Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Hongjie Chen; Arunabha Majumbar; Lu Wang; Siddhartha Kar; Kevin Brown; Helian Feng; Constance Turman; Joe Dennis; Douglas Easton; Kyriaki Michailidou; Jacques Simard; Timothy Bishop; Iona Cheng; Jereon R. Huyghe; Stephanie Schmit; Tracey O'Mara; Amanda Spurdle; Puya Gharakhani; Johannes Schumacher; Janusz Jankowski; Ines Gockel; Melissa Bondy; Richard Houlston; Robert Jenkins; Beatrice Melin; Corina Lesseur; Andrew R Ness; Brenda Disgaarde; Andrew Olshan; Christopher Amos; David C. Christiani; Maria Landi; James McKay; Myriam Brossard; Mark M. Iles; Mathew L. Law; Stuart MacGregor; Jonathan Beesley; Michele Jones; Jonathan Tyrer; Stacey J. Winham; Alison P. Klein; Gloria Petersen; Donghui Li; Brian Wolpin; Rosalind Eeles; Christopher Haiman; Zsofia Kote-Jarai; Frederick Schumacher; Paul Brennan; Stephanie Channock; Valérie Gaborieau; Mark P. Purdue; Paul Pharoah; Rayjean J. Hung; Laufey T. Amundadottir; Peter Kraft; Bogdan Pasaniuc; Sara Lindstrom

doi:10.1016/j.xhgg.2021.100041

Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Hongjie Chen, Arunabha Majumbar, Lu Wang, Siddhartha Kar, Kevin Brown, Helian Feng, Constance Turman, Joe Dennis, Douglas Easton, Kyriaki Michailidou, Jacques Simard, Timothy Bishop, Iona Cheng, Jereon R. Huyghe, Stephanie Schmit, Tracey O'Mara, Amanda Spurdle, Puya Gharakhani, Johannes Schumacher, Janusz JankowskiInes Gockel, Melissa Bondy, Richard Houlston, Robert Jenkins, Beatrice Melin, Corina Lesseur, Andrew R Ness, Brenda Disgaarde, Andrew Olshan, Christopher Amos, David C. Christiani, Maria Landi, James McKay, Myriam Brossard, Mark M. Iles, Mathew L. Law, Stuart MacGregor, Jonathan Beesley, Michele Jones, Jonathan Tyrer, Stacey J. Winham, Alison P. Klein, Gloria Petersen, Donghui Li, Brian Wolpin, Rosalind Eeles, Christopher Haiman, Zsofia Kote-Jarai, Frederick Schumacher, Paul Brennan, Stephanie Channock, Valérie Gaborieau, Mark P. Purdue, Paul Pharoah, Rayjean J. Hung, Laufey T. Amundadottir, Peter Kraft, Bogdan Pasaniuc, Sara Lindstrom^*

^*Corresponding author for this work

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Abstract

Genome-wide association studies (GWAS) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor (ER)-positive and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.

Original language	English
Article number	100041
Journal	Human Genetics and Genomics Advances
Volume	2
Issue number	3
Early online date	12 Jun 2021
DOIs	https://doi.org/10.1016/j.xhgg.2021.100041
Publication status	Published - 8 Jul 2021

Bibliographical note

Funding Information:
B.M.W. has received research grants from Celgene and Eli Lilly and has consulting relationship with BioLineRx, Celgene, and Grail. R.A.E. has received speaker honoraria from the GU-ASCO meeting (January 2016), RMH FR meeting (November 2017, supported by Janssen), University of Chicago invited talk (May 2018), and ESMO (September 2019, supported by Bayer & Ipsen) and served as member of external expert committee at the Prostate Dx Advisory Panel (June 2020). All other authors declare no competing interests.

Publisher Copyright:
© 2021 The Authors

Keywords

Cancer
Pleiotropy
Fine-mapping
5p15.33 region
TERT
CLPTM1L

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Chen, H., Majumbar, A., Wang, L., Kar, S., Brown, K., Feng, H., Turman, C., Dennis, J., Easton, D., Michailidou, K., Simard, J., Bishop, T., Cheng, I., Huyghe, J. R., Schmit, S., O'Mara, T., Spurdle, A., Gharakhani, P., Schumacher, J., ... Lindstrom, S. (2021). Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals. Human Genetics and Genomics Advances, 2(3), Article 100041. https://doi.org/10.1016/j.xhgg.2021.100041

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title = "Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals",

abstract = "Genome-wide association studies (GWAS) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor (ER)-positive and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.",

keywords = "Cancer, Pleiotropy, Fine-mapping, 5p15.33 region, TERT, CLPTM1L",

author = "Hongjie Chen and Arunabha Majumbar and Lu Wang and Siddhartha Kar and Kevin Brown and Helian Feng and Constance Turman and Joe Dennis and Douglas Easton and Kyriaki Michailidou and Jacques Simard and Timothy Bishop and Iona Cheng and Huyghe, {Jereon R.} and Stephanie Schmit and Tracey O'Mara and Amanda Spurdle and Puya Gharakhani and Johannes Schumacher and Janusz Jankowski and Ines Gockel and Melissa Bondy and Richard Houlston and Robert Jenkins and Beatrice Melin and Corina Lesseur and Ness, {Andrew R} and Brenda Disgaarde and Andrew Olshan and Christopher Amos and Christiani, {David C.} and Maria Landi and James McKay and Myriam Brossard and Iles, {Mark M.} and Law, {Mathew L.} and Stuart MacGregor and Jonathan Beesley and Michele Jones and Jonathan Tyrer and Winham, {Stacey J.} and Klein, {Alison P.} and Gloria Petersen and Donghui Li and Brian Wolpin and Rosalind Eeles and Christopher Haiman and Zsofia Kote-Jarai and Frederick Schumacher and Paul Brennan and Stephanie Channock and Val{\'e}rie Gaborieau and Purdue, {Mark P.} and Paul Pharoah and Hung, {Rayjean J.} and Amundadottir, {Laufey T.} and Peter Kraft and Bogdan Pasaniuc and Sara Lindstrom",

