Genome-wide scan of the effect of common nsSNPs on colorectal cancer survival outcome

Evropi Theodoratou; Susan M. Farrington; Maria Timofeeva; Farhat Vn Din; Victoria Svinti; Albert Tenesa; Tao Liu; Annika Lindblom; Steven Gallinger; Harry Campbell; Malcolm G. Dunlop

doi:10.1038/s41416-018-0117-7

Genome-wide scan of the effect of common nsSNPs on colorectal cancer survival outcome

Evropi Theodoratou
, Susan M. Farrington
, Maria Timofeeva
, Farhat Vn Din
, Victoria Svinti
, Albert Tenesa
, Tao Liu
, Annika Lindblom
, Steven Gallinger
, Harry Campbell
, Malcolm G. Dunlop^*

^*Kontaktforfatter

The University of Edinburgh
Karolinska Institutet
Mount Sinai Hospital

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Abstract

Background: We conducted a genome-wide scan to identify non-synonymous SNPs (nsSNPs) that might influence survival after a diagnosis of colorectal cancer (CRC). Methods: We genotyped 7679 nsSNPs in 1939 Scottish patients from the Scottish Colorectal Cancer Study recruited soon after a CRC diagnosis and prospectively followed for survival outcomes. All-cause and CRC-specific survival analyses were conducted using Cox proportional hazard models adjusted for stage, age and sex for all cancer cases, after cancer type stratification and assuming additive and recessive models of inheritance. For all the SNPs that had a p-value < 0.10 a meta-analysis was performed combining the results of the discovery set and a replication set of 899 Scottish CRC patients. The p-value threshold of significance was set as at p < 10⁻⁸. Results: 897 and 894 nsSNPs were associated with all-cause and CRC-specific mortality, respectively, at a p-value level < 0.10 in the discovery set. Meta-analysis of the results from the discovery and replication sets was performed overall and for cancers of colon and rectum separately and none of the variants reached a p-value < 10⁻⁸. Conclusions: This large scale well-powered analysis demonstrates that common nsSNPs are not associated with CRC prognosis overall.

Originalsprog	Engelsk
Tidsskrift	British Journal of Cancer
Vol/bind	119
Udgave nummer	8
Sider (fra-til)	988-993
ISSN	0007-0920
DOI	https://doi.org/10.1038/s41416-018-0117-7
Status	Udgivet - 16. okt. 2018
Udgivet eksternt	Ja

Bibliografisk note

Funding Information:
We thank the participants in all of the studies that contributed to this piece of work and all the recruitment teams and collaborators who make such studies possible. We acknowledge the excellent technical support from Marion Walker. We are grateful to Ruth Wilson, Donna Markie and all those who continue to contribute to recruitment, data collection and data curation for the Study of Colorectal Cancer in Scotland studies. In addition to all consultant colorectal surgeons who provided stage and other data on their patients, we are also indebted to the chairs and offices of the managed clinical networks throughout Scotland who contributed substantially to clinicopathologic data and staging information. We acknowledge the expert support on sample preparation from the Genetics Core of the Edinburgh Wellcome Trust Clinical Research Facility. We also like to thank Berith Wejderot and the members of the Swedish Colorectal Cancer Low-risk Study Group. This article is based upon work from COST Action BM1206, supported by COST (European Cooperation in Science and Technology). www.cost.eu.

Funding Information:
Funding: The work was funded by grants from Cancer Research UK (C348/A3758, C348/A8896, C348/ A18927); Scottish Government Chief Scientist Office (K/OPR/2/2/ D333, CZB/4/94); Medical Research Council (G0000657-53203, MR/K018647/1); Centre Grant from CORE as part of the Digestive Cancer Campaign (http://www.corecharity. org.uk); The Swedish Cancer Society; The Swedish Research Council; the Stockholm Cancer Society. E.T. is supported by a CRUK Career Development Fellowship (C31250/ A22804). F.V.N.D. was funded by a CRUK Clinician Scientist Fellowship (A11378) and is currently funded by a CSO fellowship.

Publisher Copyright:
© 2018, The Author(s).

Finansiering

We thank the participants in all of the studies that contributed to this piece of work and all the recruitment teams and collaborators who make such studies possible. We acknowledge the excellent technical support from Marion Walker. We are grateful to Ruth Wilson, Donna Markie and all those who continue to contribute to recruitment, data collection and data curation for the Study of Colorectal Cancer in Scotland studies. In addition to all consultant colorectal surgeons who provided stage and other data on their patients, we are also indebted to the chairs and offices of the managed clinical networks throughout Scotland who contributed substantially to clinicopathologic data and staging information. We acknowledge the expert support on sample preparation from the Genetics Core of the Edinburgh Wellcome Trust Clinical Research Facility. We also like to thank Berith Wejderot and the members of the Swedish Colorectal Cancer Low-risk Study Group. This article is based upon work from COST Action BM1206, supported by COST (European Cooperation in Science and Technology). www.cost.eu. Funding: The work was funded by grants from Cancer Research UK (C348/A3758, C348/A8896, C348/ A18927); Scottish Government Chief Scientist Office (K/OPR/2/2/ D333, CZB/4/94); Medical Research Council (G0000657-53203, MR/K018647/1); Centre Grant from CORE as part of the Digestive Cancer Campaign (http://www.corecharity. org.uk); The Swedish Cancer Society; The Swedish Research Council; the Stockholm Cancer Society. E.T. is supported by a CRUK Career Development Fellowship (C31250/ A22804). F.V.N.D. was funded by a CRUK Clinician Scientist Fellowship (A11378) and is currently funded by a CSO fellowship.

