Gene-based burden tests of rare germline variants identify six cancer susceptibility genes

Erna V Ivarsdottir; Julius Gudmundsson; Vinicius Tragante; Gardar Sveinbjornsson; Snaedis Kristmundsdottir; Simon N Stacey; Gisli H Halldorsson; Magnus I Magnusson; Asmundur Oddsson; G Bragi Walters; Asgeir Sigurdsson; Saedis Saevarsdottir; Doruk Beyter; Gudmar Thorleifsson; Bjarni V Halldorsson; Pall Melsted; Hreinn Stefansson; Ingileif Jonsdottir; Erik Sørensen; Ole B Pedersen; Christian Erikstrup; Martin Bøgsted; Mette Pøhl; Andreas Røder; Hein Vincent Stroomberg; Ismail Gögenur; Jens Hillingsø; Stig E Bojesen; Ulrik Lassen; Estrid Høgdall; Henrik Ullum; Søren Brunak; Sisse R Ostrowski; Ida Elken Sonderby; Oleksandr Frei; Srdjan Djurovic; Alexandra Havdahl; Pal Moller; Mev Dominguez-Valentin; Jan Haavik; Ole A Andreassen; Eivind Hovig; Bjarni A Agnarsson; Rafn Hilmarsson; Oskar Th Johannsson; Trausti Valdimarsson; Steinn Jonsson; Pall H Moller; Jon H Olafsson; Bardur Sigurgeirsson; Jon G Jonasson; Geir Tryggvason; Hilma Holm; Patrick Sulem; Thorunn Rafnar; Daniel F Gudbjartsson; Kari Stefansson; DBDS Genomic Consortium

doi:10.1038/s41588-024-01966-6

Gene-based burden tests of rare germline variants identify six cancer susceptibility genes

Erna V Ivarsdottir^*, Julius Gudmundsson, Vinicius Tragante, Gardar Sveinbjornsson, Snaedis Kristmundsdottir, Simon N Stacey, Gisli H Halldorsson, Magnus I Magnusson, Asmundur Oddsson, G Bragi Walters, Asgeir Sigurdsson, Saedis Saevarsdottir, Doruk Beyter, Gudmar Thorleifsson, Bjarni V Halldorsson, Pall Melsted, Hreinn Stefansson, Ingileif Jonsdottir, Erik Sørensen, Ole B PedersenChristian Erikstrup, Martin Bøgsted, Mette Pøhl, Andreas Røder, Hein Vincent Stroomberg, Ismail Gögenur, Jens Hillingsø, Stig E Bojesen, Ulrik Lassen, Estrid Høgdall, Henrik Ullum, Søren Brunak, Sisse R Ostrowski, Ida Elken Sonderby, Oleksandr Frei, Srdjan Djurovic, Alexandra Havdahl, Pal Moller, Mev Dominguez-Valentin, Jan Haavik, Ole A Andreassen, Eivind Hovig, Bjarni A Agnarsson, Rafn Hilmarsson, Oskar Th Johannsson, Trausti Valdimarsson, Steinn Jonsson, Pall H Moller, Jon H Olafsson, Bardur Sigurgeirsson, Jon G Jonasson, Geir Tryggvason, Hilma Holm, Patrick Sulem, Thorunn Rafnar, Daniel F Gudbjartsson, Kari Stefansson^*, DBDS Genomic Consortium

^*Kontaktforfatter

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

Abstract

Discovery of cancer risk variants in the sequence of the germline genome can shed light on carcinogenesis. Here we describe gene burden association analyses, aggregating rare missense and loss of function variants, at 22 cancer sites, including 130,991 cancer cases and 733,486 controls from Iceland, Norway and the United Kingdom. We identified four genes associated with increased cancer risk; the pro-apoptotic BIK for prostate cancer, the autophagy involved ATG12 for colorectal cancer, TG for thyroid cancer and CMTR2 for both lung cancer and cutaneous melanoma. Further, we found genes with rare variants that associate with decreased risk of cancer; AURKB for any cancer, irrespective of site, and PPP1R15A for breast cancer, suggesting that inhibition of PPP1R15A may be a preventive strategy for breast cancer. Our findings pinpoint several new cancer risk genes and emphasize autophagy, apoptosis and cell stress response as a focus point for developing new therapeutics.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	56
Udgave nummer	11
Sider (fra-til)	2422–2433
Antal sider	12
ISSN	1061-4036
DOI	https://doi.org/10.1038/s41588-024-01966-6
Status	Udgivet - nov. 2024