note = "Funding Information: B.M.W. has received research grants from Celgene and Eli Lilly and has consulting relationship with BioLineRx, Celgene, and Grail. R.A.E. has received speaker honoraria from the GU-ASCO meeting (January 2016), RMH FR meeting (November 2017, supported by Janssen), University of Chicago invited talk (May 2018), and ESMO (September 2019, supported by Bayer & Ipsen) and served as member of external expert committee at the Prostate Dx Advisory Panel (June 2020). All other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Authors",

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doi = "10.1016/j.xhgg.2021.100041",

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Chen, H, Majumbar, A, Wang, L, Kar, S, Brown, K, Feng, H, Turman, C, Dennis, J, Easton, D, Michailidou, K, Simard, J, Bishop, T, Cheng, I, Huyghe, JR, Schmit, S, O'Mara, T, Spurdle, A, Gharakhani, P, Schumacher, J, Jankowski, J, Gockel, I, Bondy, M, Houlston, R, Jenkins, R, Melin, B, Lesseur, C, Ness, AR, Disgaarde, B, Olshan, A, Amos, C, Christiani, DC, Landi, M, McKay, J, Brossard, M, Iles, MM, Law, ML, MacGregor, S, Beesley, J, Jones, M, Tyrer, J, Winham, SJ, Klein, AP, Petersen, G, Li, D, Wolpin, B, Eeles, R, Haiman, C, Kote-Jarai, Z, Schumacher, F, Brennan, P, Channock, S, Gaborieau, V, Purdue, MP, Pharoah, P, Hung, RJ, Amundadottir, LT, Kraft, P, Pasaniuc, B & Lindstrom, S 2021, 'Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals', Human Genetics and Genomics Advances, vol. 2, no. 3, 100041. https://doi.org/10.1016/j.xhgg.2021.100041

TY - JOUR

T1 - Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

AU - Chen, Hongjie

AU - Majumbar, Arunabha

AU - Wang, Lu

AU - Kar, Siddhartha

AU - Brown, Kevin

AU - Feng, Helian

AU - Turman, Constance

AU - Dennis, Joe

AU - Easton, Douglas

AU - Michailidou, Kyriaki

AU - Simard, Jacques

AU - Bishop, Timothy

AU - Cheng, Iona

AU - Huyghe, Jereon R.

AU - Schmit, Stephanie

AU - O'Mara, Tracey

AU - Spurdle, Amanda

AU - Gharakhani, Puya

AU - Schumacher, Johannes

AU - Jankowski, Janusz

AU - Gockel, Ines

AU - Bondy, Melissa

AU - Houlston, Richard

AU - Jenkins, Robert

AU - Melin, Beatrice

AU - Lesseur, Corina

AU - Ness, Andrew R

AU - Disgaarde, Brenda

AU - Olshan, Andrew

AU - Amos, Christopher

AU - Christiani, David C.

AU - Landi, Maria

AU - McKay, James

AU - Brossard, Myriam

AU - Iles, Mark M.

AU - Law, Mathew L.

AU - MacGregor, Stuart

AU - Beesley, Jonathan

AU - Jones, Michele

AU - Tyrer, Jonathan

AU - Winham, Stacey J.

AU - Klein, Alison P.

AU - Petersen, Gloria

AU - Li, Donghui

AU - Wolpin, Brian

AU - Eeles, Rosalind

AU - Haiman, Christopher

AU - Kote-Jarai, Zsofia

AU - Schumacher, Frederick

AU - Brennan, Paul

AU - Channock, Stephanie

AU - Gaborieau, Valérie

AU - Purdue, Mark P.

AU - Pharoah, Paul

AU - Hung, Rayjean J.

AU - Amundadottir, Laufey T.

AU - Kraft, Peter

AU - Pasaniuc, Bogdan

AU - Lindstrom, Sara

N1 - Funding Information: B.M.W. has received research grants from Celgene and Eli Lilly and has consulting relationship with BioLineRx, Celgene, and Grail. R.A.E. has received speaker honoraria from the GU-ASCO meeting (January 2016), RMH FR meeting (November 2017, supported by Janssen), University of Chicago invited talk (May 2018), and ESMO (September 2019, supported by Bayer & Ipsen) and served as member of external expert committee at the Prostate Dx Advisory Panel (June 2020). All other authors declare no competing interests. Publisher Copyright: © 2021 The Authors

PY - 2021/7/8

Y1 - 2021/7/8

N2 - Genome-wide association studies (GWAS) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor (ER)-positive and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.

AB - Genome-wide association studies (GWAS) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor (ER)-positive and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.

KW - Cancer

KW - Pleiotropy

KW - Fine-mapping

KW - 5p15.33 region

KW - TERT

KW - CLPTM1L

U2 - 10.1016/j.xhgg.2021.100041

DO - 10.1016/j.xhgg.2021.100041

M3 - Article (Academic Journal)

C2 - 34355204

SN - 2666-2477

VL - 2

JO - Human Genetics and Genomics Advances

JF - Human Genetics and Genomics Advances

IS - 3

M1 - 100041

ER -

Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Abstract

Bibliographical note

Keywords

UN SDGs

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