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10.1038/s41416-018-0117-7Licens: CC BY

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Citationsformater

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abstract = "Background: We conducted a genome-wide scan to identify non-synonymous SNPs (nsSNPs) that might influence survival after a diagnosis of colorectal cancer (CRC). Methods: We genotyped 7679 nsSNPs in 1939 Scottish patients from the Scottish Colorectal Cancer Study recruited soon after a CRC diagnosis and prospectively followed for survival outcomes. All-cause and CRC-specific survival analyses were conducted using Cox proportional hazard models adjusted for stage, age and sex for all cancer cases, after cancer type stratification and assuming additive and recessive models of inheritance. For all the SNPs that had a p-value < 0.10 a meta-analysis was performed combining the results of the discovery set and a replication set of 899 Scottish CRC patients. The p-value threshold of significance was set as at p < 10−8. Results: 897 and 894 nsSNPs were associated with all-cause and CRC-specific mortality, respectively, at a p-value level < 0.10 in the discovery set. Meta-analysis of the results from the discovery and replication sets was performed overall and for cancers of colon and rectum separately and none of the variants reached a p-value < 10−8. Conclusions: This large scale well-powered analysis demonstrates that common nsSNPs are not associated with CRC prognosis overall.",

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author = "Evropi Theodoratou and Farrington, \{Susan M.\} and Maria Timofeeva and Din, \{Farhat Vn\} and Victoria Svinti and Albert Tenesa and Tao Liu and Annika Lindblom and Steven Gallinger and Harry Campbell and Dunlop, \{Malcolm G.\}",

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doi = "10.1038/s41416-018-0117-7",

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AU - Theodoratou, Evropi

AU - Farrington, Susan M.

AU - Timofeeva, Maria

AU - Din, Farhat Vn

AU - Svinti, Victoria

AU - Tenesa, Albert

AU - Liu, Tao

AU - Lindblom, Annika

AU - Gallinger, Steven

AU - Campbell, Harry

AU - Dunlop, Malcolm G.

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N2 - Background: We conducted a genome-wide scan to identify non-synonymous SNPs (nsSNPs) that might influence survival after a diagnosis of colorectal cancer (CRC). Methods: We genotyped 7679 nsSNPs in 1939 Scottish patients from the Scottish Colorectal Cancer Study recruited soon after a CRC diagnosis and prospectively followed for survival outcomes. All-cause and CRC-specific survival analyses were conducted using Cox proportional hazard models adjusted for stage, age and sex for all cancer cases, after cancer type stratification and assuming additive and recessive models of inheritance. For all the SNPs that had a p-value < 0.10 a meta-analysis was performed combining the results of the discovery set and a replication set of 899 Scottish CRC patients. The p-value threshold of significance was set as at p < 10−8. Results: 897 and 894 nsSNPs were associated with all-cause and CRC-specific mortality, respectively, at a p-value level < 0.10 in the discovery set. Meta-analysis of the results from the discovery and replication sets was performed overall and for cancers of colon and rectum separately and none of the variants reached a p-value < 10−8. Conclusions: This large scale well-powered analysis demonstrates that common nsSNPs are not associated with CRC prognosis overall.

AB - Background: We conducted a genome-wide scan to identify non-synonymous SNPs (nsSNPs) that might influence survival after a diagnosis of colorectal cancer (CRC). Methods: We genotyped 7679 nsSNPs in 1939 Scottish patients from the Scottish Colorectal Cancer Study recruited soon after a CRC diagnosis and prospectively followed for survival outcomes. All-cause and CRC-specific survival analyses were conducted using Cox proportional hazard models adjusted for stage, age and sex for all cancer cases, after cancer type stratification and assuming additive and recessive models of inheritance. For all the SNPs that had a p-value < 0.10 a meta-analysis was performed combining the results of the discovery set and a replication set of 899 Scottish CRC patients. The p-value threshold of significance was set as at p < 10−8. Results: 897 and 894 nsSNPs were associated with all-cause and CRC-specific mortality, respectively, at a p-value level < 0.10 in the discovery set. Meta-analysis of the results from the discovery and replication sets was performed overall and for cancers of colon and rectum separately and none of the variants reached a p-value < 10−8. Conclusions: This large scale well-powered analysis demonstrates that common nsSNPs are not associated with CRC prognosis overall.

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KW - Genetic Predisposition to Disease/genetics

KW - Genome-Wide Association Study/methods

KW - Humans

KW - Polymorphism, Single Nucleotide/genetics

KW - Prognosis

KW - Prospective Studies

KW - Risk Factors

KW - Scotland

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EP - 993

JO - British Journal of Cancer

JF - British Journal of Cancer

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ER -

Genome-wide scan of the effect of common nsSNPs on colorectal cancer survival outcome

Abstract

Bibliografisk note

Finansiering

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