Olfat G Shaker1, Mahmoud A Senousy2. 1. Medical Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt. 2. Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address: mohmoud.ali@pharma.cu.edu.eg.
Abstract
BACKGROUND: Genetic susceptibility for breast cancer (BC) is still poorly understood. A combination of multiple low-penetrant alleles of cancer-related genes and gene-gene interactions (epistasis) contributes to BC risk. Genetic variants in receptor activator of nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), chitinase-3-like protein 1 (CHI3L1), and vitamin D receptor (VDR) genes are implicated in breast carcinogenesis; however, the influence of their epistatic effects on BC susceptibility has not yet been studied. We investigated the association of single nucleotide polymorphism (SNP)-SNP interactions and haplotypes of 6 SNPs in these 4 genes with the genetic predisposition of BC in Egyptian women. PATIENTS AND METHODS: Data of 115 BC patients and 120 cancer-free controls were studied. Association tests were conducted using logistic regression models. RESULTS: Individual SNPs showed weak statistical significance with BC susceptibility. The interactions between RANKL-rs9533156 and OPG-rs2073618; OPG-rs2073618 with CHI3L1-rs4950928, VDR-rs2228570 and VDR-rs1544410; OPG-rs2073617 and VDR-rs1544410; VDR-rs2228570 and VDR-rs1544410 were strongly associated with increased BC risk after adjustment for multiple comparisons. No SNPs were in strong linkage disequilibrium. The TCTCTG-rs9533156-rs2073618-rs2073617-rs4950928-rs2228570-rs1544410 haplotype was significantly associated with increased BC risk (adjusted odds ratio = 8.33; 95% confidence interval, 1.32-52.46; P = .025) compared with controls. TCCCTG haplotype stratified BC patients according to estrogen receptor/progesterone receptor status. TCTCTA was positively associated, and TCTCTG and TGTCTG haplotypes inversely correlated with bone metastasis. Bioinformatic analysis revealed 13 proteins commonly interacting with our 4 genes; the most significant was signal transducer and activator of transcription 5B. CONCLUSION: Our results suggested that a stronger combined effect of SNPs in RANKL, OPG, CHI3L1, and VDR genes via gene-gene interaction may help predict BC risk and prognosis.
BACKGROUND: Genetic susceptibility for breast cancer (BC) is still poorly understood. A combination of multiple low-penetrant alleles of cancer-related genes and gene-gene interactions (epistasis) contributes to BC risk. Genetic variants in receptor activator of nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), chitinase-3-like protein 1 (CHI3L1), and vitamin D receptor (VDR) genes are implicated in breast carcinogenesis; however, the influence of their epistatic effects on BC susceptibility has not yet been studied. We investigated the association of single nucleotide polymorphism (SNP)-SNP interactions and haplotypes of 6 SNPs in these 4 genes with the genetic predisposition of BC in Egyptian women. PATIENTS AND METHODS: Data of 115 BC patients and 120 cancer-free controls were studied. Association tests were conducted using logistic regression models. RESULTS: Individual SNPs showed weak statistical significance with BC susceptibility. The interactions between RANKL-rs9533156 and OPG-rs2073618; OPG-rs2073618 with CHI3L1-rs4950928, VDR-rs2228570 and VDR-rs1544410; OPG-rs2073617 and VDR-rs1544410; VDR-rs2228570 and VDR-rs1544410 were strongly associated with increased BC risk after adjustment for multiple comparisons. No SNPs were in strong linkage disequilibrium. The TCTCTG-rs9533156-rs2073618-rs2073617-rs4950928-rs2228570-rs1544410 haplotype was significantly associated with increased BC risk (adjusted odds ratio = 8.33; 95% confidence interval, 1.32-52.46; P = .025) compared with controls. TCCCTG haplotype stratified BC patients according to estrogen receptor/progesterone receptor status. TCTCTA was positively associated, and TCTCTG and TGTCTG haplotypes inversely correlated with bone metastasis. Bioinformatic analysis revealed 13 proteins commonly interacting with our 4 genes; the most significant was signal transducer and activator of transcription 5B. CONCLUSION: Our results suggested that a stronger combined effect of SNPs in RANKL, OPG, CHI3L1, and VDR genes via gene-gene interaction may help predict BC risk and prognosis.
Authors: Moataza H Omran; Basma E Fotouh; Wafaa G Shousha; Abeer Ismail; Noha E Ibrahim; Shimaa S Ramadan Journal: Asian Pac J Cancer Prev Date: 2021-02-01