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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10549-012-2202-6) contains supplementary material, which is available to authorized users

Hereditary breast cancer in Middle Eastern and North African (MENA) populations: identification of novel, recurrent and founder BRCA1 mutations in the Tunisian population

Germ-line mutations in BRCA1 breast cancer susceptibility gene account for a large proportion of hereditary breast cancer families and show considerable ethnic and geographical variations. The contribution of BRCA1 mutations to hereditary breast cancer has not yet been thoroughly investigated in Middle Eastern and North African populations. In this study, 16 Tunisian high-risk breast cancer families were screened for germline mutations in the entire BRCA1 coding region and exon–intron boundaries using direct sequencing. Six families were found to carry BRCA1 mutations with a prevalence of 37.5%. Four different deleterious mutations were detected. Three truncating mutations were previously described: c.798_799delTT (916 delTT), c.3331_3334delCAAG (3450 delCAAG), c.5266dupC (5382 insC) and one splice site mutation which seems to be specific to the Tunisian population: c.212 + 2insG (IVS5 + 2insG). We also identified 15 variants of unknown clinical significance. The c.798_799delTT mutation occurred at an 18% frequency and was shared by three apparently unrelated families. Analyzing five microsatellite markers in and flanking the BRCA1 locus showed a common haplotype associated with this mutation. This suggests that the c.798_799delTT mutation is a Tunisian founder mutation. Our findings indicate that the Tunisian population has a spectrum of prevalent BRCA1 mutations, some of which appear as recurrent and founding mutations

Implication of Xenobiotic Metabolizing Enzyme gene (CYP2E1, CYP2C19, CYP2D6, mEH and NAT2) Polymorphisms in Breast Carcinoma

<p>Abstract</p> <p>Background</p> <p>Xenobiotic Metabolizing Enzymes (XMEs) contribute to the detoxification of numerous cancer therapy-induced products. This study investigated the susceptibility and prognostic implications of the CYP2E1, CYP2C19, CYP2D6, mEH and NAT2 gene polymorphisms in breast carcinoma patients.</p> <p>Methods</p> <p>The authors used polymerase chain reaction and restriction enzyme digestion to characterize the variation of the CYP2E1, CYP2C19, CYP2D6, mEH and NAT2 gene in a total of 560 unrelated subjects (246 controls and 314 patients).</p> <p>Results</p> <p>The mEH (C/C) mutant and the NAT2 slow acetylator genotypes were significantly associated with breast carcinoma risk (p = 0.02; p = 0.01, respectively). For NAT2 the association was more pronounced among postmenopausal patients (p = 0.006). A significant association was found between CYP2D6 (G/G) wild type and breast carcinoma risk only in postmenopausal patients (p = 0.04). Association studies of genetic markers with the rates of breast carcinoma specific overall survival (OVS) and the disease-free survival (DFS) revealed among all breast carcinoma patients no association to DFS but significant differences in OVS only with the mEH gene polymorphisms (p = 0.02). In addition, the mEH wild genotype showed a significant association with decreased OVS in patients with axillary lymph node-negative patients (p = 0.03) and with decreasesd DFS in patients with axillary lymph node-positive patients (p = 0.001). However, the NAT2 intermediate acetylator genotype was associated with decreased DFS in axillary lymph node-negative patients.</p> <p>Conclusion</p> <p>The present study may prove that polymorphisms of some XME genes may predict the onset of breast carcinoma as well as survival after treatment.</p

Contribution of BRCA1 5382insC mutation in triple negative breast cancer in Tunisia

Abstract Background Triple negative breast cancer (TNBC) has been classified as a disease subgroup defined by the lack of expression of estrogen and progesterone receptors as well as the absence of the human epidermal growth factor receptor-2 (HER2) overexpression. Germline mutations in the BRCA1 gene have been associated with TNBC. Approximately 70% of breast cancers arising in BRCA1 mutation carriers and up to 23% of breast cancers in BRCA2 carriers display a triple negative phenotype. However, the contribution and the frequency of BRCA1 mutations in individuals with TNBC, not specifically selected for age at diagnosis or enriched family history of breast/ovarian cancer, have not been investigated in the Tunisian population and are to be established. The aim of the present study was to assess the contribution and the prevalence of recurrent BRCA1 germline mutation (5382inC) in Tunisian women with TNBC unselected for family history or age at onset. Methods For BRCA1 5382inC mutation detection, the exon 20 coding region and exon–intron boundaries of BRCA1 was analyzed using direct DNA sequencing. A total of 33 DNA samples from Tunisian women diagnosed with TNBC and unselected for family history or age at onset were analyzed. Results The 5382inC mutation was identified in 2 out of 33 women with TNBC with an overall prevalence of 6% (2/33). The detection rate of the 5382inC mutation among TNBC women with family history of breast cancer was 25% (2/8). The two 5382inC mutation carriers were postmenopausal and diagnosed at the age of 50 and 57. When stratified by age, the frequency of BRCA1 mutation in patients diagnosed at age ≥ 50 years was 8.7% (2/23). Conclusions Our results confirm a noticeable contribution of BRCA1 5382inC mutation in TNBC development in Tunisia and further indicate that screening for 5382insC mutation in the BRCA1 gene is of interest in genetic testing in our population. Additionally, our data highlight that receptor triple negativity could be an effective selection criterion for BRCA1 genetic test in our population and should therefore be considered in genetic testing guidelines in Tunisia

