Exploring the link between germline and somatic genetic alterations in breast carcinogenesis.

Recent genome-wide association studies (GWASs) have identified candidate genes contributing to cancer risk through low-penetrance mutations. Many of these genes were unexpected and, intriguingly, included well-known players in carcinogenesis at the somatic level. To assess the hypothesis of a germli...

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Autores principales:	Núria Bonifaci, Bohdan Górski, Bartlomiej Masojć, Dominika Wokołorczyk, Anna Jakubowska, Tadeusz Dębniak, Antoni Berenguer, Jordi Serra Musach, Joan Brunet, Joaquín Dopazo, Steven A Narod, Jan Lubiński, Conxi Lázaro, Cezary Cybulski, Miguel Angel Pujana
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3b8960dabb5348e1918a4064e9b2dc72
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spelling	oai:doaj.org-article:3b8960dabb5348e1918a4064e9b2dc722021-11-18T07:36:38ZExploring the link between germline and somatic genetic alterations in breast carcinogenesis.1932-620310.1371/journal.pone.0014078https://doaj.org/article/3b8960dabb5348e1918a4064e9b2dc722010-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21124932/?tool=EBIhttps://doaj.org/toc/1932-6203Recent genome-wide association studies (GWASs) have identified candidate genes contributing to cancer risk through low-penetrance mutations. Many of these genes were unexpected and, intriguingly, included well-known players in carcinogenesis at the somatic level. To assess the hypothesis of a germline-somatic link in carcinogenesis, we evaluated the distribution of somatic gene labels within the ordered results of a breast cancer risk GWAS. This analysis suggested frequent influence on risk of genetic variation in loci encoding for "driver kinases" (i.e., kinases encoded by genes that showed higher somatic mutation rates than expected by chance and, therefore, whose deregulation may contribute to cancer development and/or progression). Assessment of these predictions using a population-based case-control study in Poland replicated the association for rs3732568 in EPHB1 (odds ratio (OR) = 0.79; 95% confidence interval (CI): 0.63-0.98; P(trend) = 0.031). Analyses by early age at diagnosis and by estrogen receptor α (ERα) tumor status indicated potential associations for rs6852678 in CDKL2 (OR = 0.32, 95% CI: 0.10-1.00; P(recessive) = 0.044) and rs10878640 in DYRK2 (OR = 2.39, 95% CI: 1.32-4.30; P(dominant) = 0.003), and for rs12765929, rs9836340, rs4707795 in BMPR1A, EPHA3 and EPHA7, respectively (ERα tumor status P(interaction)<0.05). The identification of three novel candidates as EPH receptor genes might indicate a link between perturbed compartmentalization of early neoplastic lesions and breast cancer risk and progression. Together, these data may lay the foundations for replication in additional populations and could potentially increase our knowledge of the underlying molecular mechanisms of breast carcinogenesis.Núria BonifaciBohdan GórskiBartlomiej MasojćDominika WokołorczykAnna JakubowskaTadeusz DębniakAntoni BerenguerJordi Serra MusachJoan BrunetJoaquín DopazoSteven A NarodJan LubińskiConxi LázaroCezary CybulskiMiguel Angel PujanaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 11, p e14078 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Núria Bonifaci Bohdan Górski Bartlomiej Masojć Dominika Wokołorczyk Anna Jakubowska Tadeusz Dębniak Antoni Berenguer Jordi Serra Musach Joan Brunet Joaquín Dopazo Steven A Narod Jan Lubiński Conxi Lázaro Cezary Cybulski Miguel Angel Pujana Exploring the link between germline and somatic genetic alterations in breast carcinogenesis.
description	Recent genome-wide association studies (GWASs) have identified candidate genes contributing to cancer risk through low-penetrance mutations. Many of these genes were unexpected and, intriguingly, included well-known players in carcinogenesis at the somatic level. To assess the hypothesis of a germline-somatic link in carcinogenesis, we evaluated the distribution of somatic gene labels within the ordered results of a breast cancer risk GWAS. This analysis suggested frequent influence on risk of genetic variation in loci encoding for "driver kinases" (i.e., kinases encoded by genes that showed higher somatic mutation rates than expected by chance and, therefore, whose deregulation may contribute to cancer development and/or progression). Assessment of these predictions using a population-based case-control study in Poland replicated the association for rs3732568 in EPHB1 (odds ratio (OR) = 0.79; 95% confidence interval (CI): 0.63-0.98; P(trend) = 0.031). Analyses by early age at diagnosis and by estrogen receptor α (ERα) tumor status indicated potential associations for rs6852678 in CDKL2 (OR = 0.32, 95% CI: 0.10-1.00; P(recessive) = 0.044) and rs10878640 in DYRK2 (OR = 2.39, 95% CI: 1.32-4.30; P(dominant) = 0.003), and for rs12765929, rs9836340, rs4707795 in BMPR1A, EPHA3 and EPHA7, respectively (ERα tumor status P(interaction)<0.05). The identification of three novel candidates as EPH receptor genes might indicate a link between perturbed compartmentalization of early neoplastic lesions and breast cancer risk and progression. Together, these data may lay the foundations for replication in additional populations and could potentially increase our knowledge of the underlying molecular mechanisms of breast carcinogenesis.
format	article
author	Núria Bonifaci Bohdan Górski Bartlomiej Masojć Dominika Wokołorczyk Anna Jakubowska Tadeusz Dębniak Antoni Berenguer Jordi Serra Musach Joan Brunet Joaquín Dopazo Steven A Narod Jan Lubiński Conxi Lázaro Cezary Cybulski Miguel Angel Pujana
author_facet	Núria Bonifaci Bohdan Górski Bartlomiej Masojć Dominika Wokołorczyk Anna Jakubowska Tadeusz Dębniak Antoni Berenguer Jordi Serra Musach Joan Brunet Joaquín Dopazo Steven A Narod Jan Lubiński Conxi Lázaro Cezary Cybulski Miguel Angel Pujana
author_sort	Núria Bonifaci
title	Exploring the link between germline and somatic genetic alterations in breast carcinogenesis.
title_short	Exploring the link between germline and somatic genetic alterations in breast carcinogenesis.
title_full	Exploring the link between germline and somatic genetic alterations in breast carcinogenesis.
title_fullStr	Exploring the link between germline and somatic genetic alterations in breast carcinogenesis.
title_full_unstemmed	Exploring the link between germline and somatic genetic alterations in breast carcinogenesis.
title_sort	exploring the link between germline and somatic genetic alterations in breast carcinogenesis.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/3b8960dabb5348e1918a4064e9b2dc72
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Exploring the link between germline and somatic genetic alterations in breast carcinogenesis.

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