br of transcription B Conclusion Our
of transcription 5B. Conclusion: Our results suggested that a stronger combined effect of SNPs in RANKL, OPG, CHI3L1, and VDR SQ109 via geneegene interaction may help predict BC risk and prognosis.
Keywords: Epistasis, Geneegene interaction, Haplotype, Metastasis, Polymorphism
1Medical Biochemistry and Molecular Biology Department
2Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
Address for correspondence: Mahmoud A. Senousy, PhD, Biochemistry Department, Faculty of Pharmacy, Cairo University, 23-Kasr El-Ainy Street, Cairo, 11562, Egypt E-mail contact: [email protected]
Breast cancer (BC) is the most common cancer and is the leading cause of cancer death among women worldwide (25% of cancer cases and 15% of cancer deaths); it is the deadliest cancer among women in less developed countries.1 In Egypt, BC ranks the second most common cancer after liver cancer, accounting for 15.4% of all cancers, and is the most frequent cancer among women (32.04% of cancer cases).2
BC is a multifactorial disease resulting from combined effects of genetic and environmental risk factors. To date, the full genetic
D.20 basis of BC susceptibility is poorly understood. High risk of developing BC is attributable to germ-line mutations in high-penetrance genes such as breast cancer (BRCA) 1 and BRCA2; however, such mutations are rare (much less than 1%) in the general population. They only account for 5% to 10% of all female BC cases and 15% to 20% of all familial BC cases.3 By comparison, variants in low-penetrance genes (ie, single nucleotide poly-morphisms, SNPs) are more common and have been shown by genome-wide association studies to incrementally contribute to BC risk; however, their individual contributions are relatively small.4-7 Hence, combinations of variants of multiple low-penetrance loci/ genes (ie, genetic interactions) across the genome have been pro-posed to contribute to overall genetic BC risk.8
Epistasis, or geneegene interaction, describes how genes/loci interact to affect phenotypes and is a component of the genetic framework of complex diseases, including BC.9-11 However, the current tests for genetic interactions from genome-wide association studies data mainly focus on small sets of genes or SNPs with known association with BC, given that many genetic interactions, particularly among novel variants, remain understudied.10 In addi-tion, many independent studies have demonstrated the epistatic effects of 2 or more SNPs with reproducible weak single-locus ef-fects on BC susceptibility.12-14 However, these studies have exten-sively focused on assessing SNP-SNP interactions in DNA repair, modification, and metabolism-related pathway genes. Thus, iden-tification of interactions between SNPs in other cancer-related genes may shed more light into the unexplained heritability of BC.
To estimate the BC risk conferred by SNP-SNP interactions, we studied 6 SNPs from 4 cancer-related genes: receptor activator of nuclear factor kB ligand (RANKL), osteoprotegerin (OPG), chiti-nase-3elike protein 1 (CHI3L1), and vitamin D receptor (VDR). Beyond regulation of bone remodeling, the receptor activator of nuclear factor kB (RANK)/RANKL/OPG system is expressed by breast normal and tumor cells and is implicated in breast carcino-genesis. RANKL, binding with its receptor RANK, is involved in progesterone-mediated cell proliferation, tumor formation, and bone metastasis in BC.15,16 OPG, a decoy receptor for RANKL, blocks tumor necrosis factorerelated apoptosis ligand (TRAIL)-induced apoptosis, enhances tumor growth and metastasis, and may indirectly promote tumor progression by affecting angiogenesis in BC.17 The CHI3L1 gene encodes for YKL-40 glycoprotein, a proinflammatory cytokine secreted by neutrophils and activated macrophages that is involved in inflammatory processes of tumors such as cell proliferation, differentiation, and angiogenesis as well as remodeling of extracellular matrix.18 In addition, high-tumor-tissue YKL-40 expression has been shown to be closely linked with the recurrence and metastasis of BC.19 Active vitamin D [1,25(OH)2D3] binds to VDR, a ligand-dependent transcription factor that attenuates mammary gland formation via regulating transcription of a number of growth-regulatory genes in mammary and BC cells, suggesting tumor suppressive functions of vitamin Reduced vitamin D status—in particular the interaction r> between vitamin D levels and genetic variants of VDR—has been associated with the development and/or poor prognosis of BC.21,22 RANKL-rs9533156, OPG-rs2073618, OPG-rs2073617, CHI3L1-rs4950928, VDR FokI-rs2228570, and VDR