A germline variant in the TP53 polyadenylation signal confers cancer susceptibility

Simon N Stacey; Patrick Sulem; Aslaug Jonasdottir; Gisli Masson; Julius Gudmundsson; Daniel F Gudbjartsson; Olafur T Magnusson; Sigurjon A Gudjonsson; Bardur Sigurgeirsson; Kristin Thorisdottir; Rafn Ragnarsson; Kristrun R Benediktsdottir; Bjørn Andersen Nexø; Anne Tjønneland; Kim Overvad; Peter Rudnai; Eugene Gurzau; Kvetoslava Koppova; Kari Hemminki; Cristina Corredera; Victoria Fuentelsaz; Pilar Grasa; Sebastian Navarrete; Fernando Fuertes; Maria D García-Prats; Enrique Sanambrosio; Angeles Panadero; Ana De Juan; Almudena Garcia; Fernando Rivera; Dolores Planelles; Virtudes Soriano; Celia Requena; Katja K Aben; Michelle M van Rossum; Ruben G H M Cremers; Inge M van Oort; Dick-Johan van Spronsen; Jack A Schalken; Wilbert H M Peters; Brian T Helfand; Jenny L Donovan; Freddie C Hamdy; Daniel Badescu; Ovidiu Codreanu; Karina Banasik; Torben Jørgensen; Daniel R Witte; Torben Hansen; Oluf Pedersen; Swedish Low-risk Colorectal Cancer Study Group

doi:10.1038/ng.926

A germline variant in the TP53 polyadenylation signal confers cancer susceptibility

Simon N Stacey, Patrick Sulem, Aslaug Jonasdottir, Gisli Masson, Julius Gudmundsson, Daniel F Gudbjartsson, Olafur T Magnusson, Sigurjon A Gudjonsson, Bardur Sigurgeirsson, Kristin Thorisdottir, Rafn Ragnarsson, Kristrun R Benediktsdottir, Bjørn Andersen Nexø, Anne Tjønneland, Kim Overvad, Peter Rudnai, Eugene Gurzau, Kvetoslava Koppova, Kari Hemminki, Cristina CorrederaVictoria Fuentelsaz, Pilar Grasa, Sebastian Navarrete, Fernando Fuertes, Maria D García-Prats, Enrique Sanambrosio, Angeles Panadero, Ana De Juan, Almudena Garcia, Fernando Rivera, Dolores Planelles, Virtudes Soriano, Celia Requena, Katja K Aben, Michelle M van Rossum, Ruben G H M Cremers, Inge M van Oort, Dick-Johan van Spronsen, Jack A Schalken, Wilbert H M Peters, Brian T Helfand, Jenny L Donovan, Freddie C Hamdy, Daniel Badescu, Ovidiu Codreanu, Karina Banasik, Torben Jørgensen, Daniel R Witte, Torben Hansen, Oluf Pedersen, Swedish Low-risk Colorectal Cancer Study Group

181 Citations (Scopus)

Abstract

To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).

Original language	English
Journal	Nature Genetics
Volume	43
Issue number	11
Pages (from-to)	1098-1103
Number of pages	6
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.926
Publication status	Published - Nov 2011

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Stacey, S. N., Sulem, P., Jonasdottir, A., Masson, G., Gudmundsson, J., Gudbjartsson, D. F., Magnusson, O. T., Gudjonsson, S. A., Sigurgeirsson, B., Thorisdottir, K., Ragnarsson, R., Benediktsdottir, K. R., Nexø, B. A., Tjønneland, A., Overvad, K., Rudnai, P., Gurzau, E., Koppova, K., Hemminki, K., ... Swedish Low-risk Colorectal Cancer Study Group (2011). A germline variant in the TP53 polyadenylation signal confers cancer susceptibility. Nature Genetics, 43(11), 1098-1103. https://doi.org/10.1038/ng.926

Stacey, SN, Sulem, P, Jonasdottir, A, Masson, G, Gudmundsson, J, Gudbjartsson, DF, Magnusson, OT, Gudjonsson, SA, Sigurgeirsson, B, Thorisdottir, K, Ragnarsson, R, Benediktsdottir, KR, Nexø, BA, Tjønneland, A, Overvad, K, Rudnai, P, Gurzau, E, Koppova, K, Hemminki, K, Corredera, C, Fuentelsaz, V, Grasa, P, Navarrete, S, Fuertes, F, García-Prats, MD, Sanambrosio, E, Panadero, A, De Juan, A, Garcia, A, Rivera, F, Planelles, D, Soriano, V, Requena, C, Aben, KK, van Rossum, MM, Cremers, RGHM, van Oort, IM, van Spronsen, D-J, Schalken, JA, Peters, WHM, Helfand, BT, Donovan, JL, Hamdy, FC, Badescu, D, Codreanu, O, Banasik, K, Jørgensen, T, Witte, DR, Hansen, T , Pedersen, O & Swedish Low-risk Colorectal Cancer Study Group 2011, 'A germline variant in the TP53 polyadenylation signal confers cancer susceptibility', Nature Genetics, vol. 43, no. 11, pp. 1098-1103. https://doi.org/10.1038/ng.926

