Germline HVR-II mitochondrial polymorphisms associated with breast cancer in Tunisian women.

A high incidence of somatic mtDNA polymorphisms has been reported in a wide variety of human cancers; some of them have been proposed as markers for the early detection of breast cancer. However, little attention has been paid to the potential of germline mitochondrial sequence variations as genetic risk factors for cancer. We performed a case-control study of 70 unrelated Tunisian women with breast cancer and 80 healthy age- and gender-matched blood donors, taking into account clinicopathological data, to evaluate germline polymorphism of mitochondrial HVR-II region as a genetic risk factor for breast cancer. Through direct sequencing, we detected 351 polymorphisms in controls and 248 variants in patients, with 47 and 39 segregating sites, respectively. In both groups, more than 50% of the polymorphisms were due to four variants: 315 ins C, 309 ins C, 263 A>G, and 73 A>G. The HVR-II sequences were also classified into haplotypes on the basis of the polymorphisms. Fifty-nine different haplotypes were found, 20 of them shared between patients and controls. Both groups had specific haplotypes, 18 in breast cancer patients and 21 in controls. Statistical analysis revealed a weak protective effect against breast cancer risk for two mitochondrial polymorphisms - 152 T>C (odds ratio (OR) = 0.33, 95% confidence interval (CI) = 0.12-0.91) and 263 A>G (OR = 0.17, 95%CI = 0.06-0.47). In contrast, an increased risk of breast cancer was detected for the 315+C haplotype (OR = 11.66, 95%CI = 1.44-252.23). We conclude that mitochondrial variants can affect breast cancer risk. More extensive studies, involving different types of cancer and patients with different genetic makeup, will be required to improve our understanding of the effects of germline mtDNA polymorphisms on carcinogenesis.

Comparative clinical and transcriptomal profiles of breast cancer between French and South Mediterranean patients show minor but significative biological differences.

BACKGROUND: In Western countries, breast cancer incidence and mortality are higher than in Mediterranean countries. These differences have been ascribed to environmental factors but also to late-stage diagnostic and biological specific characteristics. PATIENTS AND METHODS: Between September 2002 and September 2005, we collected clinical data by phone counselling 180 French and Mediterranean breast cancer patients and performed microarray experiments. RESULTS: Characteristics of breast cancer in patients from Lebanon, Tunisia and Morocco were more aggressive (more SBR grade III and positive node invasion) and patients were 10 years younger at diagnosis. Sixteen differentially expressed genes such as MMP9, VEGF, PHB1, BRCA1, TFAP2C, GJA1 and TFF1 were also found. Additionally, an up-regulation of cytokeratins KRT8 and KRT18 may indicate a luminal B subtype in "South" (Lebanon, Tunisia and Morocco) tumors while "North" (France) tumors may more frequently be luminal A type. CONCLUSION: This study allowed the identification of specific clinical and transcriptomic parameters in patients from South Mediterranean countries.

Complete mutation screening and haplotype characterization of BRCA1 gene in Tunisian patients with familial breast cancer.

Breast cancer, the most commonly diagnosed cancer in women, is the second leading cause of cancer death in women worldwide. To investigate the contribution of BRCA1 gene mutations to familial breast cancer in Tunisia, 32 unrelated patients who had at least one first degree relative affected with breast and/or ovarian cancer were analysed. BRCA1 mutation analysis was performed by DNA sequencing of all BRCA1 exons. We identified four different BRCA1 frameshift mutations: c.4041delAG, c.2551delG and c.5266dupC already been described and one novel mutation, c.211dupA, observed in two unrelated families. C.5266dupC has previously been found among Jewish Ashkenazi and Eastern European populations. Our study describes it in Arabic/Berber population. Five out of thirty two familial cases had deleterious BRCA1 mutations. Fifteen additional cases carried unclassified variants (UV) or single nucleotide polymorphisms (SNPs). Our study is the first molecular investigation on the role of BRCA1 in hereditary breast cancer in North Tunisia.