas. The panel also covers coding regions of 15 genes with germline high penetrance mutations in CRC, 54 regions to detect CRC-related copy number alterations (CNAs), and microsatellite and homopolymer repeat regions to identify defective DNA mismatch repair. Primers were also included to detect Fusobacterium nucleatum DNA in tumor biopsies, as F. nucleatum is thought to promote CRC carcinogenesis.

Sequencing of the DNA libraries on Illumina HiSeq 2500 produced a mean coverage of greater than 500X for tumor DNA and 100X for normal DNA, with >85% of the bases covered at the target at 50x. So far, targeted sequencing of >1,500 DNA samples from CRC tumors and normal tissues has identified recurrent and novel somatic mutations, germline genetic variants, and hypermutation status of the tumors due to defective DNA mismatch repair or pathogenic mutations in the POLE gene. Targeted sequencing has also allowed quantification of the F. nucleatum DNA in tumor biopsies; the results were validated by a multiplex QPCR assay.

At the AACR annual meeting, we will present targeted sequencing results generated from the first two GECCO-participating studies (n=1,300 cases). These data will be valuable for future association testing of somatic mutations, CNAs, hypermutation status, and F. nucleatum with germline genetic variants, lifestyle, and environmental risk factors and survival. This large study will allow development of better strategies for diagnosis, treatment, and prevention of CRC.

Citation Format: Syed H. Zaidi, Wei Sun, Jeroen Huyghe, Catherine S. Grasso, Quang Trinh, Charles Connolly, Amy French, Jasmine Mu, Marios Giannakis, Eve Shinbrot, Ivan Borozan, Michael J. Quist, Hermann Brenner, Daniel Buchanan, Peter Campbell, Andrew Chan, Jenny Chang-Claude, Vincent Ferretti, Charles Fuchs, Andrea Gsur, Marc Gunter, Tabitha Harrison, Michael Hoffmeister, Wen-Yi Huang, Paul Krzyzanowski, Stephen Lee, Mathieu Lemire, Jessica Miller, Danielle Pasternack, Cherie Teney, Elaine Mardis, Polly Newcomb, Lincoln Stein, Lee Timms, David Wheeler, Christina Yung, Niha Zubair, Levi Garraway, Shuji Ogino, Li Hsu, Steven Gallinger, Stephen Thibodeau, Thomas Hudson, Ulrike Peters. Targeted deep sequencing of colorectal tumor tissues to study associations of tumor subtypes with germline genetic, lifestyle, and environmental risk factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1286. doi:10.1158/1538-7445.AM2017-1286

  • ©2017 American Association for Cancer Research.
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Cancer Research: 77 (13 Supplement)
July 2017
Volume 77, Issue 13 Supplement
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Abstract 1286: Targeted deep sequencing of colorectal tumor tissues to study associations of tumor subtypes with germline genetic, lifestyle, and environmental risk factors
Syed H. Zaidi, Wei Sun, Jeroen Huyghe, Catherine S. Grasso, Quang Trinh, Charles Connolly, Amy French, Jasmine Mu, Marios Giannakis, Eve Shinbrot, Ivan Borozan, Michael J. Quist, Hermann Brenner, Daniel Buchanan, Peter Campbell, Andrew Chan, Jenny Chang-Claude, Vincent Ferretti, Charles Fuchs, Andrea Gsur, Marc Gunter, Tabitha Harrison, Michael Hoffmeister, Wen-Yi Huang, Paul Krzyzanowski, Stephen Lee, Mathieu Lemire, Jessica Miller, Danielle Pasternack, Cherie Teney, Elaine Mardis, Polly Newcomb, Lincoln Stein, Lee Timms, David Wheeler, Christina Yung, Niha Zubair, Levi Garraway, Shuji Ogino, Li Hsu, Steven Gallinger, Stephen Thibodeau, Thomas Hudson and Ulrike Peters
Cancer Res July 1 2017 (77) (13 Supplement) 1286; DOI: 10.1158/1538-7445.AM2017-1286

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Abstract 1286: Targeted deep sequencing of colorectal tumor tissues to study associations of tumor subtypes with germline genetic, lifestyle, and environmental risk factors
Syed H. Zaidi, Wei Sun, Jeroen Huyghe, Catherine S. Grasso, Quang Trinh, Charles Connolly, Amy French, Jasmine Mu, Marios Giannakis, Eve Shinbrot, Ivan Borozan, Michael J. Quist, Hermann Brenner, Daniel Buchanan, Peter Campbell, Andrew Chan, Jenny Chang-Claude, Vincent Ferretti, Charles Fuchs, Andrea Gsur, Marc Gunter, Tabitha Harrison, Michael Hoffmeister, Wen-Yi Huang, Paul Krzyzanowski, Stephen Lee, Mathieu Lemire, Jessica Miller, Danielle Pasternack, Cherie Teney, Elaine Mardis, Polly Newcomb, Lincoln Stein, Lee Timms, David Wheeler, Christina Yung, Niha Zubair, Levi Garraway, Shuji Ogino, Li Hsu, Steven Gallinger, Stephen Thibodeau, Thomas Hudson and Ulrike Peters
Cancer Res July 1 2017 (77) (13 Supplement) 1286; DOI: 10.1158/1538-7445.AM2017-1286
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