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 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.
Biomarkers and Susceptibility Unit, Spanish Biomedical Research Centre Network for Epidemiology and Public Health, Catalan Institute of Oncology, L'Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet, Barcelona, Spain.
Núria
N
Bonifaci
Bohdan
B
Górski
Bartlomiej
B
Masojć
Dominika
D
Wokołorczyk
Anna
A
Jakubowska
Tadeusz
T
Dębniak
Antoni
A
Berenguer
Jordi
J
Serra Musach
Joan
J
Brunet
Joaquín
J
Dopazo
Steven A
SA
Narod
Jan
J
Lubiński
Conxi
C
Lázaro
Cezary
C
Cybulski
Miguel Angel
MA
Pujana
D000328:Adult; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D016022:Case-Control Studies; D018844:Cyclin-Dependent Kinases; D018450:Disease Progression; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D016017:Odds Ratio; D011044:Poland; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D036121:Receptor, EphA3; D036141:Receptor, EphA7 / Q000235:genetics; D036225:Receptor, EphB1 / Q000235:genetics; D012307:Risk Factors; D000097603:Dyrk Kinases
D052005:Bone Morphogenetic Protein Receptors, Type I; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018844:Cyclin-Dependent Kinases; D047628:Estrogen Receptor alpha; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D036121:Receptor, EphA3; D036141:Receptor, EphA7; D036225:Receptor, EphB1; D000097603:Dyrk Kinases; C491718:EPHA3 protein, human; C103570:CDKL2 protein, human; C498211:BMPR1A protein, human