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10.1038/s41588-024-01966-6

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Ivarsdottir, E. V., Gudmundsson, J., Tragante, V., Sveinbjornsson, G., Kristmundsdottir, S., Stacey, S. N., Halldorsson, G. H., Magnusson, M. I., Oddsson, A., Walters, G. B., Sigurdsson, A., Saevarsdottir, S., Beyter, D., Thorleifsson, G., Halldorsson, B. V., Melsted, P., Stefansson, H., Jonsdottir, I., Sørensen, E., ... DBDS Genomic Consortium (2024). Gene-based burden tests of rare germline variants identify six cancer susceptibility genes. Nature Genetics, 56(11), 2422–2433. https://doi.org/10.1038/s41588-024-01966-6

@article{609b8cd0c69549ee8342869d754b87a2,

title = "Gene-based burden tests of rare germline variants identify six cancer susceptibility genes",

abstract = "Discovery of cancer risk variants in the sequence of the germline genome can shed light on carcinogenesis. Here we describe gene burden association analyses, aggregating rare missense and loss of function variants, at 22 cancer sites, including 130,991 cancer cases and 733,486 controls from Iceland, Norway and the United Kingdom. We identified four genes associated with increased cancer risk; the pro-apoptotic BIK for prostate cancer, the autophagy involved ATG12 for colorectal cancer, TG for thyroid cancer and CMTR2 for both lung cancer and cutaneous melanoma. Further, we found genes with rare variants that associate with decreased risk of cancer; AURKB for any cancer, irrespective of site, and PPP1R15A for breast cancer, suggesting that inhibition of PPP1R15A may be a preventive strategy for breast cancer. Our findings pinpoint several new cancer risk genes and emphasize autophagy, apoptosis and cell stress response as a focus point for developing new therapeutics.",

author = "Ivarsdottir, {Erna V} and Julius Gudmundsson and Vinicius Tragante and Gardar Sveinbjornsson and Snaedis Kristmundsdottir and Stacey, {Simon N} and Halldorsson, {Gisli H} and Magnusson, {Magnus I} and Asmundur Oddsson and Walters, {G Bragi} and Asgeir Sigurdsson and Saedis Saevarsdottir and Doruk Beyter and Gudmar Thorleifsson and Halldorsson, {Bjarni V} and Pall Melsted and Hreinn Stefansson and Ingileif Jonsdottir and Erik S{\o}rensen and Pedersen, {Ole B} and Christian Erikstrup and Martin B{\o}gsted and Mette P{\o}hl and Andreas R{\o}der and Stroomberg, {Hein Vincent} and Ismail G{\"o}genur and Jens Hillings{\o} and Bojesen, {Stig E} and Ulrik Lassen and Estrid H{\o}gdall and Henrik Ullum and S{\o}ren Brunak and Ostrowski, {Sisse R} and Sonderby, {Ida Elken} and Oleksandr Frei and Srdjan Djurovic and Alexandra Havdahl and Pal Moller and Mev Dominguez-Valentin and Jan Haavik and Andreassen, {Ole A} and Eivind Hovig and Agnarsson, {Bjarni A} and Rafn Hilmarsson and Johannsson, {Oskar Th} and Trausti Valdimarsson and Steinn Jonsson and Moller, {Pall H} and Olafsson, {Jon H} and Bardur Sigurgeirsson and Jonasson, {Jon G} and Geir Tryggvason and Hilma Holm and Patrick Sulem and Thorunn Rafnar and Gudbjartsson, {Daniel F} and Kari Stefansson and {DBDS Genomic Consortium}",

note = "{\textcopyright} 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2024",

month = nov,

doi = "10.1038/s41588-024-01966-6",

language = "English",

volume = "56",

pages = "2422–2433",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "11",

}

Ivarsdottir, EV, Gudmundsson, J, Tragante, V, Sveinbjornsson, G, Kristmundsdottir, S, Stacey, SN, Halldorsson, GH, Magnusson, MI, Oddsson, A, Walters, GB, Sigurdsson, A, Saevarsdottir, S, Beyter, D, Thorleifsson, G, Halldorsson, BV, Melsted, P, Stefansson, H, Jonsdottir, I, Sørensen, E, Pedersen, OB, Erikstrup, C, Bøgsted, M, Pøhl, M, Røder, A, Stroomberg, HV, Gögenur, I, Hillingsø, J, Bojesen, SE, Lassen, U, Høgdall, E, Ullum, H, Brunak, S, Ostrowski, SR, Sonderby, IE, Frei, O, Djurovic, S, Havdahl, A, Moller, P, Dominguez-Valentin, M, Haavik, J, Andreassen, OA, Hovig, E, Agnarsson, BA, Hilmarsson, R, Johannsson, OT, Valdimarsson, T, Jonsson, S, Moller, PH, Olafsson, JH, Sigurgeirsson, B, Jonasson, JG, Tryggvason, G, Holm, H, Sulem, P, Rafnar, T, Gudbjartsson, DF, Stefansson, K & DBDS Genomic Consortium 2024, 'Gene-based burden tests of rare germline variants identify six cancer susceptibility genes', Nature Genetics, bind 56, nr. 11, s. 2422–2433. https://doi.org/10.1038/s41588-024-01966-6

