Analysis of functional germline variants in APOBEC3 and driver genes on breast cancer risk in Moroccan study population.

BACKGROUND: Breast cancer (BC) is the most prevalent cancer in women and a major public health problem in Morocco. Several Moroccan studies have focused on studying this disease, but more are needed, especially at the genetic and molecular levels. Therefore, we investigated the potential association of several functional germline variants in the genes commonly mutated in sporadic breast cancer. METHODS: In this case-control study, we examined 36 single nucleotide polymorphisms (SNPs) in 13 genes (APOBEC3A, APOBEC3B, ARID1B, ATR, MAP3K1, MLL2, MLL3, NCOR1, RUNX1, SF3B1, SMAD4, TBX3, TTN), which were located in the core promoter, 5'-and 3'UTR or which were nonsynonymous SNPs to assess their potential association with inherited predisposition to breast cancer development. Additionally, we identified a ~29.5-kb deletion polymorphism between APOBEC3A and APOBEC3B and explored possible associations with BC. A total of 226 Moroccan breast cancer cases and 200 matched healthy controls were included in this study. RESULTS: The analysis showed that12 SNPs in 8 driver genes, 4 SNPs in APOBEC3B gene and 1 SNP in APOBEC3A gene were associated with BC risk and/or clinical outcome at P ≤ 0.05 level. RUNX1_rs8130963 (odds ratio (OR) = 2.25; 95 % CI 1.42-3.56; P = 0.0005; dominant model), TBX3_rs8853 (OR = 2.04; 95 % CI 1.38-3.01; P = 0.0003; dominant model), TBX3_rs1061651 (OR= 2.14; 95 % CI1.43-3.18; P = 0.0002; dominant model), TTN_rs12465459 (OR = 2.02; 95 % confidence interval 1.33-3.07; P = 0.0009; dominant model), were the most significantly associated SNPs with BC risk. A strong association with clinical outcome were detected for the genes SMAD4 _rs3819122 with tumor size (OR = 0.45; 95 % CI 0.25-0.82; P = 0.009) and TTN_rs2244492 with estrogen receptor (OR = 0.45; 95 % CI 0.25-0.82; P = 0.009). CONCLUSION: Our results suggest that genetic variations in driver and APOBEC3 genes were associated with the risk of BC and may have impact on clinical outcome. However, the reported association between the deletion polymorphism and BC risk was not confirmed in the Moroccan population. These preliminary findings require replication in larger studies.

The CHEK2 1100delC allelic variant is not present in familial and sporadic breast cancer cases from Moroccan population.

PURPOSE: The cell-cycle checkpoint kinase 2 (CHEK2) is an important signal transducer of cellular responses to DNA damage, whose defects has been associated with increased risk for breast cancer. The CHEK2 1100delC mutation has been reported to confer a twofold increased risk of breast cancer among carriers. The frequency of the mutation varies among populations. The highest frequency has been described in Northern and Eastern European countries. However, the 1100delC mutation has been investigated in different case-control studies and none in Moroccan population. The aim of this study was to evaluate the prevalence of this variant and determine its contribution to the development of breast cancer in sporadic cases and also in members of breast cancer families who tested negative or positive for a deleterious mutation in BRCA1/BRCA2. METHODS: In this case-control study we performed the CHEK2 1100delC mutation analysis by ASO-PCR in 134 breast cancer patients and 114 unaffected control individuals. Most of these families had several cases of breast cancer or ovarian cancer (or both). RESULTS: No CHEK2 1100delC mutations were detected in any of 134 individuals, including 59 women diagnosed with breast cancer at an early age (<40 years), 10 women with bilateral breast cancer, and 6 women with ovarian cancer. CONCLUSION: Our preliminary genetic analysis are consistent with the reported very low frequency of CHEK2 1100delC mutation in North American populations (compared with Northern Europe), rendering CHEK2 1100delC such as an unlikely to be major breast cancer susceptibility genes.

Impairment of axotomy-induced pituitary adenylyl cyclase-activating peptide gene expression in T helper 2 lymphocyte-deficient mice.

CD4+ (T helper) lymphocytes appear to play important roles in neuron survival and regeneration after injury, although their functions in regulating gene expression in injured neurons are unknown. Mice with targeted mutations in the STAT4 and STAT6 genes are deficient in T helper (Th)1 and Th2 responses, respectively, and have been used to determine the relative importance of T helper subsets in a variety of inflammatory processes. As pituitary adenylyl cyclase-activating peptide mRNA is normally strongly induced in facial motor neurons after axotomy, we examined this induction in Th1 and Th2 lymphocyte-deficient and control Balb/C wild-type mice. As previously reported, pituitary adenylyl cyclase-activating peptide gene expression was strongly induced in ipsilateral but not contralateral motor neurons in the facial motor nucleus of wild-type mice. The mean number of hybridizing motor neurons in STAT4-deficient mice did not differ from that in wild-type mice, whereas the number in STAT6 mice was reduced by more than 50%. The results indicate that STAT6 plays a key role in the upregulation of pituitary adenylyl cyclase-activating peptide gene expression in facial motor neurons after injury, possibly through its role in regulating T helper cell differentiation to the type 2 phenotype.