@article{eee466634466411fa667bc2a1ee3e5cd,

title = "A germline variant in the TP53 polyadenylation signal confers cancer susceptibility",

abstract = "To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).",

author = "Stacey, {Simon N} and Patrick Sulem and Aslaug Jonasdottir and Gisli Masson and Julius Gudmundsson and Gudbjartsson, {Daniel F} and Magnusson, {Olafur T} and Gudjonsson, {Sigurjon A} and Bardur Sigurgeirsson and Kristin Thorisdottir and Rafn Ragnarsson and Benediktsdottir, {Kristrun R} and Nex{\o}, {Bj{\o}rn Andersen} and Anne Tj{\o}nneland and Kim Overvad and Peter Rudnai and Eugene Gurzau and Kvetoslava Koppova and Kari Hemminki and Cristina Corredera and Victoria Fuentelsaz and Pilar Grasa and Sebastian Navarrete and Fernando Fuertes and Garc{\'i}a-Prats, {Maria D} and Enrique Sanambrosio and Angeles Panadero and {De Juan}, Ana and Almudena Garcia and Fernando Rivera and Dolores Planelles and Virtudes Soriano and Celia Requena and Aben, {Katja K} and {van Rossum}, {Michelle M} and Cremers, {Ruben G H M} and {van Oort}, {Inge M} and {van Spronsen}, Dick-Johan and Schalken, {Jack A} and Peters, {Wilbert H M} and Helfand, {Brian T} and Donovan, {Jenny L} and Hamdy, {Freddie C} and Daniel Badescu and Ovidiu Codreanu and Karina Banasik and Torben J{\o}rgensen and Witte, {Daniel R} and Torben Hansen and Oluf Pedersen and {Swedish Low-risk Colorectal Cancer Study Group}",

year = "2011",

month = nov,

doi = "10.1038/ng.926",

language = "English",

volume = "43",

pages = "1098--1103",

journal = "Nature: New biology",

issn = "1061-4036",

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T1 - A germline variant in the TP53 polyadenylation signal confers cancer susceptibility

AU - Stacey, Simon N

AU - Sulem, Patrick

AU - Jonasdottir, Aslaug

AU - Masson, Gisli

AU - Gudmundsson, Julius

AU - Gudbjartsson, Daniel F

AU - Magnusson, Olafur T

AU - Gudjonsson, Sigurjon A

AU - Sigurgeirsson, Bardur

AU - Thorisdottir, Kristin

AU - Ragnarsson, Rafn

AU - Benediktsdottir, Kristrun R

AU - Nexø, Bjørn Andersen

AU - Tjønneland, Anne

AU - Overvad, Kim

AU - Rudnai, Peter

AU - Gurzau, Eugene

AU - Koppova, Kvetoslava

AU - Hemminki, Kari

AU - Corredera, Cristina

AU - Fuentelsaz, Victoria

AU - Grasa, Pilar

AU - Navarrete, Sebastian

AU - Fuertes, Fernando

AU - García-Prats, Maria D

AU - Sanambrosio, Enrique

AU - Panadero, Angeles

AU - De Juan, Ana

AU - Garcia, Almudena

AU - Rivera, Fernando

AU - Planelles, Dolores

AU - Soriano, Virtudes

AU - Requena, Celia

AU - Aben, Katja K

AU - van Rossum, Michelle M

AU - Cremers, Ruben G H M

AU - van Oort, Inge M

AU - van Spronsen, Dick-Johan

AU - Schalken, Jack A

AU - Peters, Wilbert H M

AU - Helfand, Brian T

AU - Donovan, Jenny L

AU - Hamdy, Freddie C

AU - Badescu, Daniel

AU - Codreanu, Ovidiu

AU - Banasik, Karina

AU - Jørgensen, Torben

AU - Witte, Daniel R

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Swedish Low-risk Colorectal Cancer Study Group

PY - 2011/11

Y1 - 2011/11

N2 - To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).

AB - To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).

U2 - 10.1038/ng.926

DO - 10.1038/ng.926

M3 - Letter

C2 - 21946351

SN - 1061-4036

VL - 43

SP - 1098

EP - 1103

JO - Nature: New biology

JF - Nature: New biology

IS - 11

ER -

A germline variant in the TP53 polyadenylation signal confers cancer susceptibility

Abstract

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