Genome-Wide Association Studies (GWAS) breast cancer susceptibility loci in Arabs: susceptibility and prognostic implications in Tunisians.
Genome-wide Association Studies (GWAS) revealed novel genetic markers for breast cancer susceptibility. But little is known about the risk factors and molecular events associated with breast cancer in Arab Population. Therefore, we designed a broad study to investigate the susceptibility and prognostic implications of the GWAS breast cancer loci in the Tunisian population. In a cohort of 640 unrelated patients with breast cancer and 371 healthy control subjects, we characterized the variation of 9 single nucleotide polymorphisms (SNPs), namely rs1219648, rs2981582; rs8051542, rs12443621, and rs3803662; rs889312; rs3817198; rs13387042 and rs13281615. Only 5 out of 9 GWAS breast cancer loci were found to be significantly associated with breast cancer in Tunisians: The rs1219648 (G vs. A allele: OR = 1.36, P = 1 × 10(-3)) and rs2981582 (A vs. G allele: OR = 1.55, P = 3 × 10(-6)) of FGFR2 gene; the rs8051542 of the TNRC9 gene (T vs. C allele: OR = 1.40, P = 4 × 10(-4)); the rs889312 of the MAP3K1 gene (C vs. A allele: OR = 1.33, P = 3 × 10(-3)) and the rs13281615 located on 8q24 (G vs. A allele: OR = 1.21, P = 0.03). Homozygous variant genotypes of rs2981582 were strongly related to lymph node negative breast cancer (OR = 3.33, P = 6 × 10(-7)) and the minor allele of rs2981582 was associated with increased risk of ER+ tumors (OR = 1.57, P = 0.02; OR = 2.15, P = 0.001, for heterozygous and homozygous variant genotypes, respectively) and increased risk of distant metastasis development (OR = 2.30, P = 4 × 10(-3); OR = 3.57, P = 6 × 10(-5), for heterozygous and homozygous variant genotypes, respectively) in a dose dependent manner. The association for rs8051542 was stronger for high-grade SBR tumors (OR = 2.54, P = 2 × 10(-4)). GG genotype of rs13387042 on 2q35 showed a significant association with the risk of developing distant metastasis (OR = 1.94, P = 0.02). The G allele of rs1219648 in FGFR2 and the A allele of rs13387042 on 2q35 indicated a better prognosis by showing a significantly higher overall survival rates (P = 0.013 and P = 0.005, respectively). In conclusion, GWAS breast cancer FGFR2, TNRC9, MAP3K1, and 8q24 loci are associated with an increased risk of breast cancer and genetic variation in FGFR2 gene may predict the aggressiveness of breast cancer in Tunisians.
Genetic Medicine and Immunology Laboratory, Weill Cornell Medical College in Qatar, Qatar Foundation, Education City, P.O. Box 24144, Doha, Qatar.
Jingxuan
J
Shan
Wijden
W
Mahfoudh
Shoba P
SP
Dsouza
Elham
E
Hassen
Noureddine
N
Bouaouina
Sonia
S
Abdelhak
Ahlem
A
Benhadjayed
Hager
H
Memmi
Rebecca Ann
RA
Mathew
Idil I
II
Aigha
Sallouha
S
Gabbouj
Yassmine
Y
Remadi
Lotfi
L
Chouchane
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins; D018912:Arabs / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D016022:Case-Control Studies; D002889:Chromosomes, Human, Pair 2; D002898:Chromosomes, Human, Pair 8; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006579:Heterozygote; D006609:High Mobility Group Proteins; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D015534:Trans-Activators; D014416:Tunisia
D051017:Apoptosis Regulatory Proteins; D006609:High Mobility Group Proteins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C521752:TOX3 protein, human; D015534:Trans-Activators; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human