TY - JOUR

T1 - Gene-based burden tests of rare germline variants identify six cancer susceptibility genes

AU - Ivarsdottir, Erna V

AU - Gudmundsson, Julius

AU - Tragante, Vinicius

AU - Sveinbjornsson, Gardar

AU - Kristmundsdottir, Snaedis

AU - Stacey, Simon N

AU - Halldorsson, Gisli H

AU - Magnusson, Magnus I

AU - Oddsson, Asmundur

AU - Walters, G Bragi

AU - Sigurdsson, Asgeir

AU - Saevarsdottir, Saedis

AU - Beyter, Doruk

AU - Thorleifsson, Gudmar

AU - Halldorsson, Bjarni V

AU - Melsted, Pall

AU - Stefansson, Hreinn

AU - Jonsdottir, Ingileif

AU - Sørensen, Erik

AU - Pedersen, Ole B

AU - Erikstrup, Christian

AU - Bøgsted, Martin

AU - Pøhl, Mette

AU - Røder, Andreas

AU - Stroomberg, Hein Vincent

AU - Gögenur, Ismail

AU - Hillingsø, Jens

AU - Bojesen, Stig E

AU - Lassen, Ulrik

AU - Høgdall, Estrid

AU - Ullum, Henrik

AU - Brunak, Søren

AU - Ostrowski, Sisse R

AU - Sonderby, Ida Elken

AU - Frei, Oleksandr

AU - Djurovic, Srdjan

AU - Havdahl, Alexandra

AU - Moller, Pal

AU - Dominguez-Valentin, Mev

AU - Haavik, Jan

AU - Andreassen, Ole A

AU - Hovig, Eivind

AU - Agnarsson, Bjarni A

AU - Hilmarsson, Rafn

AU - Johannsson, Oskar Th

AU - Valdimarsson, Trausti

AU - Jonsson, Steinn

AU - Moller, Pall H

AU - Olafsson, Jon H

AU - Sigurgeirsson, Bardur

AU - Jonasson, Jon G

AU - Tryggvason, Geir

AU - Holm, Hilma

AU - Sulem, Patrick

AU - Rafnar, Thorunn

AU - Gudbjartsson, Daniel F

AU - Stefansson, Kari

AU - DBDS Genomic Consortium

PY - 2024/11

Y1 - 2024/11

N2 - Discovery of cancer risk variants in the sequence of the germline genome can shed light on carcinogenesis. Here we describe gene burden association analyses, aggregating rare missense and loss of function variants, at 22 cancer sites, including 130,991 cancer cases and 733,486 controls from Iceland, Norway and the United Kingdom. We identified four genes associated with increased cancer risk; the pro-apoptotic BIK for prostate cancer, the autophagy involved ATG12 for colorectal cancer, TG for thyroid cancer and CMTR2 for both lung cancer and cutaneous melanoma. Further, we found genes with rare variants that associate with decreased risk of cancer; AURKB for any cancer, irrespective of site, and PPP1R15A for breast cancer, suggesting that inhibition of PPP1R15A may be a preventive strategy for breast cancer. Our findings pinpoint several new cancer risk genes and emphasize autophagy, apoptosis and cell stress response as a focus point for developing new therapeutics.

AB - Discovery of cancer risk variants in the sequence of the germline genome can shed light on carcinogenesis. Here we describe gene burden association analyses, aggregating rare missense and loss of function variants, at 22 cancer sites, including 130,991 cancer cases and 733,486 controls from Iceland, Norway and the United Kingdom. We identified four genes associated with increased cancer risk; the pro-apoptotic BIK for prostate cancer, the autophagy involved ATG12 for colorectal cancer, TG for thyroid cancer and CMTR2 for both lung cancer and cutaneous melanoma. Further, we found genes with rare variants that associate with decreased risk of cancer; AURKB for any cancer, irrespective of site, and PPP1R15A for breast cancer, suggesting that inhibition of PPP1R15A may be a preventive strategy for breast cancer. Our findings pinpoint several new cancer risk genes and emphasize autophagy, apoptosis and cell stress response as a focus point for developing new therapeutics.

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U2 - 10.1038/s41588-024-01966-6

DO - 10.1038/s41588-024-01966-6

M3 - Journal article

C2 - 39472694

SN - 1061-4036

VL - 56

SP - 2422

EP - 2433

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

Gene-based burden tests of rare germline variants identify six cancer susceptibility genes

Abstract

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