Combined analysis of interferon-γ and interleukin-10 gene polymorphisms and chronic hepatitis C severity

International audienceToday there is increasing evidence concerning the contribution of pro-/anti-inflammatory cytokine balance and genetic factors in hepatitis C pathogenesis and interindividual heterogeneity of disease outcome. In the current study, we investigated the influence of functionally described single nucleotide polymorphisms (SNPs) present in interferon-γ (IFNγ) and interleukin-10 (IL-10) genes, on chronic hepatitis C severity. IFNγ (+874T/A) and IL-10 (−1082G/A) genotypes were determined in 100 hepatitis C patients with different disease severities (chronic hepatitis, n = 42, liver cirrhosis [LC], and hepatocellular carcinoma in liver cirrhosis [HCC], n = 58) and 103 healthy controls using allele-specific polymerase chain reaction. No statistical differences in allele or genotype distributions of IFNγ and IL-10 genes were observed between patients and controls. However, some significant differences in IFNγ genotype frequencies were observed between the two groups of patients. IFNγhigh producer genotypes TT and TA were significantly more common in patients with LC and HCC (odds ratio = 2.65; p = 0.019). Although IL-10 genotypic frequencies were comparable between the different clinical forms of the disease, the combination of IFNγlow producer and IL-10high producer genotypes was significantly associated with a lower risk of LC and HCC (odds ratio = 0.21; p = 0.015). In conclusion, our findings suggest that the imbalance between the pro-inflammatory and anti-inflammatory responses mediated by polymorphisms in the IFNγ and IL-10 genes may influence the outcome of chronic HCV infection

E-cadherin genetic variants predict survival outcome in breast cancer patients

Abstract Background E-cadherin is a major component of adherens junctions that regulates cell shape and maintains tissue integrity. A complete loss or any decrease in cell surface expression of E-cadherin will interfere with the cell-to-cell junctions’ strength and leads to cell detachment and escape from the primary tumor site. In this prospective study, three functional single nucleotide polymorphisms (−347G/GA, rs5030625; −160C/A, rs16260; +54C/T, rs1801026), were found to modulate E-cadherin expression. Methods 577 DNA samples from breast cancer (BC) cases were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP). Results We detected no significant correlations between each polymorphism and the clinical parameters of the patients whereas the GACC haplotype was significantly associated with low SBR grading. Overall survival analysis showed that both −347G/G and +54C/C wild (wt) genotypes had a significantly worse effect compared to the other genotypes (non-wt). Moreover, carrying simultaneously both the −347 and +54 wt genotypes confers a significantly higher risk of death. However, with metastatic recurrence, the death-rate was null in patients carrying the non-wt genotypes, and attained 37% in those carrying the wt genotype. A multivariate analysis showed that these two polymorphisms are independent prognostic factors for overall survival in BC patients. Conclusions Our results support the fact that E-cadherin genetic variants control disease severity and progression and could be a marker of disease outcome. These findings could be useful in selecting patients that should be monitored differently

Indoleamine 2,3‐dioxygenase gene expression and kynurenine to tryptophan ratio correlation with nasopharyngeal carcinoma progression and survival

Abstract Introduction Indoleamine 2,3‐dioxygenase (IDO) is an immunosuppressive tryptophan‐depleting enzyme expressed in nasopharyngeal carcinoma (NPC) tissue. However, IDO has not been reported in the peripheral blood of NPC patients. The aim of this study was to analyze, IDO1 and IDO2 messenger RNA (mRNA) expression, the kynurenine (Kyn) and tryptophan (Trp) plasma levels, their clinical values and their relationship with cytokine levels in NPC. Methods We evaluated IDO1 and IDO2 mRNA expression in peripheral blood mononuclear cells (PBMC) by quantitative real‐time PCR, plasma Trp and Kyn levels by HPLC, and cytokine levels by ELISA in 75 NPC patients and 51 healthy controls. Results Compared to controls, IDO1 mRNA expression was significantly upregulated and IDO2 mRNA expression was significantly downregulated in PBMC of patients. Also compared to controls, plasma Kyn levels and Kyn/Trp ratio were significantly higher in patients. At the time of diagnosis, the plasma Kyn/Trp ratio was associated with advanced cancer status and was an independent prognostic factor for worse disease‐specific survival. According to cancer stages, IDO1 mRNA expression was positively correlated with plasma Kyn/Trp ratio in patients with earlier stages (I–II–III) but negatively correlated in patients with the late‐stage cancer (IV). Tumor necrosis factor‐α, interleukin (IL)‐6 and IL‐10 levels were significantly higher in patients compared to controls. Moreover, and despite treatment, patients simultaneously carrying high plasma Kyn/Trp ratio and high plasma IL‐6 and IL‐10 levels at diagnosis died approximately 1 year after first diagnosis. Conclusion Measuring blood IDO mRNA expression and Kyn/Trp ratio at diagnosis could be a potential marker to evaluate NPC progression and predict survival outcome