A germline variant in the TP53 polyadenylation signal confers cancer susceptibility

被引：240

作者：

Stacey, Simon N. ^{[1
]}

Sulem, Patrick ^{[1
]}

Jonasdottir, Aslaug ^{[1
]}

Masson, Gisli ^{[1
]}

Gudmundsson, Julius ^{[1
]}

Gudbjartsson, Daniel F. ^{[1
]}

Magnusson, Olafur T. ^{[1
]}

Gudjonsson, Sigurjon A. ^{[1
]}

Sigurgeirsson, Bardur ^{[2
,3
]}

Thorisdottir, Kristin ^{[2
,3
]}

Ragnarsson, Rafn ^{[2
,3
]}

Benediktsdottir, Kristrun R. ^{[2
,3
]}

Nexo, Bjorn A. ^{[4
]}

Tjonneland, Anne ^{[5
]}

Overvad, Kim ^{[6
]}

Rudnai, Peter ^{[7
]}

Gurzau, Eugene ^{[8
]}

Koppova, Kvetoslava ^{[9
]}

Hemminki, Kari ^{[10
]}

Corredera, Cristina ^{[11
]}

Fuentelsaz, Victoria ^{[12
]}

Grasa, Pilar ^{[11
]}

Navarrete, Sebastian ^{[13
]}

Fuertes, Fernando ^{[13
]}

Garcia-Prats, Maria D. ^{[14
]}

Sanambrosio, Enrique ^{[15
]}

Panadero, Angeles ^{[16
]}

De Juan, Ana ^{[17
]}

Garcia, Almudena ^{[17
]}

Rivera, Fernando ^{[17
]}

Planelles, Dolores ^{[18
]}

Soriano, Virtudes ^{[19
]}

Requena, Celia ^{[20
]}

Aben, Katja K. ^{[21
,22
]}

van Rossum, Michelle M. ^{[23
]}

Cremers, Ruben G. H. M. ^{[21
,24
]}

van Oort, Inge M. ^{[24
]}

van Spronsen, Dick-Johan ^{[25
]}

Schalken, Jack A. ^{[24
]}

Peters, Wilbert H. M. ^{[26
]}

Helfand, Brian T. ^{[27
]}

Donovan, Jenny L. ^{[28
]}

Hamdy, Freddie C. ^{[29
]}

Badescu, Daniel

Codreanu, Ovidiu

Jinga, Mariana

Csiki, Irma E. ^{[31
]}

Constantinescu, Vali ^{[31
]}

Badea, Paula ^{[31
]}

Mates, Ioan N. ^{[30
]}

机构：

[1] deCODE Genet, Reykjavik, Iceland

[2] Landspitali Univ Hosp, Reykjavik, Iceland

[3] Univ Iceland, Fac Med, Reykjavik, Iceland

[4] Univ Aarhus, Inst Human Genet, Aarhus, Denmark

[5] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark

[6] Univ Aarhus, Sch Publ Hlth, Dept Epidemiol, Aarhus, Denmark

[7] Natl Inst Environm Hlth, Budapest, Hungary

[8] Ctr Environm Hlth, Cluj Napoca, Romania

[9] State Hlth Inst, Banska Bystrica, Slovakia

[10] German Canc Res Ctr, Div Mol Genet Epidemiol, D-6900 Heidelberg, Germany

[11] Univ Zaragoza, Div Dermatol, Zaragoza, Spain

[12] Gregorio Maranon Univ Hosp, Div Dermatol, Madrid, Spain

[13] Univ Zaragoza, Div Radiat Oncol, Zaragoza, Spain

[14] San Jorge Gen Hosp, Div Pathol, Huesca, Spain

[15] Gen Hosp, Div Surg, Soria, Spain

[16] Ciudad Coria Hosp, Div Med Oncol, Coria, Spain

[17] Marques de Valdecilla Univ Hosp, Div Med Oncol, Santander, Spain

[18] Ctr Transfus Comunidad Valenciana, Lab Histocompatibil Mol Biol, Valencia, Spain

[19] Inst Valenciano Oncol, Dept Oncol, Valencia, Spain

[20] Inst Valenciano Oncol, Dept Dermatol, Valencia, Spain

[21] Radboud Univ Nijmegen, Med Ctr, Dept Epidemiol Biostat & Hlth Technol Assessment, NL-6525 ED Nijmegen, Netherlands

[22] Comprehens Canc Ctr Netherlands, Nijmegen, Netherlands

[23] Radboud Univ Nijmegen, Med Ctr, Dept Dermatol, NL-6525 ED Nijmegen, Netherlands

[24] Radboud Univ Nijmegen, Med Ctr, Dept Urol, NL-6525 ED Nijmegen, Netherlands

[25] Canisius Wilhelmina Ziekenhuis, Dept Internal Med, Nijmegen, Netherlands

[26] Radboud Univ Nijmegen, Med Ctr, Dept Gastroenterol, NL-6525 ED Nijmegen, Netherlands

[27] Northwestern Univ, Feinberg Sch Med, Dept Urol, Chicago, IL 60611 USA

[28] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England

[29] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Surg Sci, Oxford OX3 9DU, England

[30] Univ Med & Pharm Carol Davila, St Mary Surg Clin, Bucharest, Romania

[31] Natl Inst Publ Hlth, Bucharest, Romania

[32] Speglun Ehf, Reykjavik, Iceland

[33] Domus Med, Reykjavik, Iceland

[34] Iceland Canc Registry, Reykjavik, Iceland

[35] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA

[36] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA

[37] Mayo Clin, Dept Neurol, Rochester, MN USA

[38] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA

[39] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden

[40] Univ N Carolina, Univ Ctr Gastrointestinal Biol & Dis, Chapel Hill, NC USA

[41] Univ Copenhagen, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark

[42] Univ Copenhagen, Fac Hlth Sci, Copenhagen, Denmark

[43] Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark

[44] Steno Diabet Ctr, DK-2820 Gentofte, Denmark

[45] Univ So Denmark, Fac Hlth Sci, Odense, Denmark

[46] Hagedorn Res Inst, Gentofte, Denmark

[47] Univ Aarhus, Fac Hlth Sci, Aarhus, Denmark

[48] Univ Cambridge, Addenbrookes Hosp, Ctr Oncol, Cambridge CB2 2QQ, England

[49] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA

[50] Natl Res Ctr Working Environm, Copenhagen, Denmark

来源：

NATURE GENETICS | 2011年 / 43卷 / 11期

基金：

美国国家卫生研究院;

关键词：

GENETIC-DETERMINANTS; SEQUENCE VARIANTS; COMMON VARIANTS; BASAL; PIGMENTATION; P53; MUTATIONS; ASSOCIATE; MELANOMA;

D O I：

10.1038/ng.926

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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 x 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 x 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 x 10(-6)), glioma (OR = 2.35, P = 1.0 x 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 x 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).

引用

页码：1098 / U85

页数：7

共 25 条

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Melanocortin-1 receptor genotype is a risk factor for basal and squamous cell carcinoma [J].