Identifying therapeutic targets for cancer among 2074 circulating proteins and risk of nine cancers

Karl Smith-Byrne (), Åsa Hedman, Marios Dimitriou, Trishna Desai, Alexandr V. Sokolov, Helgi B. Schioth, Mine Koprulu, Maik Pietzner, Claudia Langenberg, Joshua Atkins, Ricardo Cortez Penha, James McKay, Paul Brennan, Sirui Zhou, Brent J. Richards, James Yarmolinsky, Richard M. Martin, Joana Borlido, Xinmeng J. Mu, Adam Butterworth, Xia Shen, Jim Wilson, Themistocles L. Assimes, Rayjean J. Hung, Christopher Amos, Mark Purdue, Nathaniel Rothman, Stephen Chanock, Ruth C. Travis, Mattias Johansson and Anders Mälarstig
Additional contact information
Karl Smith-Byrne: University of Oxford
Åsa Hedman: Development and Medical
Marios Dimitriou: Development and Medical
Trishna Desai: University of Oxford
Alexandr V. Sokolov: Uppsala University
Helgi B. Schioth: Uppsala University
Mine Koprulu: University of Cambridge
Maik Pietzner: University of Cambridge
Claudia Langenberg: University of Cambridge
Joshua Atkins: University of Oxford
Ricardo Cortez Penha: International Agency for Research on Cancer (IARC-WHO)
James McKay: International Agency for Research on Cancer (IARC-WHO)
Paul Brennan: International Agency for Research on Cancer (IARC-WHO)
Sirui Zhou: McGill University
Brent J. Richards: McGill University
James Yarmolinsky: University of Bristol
Richard M. Martin: University of Bristol
Joana Borlido: Pfizer Inc
Xinmeng J. Mu: Pfizer Inc
Adam Butterworth: University of Cambridge
Xia Shen: University of Edinburgh
Jim Wilson: University of Edinburgh
Themistocles L. Assimes: Stanford University
Rayjean J. Hung: Sinai Health System and University of Toronto
Christopher Amos: Baylor Medical College
Mark Purdue: National Cancer Institute
Nathaniel Rothman: National Cancer Institute
Stephen Chanock: National Cancer Institute
Ruth C. Travis: University of Oxford
Mattias Johansson: International Agency for Research on Cancer (IARC-WHO)
Anders Mälarstig: Development and Medical

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Circulating proteins can reveal key pathways to cancer and identify therapeutic targets for cancer prevention. We investigate 2,074 circulating proteins and risk of nine common cancers (bladder, breast, endometrium, head and neck, lung, ovary, pancreas, kidney, and malignant non-melanoma) using cis protein Mendelian randomisation and colocalization. We conduct additional analyses to identify adverse side-effects of altering risk proteins and map cancer risk proteins to drug targets. Here we find 40 proteins associated with common cancers, such as PLAUR and risk of breast cancer [odds ratio per standard deviation increment: 2.27, 1.88-2.74], and with high-mortality cancers, such as CTRB1 and pancreatic cancer [0.79, 0.73-0.85]. We also identify potential adverse effects of protein-altering interventions to reduce cancer risk, such as hypertension. Additionally, we report 18 proteins associated with cancer risk that map to existing drugs and 15 that are not currently under clinical investigation. In sum, we identify protein-cancer links that improve our understanding of cancer aetiology. We also demonstrate that the wider consequence of any protein-altering intervention on well-being and morbidity is required to interpret any utility of proteins as potential future targets for therapeutic prevention.

Date: 2024
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DOI: 10.1038/s41467-024-46834-3

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