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

• Published in: PloS one 2010-11, Vol.5 (11), p.e14078
• Main Authors: Bonifaci, Núria, Górski, Bohdan, Masojć, Bartlomiej, Wokołorczyk, Dominika, Jakubowska, Anna, Dębniak, Tadeusz, Berenguer, Antoni, Serra Musach, Jordi, Brunet, Joan, Dopazo, Joaquín, Narod, Steven A, Lubiński, Jan, Lázaro, Conxi, Cybulski, Cezary, Pujana, Miguel Angel
• Format: Article
• Language: English
• Subjects: Adult; Age; Analysis; Binding sites; Biomarkers; Biomedical research; Bone Morphogenetic Protein Receptors, Type I - genetics; Breast - metabolism; Breast - pathology; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Calcium-Calmodulin-Dependent Protein Kinases - genetics; Cancer; Cancer genetics; Cancer research; Carcinogenesis; Carcinogens; Case-Control Studies; Cell Biology/Developmental Molecular Mechanisms; Censuses; Confidence intervals; Cyclin-Dependent Kinases; Deregulation; Development and progression; Disease Progression; Dyrk Kinases; Epidemiology; Estrogen Receptor alpha - genetics; Estrogens; Female; Gene expression; Gene Frequency; Genes; Genetic aspects; Genetic diversity; Genetic Predisposition to Disease - genetics; Genetic research; Genetics; Genetics and Genomics/Cancer Genetics; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Genotype; Germ-Line Mutation; Health aspects; Health risks; Humans; Kinases; Lesions; Medical diagnosis; Molecular modelling; Mutation; Mutation rates; Odds Ratio; Oncology; Oncology/Breast Cancer; Ovarian cancer; Pathology; Phosphotransferases; Poland; Polymorphism, Single Nucleotide; Population studies; Prostate cancer; Protein Serine-Threonine Kinases - genetics; Protein-Tyrosine Kinases - genetics; Public health; Receptor Protein-Tyrosine Kinases - genetics; Receptor, EphA3; Receptor, EphA7 - genetics; Receptor, EphB1 - genetics; Risk analysis; Risk Factors; Tumorigenesis
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0014078

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)