The distribution of reproductive risk factors disclosed the heterogeneity of receptor-defined breast cancer subtypes among Tanzanian women.

BACKGROUND: Recent epidemiological studies suggest that reproductive factors are associated with breast cancer (BC) molecular subtypes. However, these associations have not been thoroughly studied in the African populations. The present study aimed to investigate the prevalence of BC molecular subtypes and assess their association with reproductive factors in Tanzanian BC patients. METHODS: This hospital-based case-only cross-sectional study consisted of 263 histologically confirmed BC patients in Tanzania. Clinico-pathological data, socio-demographic characteristics, anthropometric measurements, and reproductive risk factors were examined using the Chi-square test and one-way ANOVA. The association among reproductive factors and BC molecular subtypes was analyzed using multinomial logistic regression. The heterogeneity of the associations was assessed using the Wald test. RESULTS: We found evident subtype heterogeneity for reproductive factors. We observed that post-menopausal status was more prevalent in luminal-A subtype, while compared to luminal-A subtype, luminal-B and HER-2 enriched subtypes were less likely to be found in post-menopausal women (OR: 0.21, 95%CI 0.10-0.41, p = 0.001; OR: 0.39, 95%CI 0.17-0.89, p = 0.026, respectively). Also, the luminal-B subtype was more likely to be diagnosed in patients aged ≤ 40 years than the luminal-A subtype (OR: 2.80, 95%CI 1.46-5.32, p = 0.002). Women who had their first full-term pregnancy at < 30 years were more likely to be of luminal-B (OR: 2.71, 95%CI 1.18-4.17, p = 0.018), and triple-negative (OR: 2.28, 95%CI 1.02-4.07, p = 0.044) subtypes relative to luminal-A subtype. Furthermore, we observed that breastfeeding might have reduced odds of developing luminal-A, luminal-B and triple-negative subtypes. Women who never breastfed were more likely to be diagnosed with luminal-B and triple-negative subtypes when compared to luminal-A subtype (OR: 0.46, 95%CI 0.22-0.95, p = 0.035; OR: 0.41, 95%CI 0.20-0.85, p = 0.017, respectively). . CONCLUSION: Our results are the first data reporting reproductive factors heterogeneity among BC molecular subtypes in Tanzania. Our findings suggest that breast-feeding may reduce the likelihood of developing luminal-A, luminal-B, and triple-negative subtypes. Meanwhile, the first full-term pregnancy after 30 years of age could increase the chance of developing luminal-A subtype, a highly prevalent subtype in Tanzania. More interventions to promote modifiable risk factors across multiple levels may most successfully reduce BC incidence in Africa.

The interplay between XPG-Asp1104His polymorphism and reproductive risk factors elevates risk of breast cancer in Tanzanian women: A multiple interaction analysis.

BACKGROUND: Reproductive history and genetics are well-known risk factors of breast cancer (BC). Little is known about how these factors interact to effect BC. This study investigated the association of ten polymorphisms in DNA repair genes with BC susceptibility in the Tanzanian samples and further analyzed the association between reproductive risk factors and disease risk METHODS: A hospital-based case-control study in 263 histopathological confirmed BC patients and 250 age-matched cancer-free controls was carried out. Allelic, genotypic, and haplotype association analyses were executed. Also, multifactor dimensionality reduction (MDR), and interaction dendrogram approaches were performed. RESULTS: The frequency of genotypic and allelic variants of XRCC1-Arg399Gln (rs25487), XRCC2-Arg188His (rs3218536), XRCC3-Thr241Met (rs861539), XPG-Asp1104His (rs17655), and MSH2-Gly322Asp (rs4987188) were significantly different between the groups (p < 0.05). Moreover, XRCC1-Arg399Gln (rs25487), XRCC3-Thr241Met (rs861539), and XPG-Asp1104His (rs17655) were associated with the increased risk of BC in co-dominant, dominant, recessive, and additive genetic-inheritance models (p < 0.05). XRCC1-Arg/Gln genotype indicated a 3.1-fold increased risk of BC in pre-menopausal patients (p = 0.001) while XPG-His/His genotype showed a 1.2-fold increased risk in younger BC patients (<40 years) (p = 0.028). Asp/His+His/His genotypes indicated a 1.3-fold increased risk of BC in PR+ patients and a 1.1-fold decreased risk of BC in luminal-A patients (p = 0.014, p = 0.020, respectively). MDR analysis revealed a positive interaction between BC and the XPG-Asp1104His (rs17655) together with family history of cancer in the first-degree relatives. Dendrogram analysis indicated that the XPG-Asp1104His (rs17655) and family history of cancer in first-degree relatives were significantly synergistic and might be associated with an elevated risk of BC in Tanzania. CONCLUSIONS: The XPG-Asp1104His (rs17655) might exert both independent and interactive effects on BC development in the Tanzanian women.

Breast cancer in East Africa: Prevalence and spectrum of germline SNV/indel and CNVs in BRCA1 and BRCA2 genes among breast cancer patients in Tanzania.

BACKGROUND: Growing prevalence and aggressiveness of breast cancer (BC) among East African women strongly indicate that the genetic risk factor implicated in the etiology of the disease may have a key role. Germline pathogenic variants in BRCA1 and BRCA2 (BRCA1/2) are known to increase the lifetime risk of BC. This study investigated the prevalence and spectrum of germline single nucleotide variant/insertion and deletion (SNV/indel), and copy number variations (CNVs) in BRCA1/2 among Tanzanian BC patients, and evaluated the associations of identified variants with patient's socio-demographic and histopathological characteristics. METHODS: One hundred BC patients were examined for BRCA1/2 variants using next-generation sequencing (NGS). Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) assay were performed for the confirmation of SNV/indel and CNVs, respectively. RESULTS: Six germline SNV/indel pathogenic variants were detected from six unrelated patients. Five of these variants were identified in BRCA1, and one in BRCA2. We also identified, in one patient, one variant of uncertain clinical significance (VUS). CNV was not detected in any of the BC patients. Furthermore, we found that in our cohort, BRCA1/2 variant carriers were triple-negative BC patients (p = 0.019). CONCLUSIONS: Our study provides first insight into BC genetic landscape by the use of NGS in the under-represented East African Tanzanian populations. Our findings support the importance of genetic risk factors in BC etiology in Tanzania and showed a relatively high overall prevalence (6%) of germline BRCA1/2 pathogenic variants in BC patients. Therefore, our results indicate that BRCA1/2 pathogenic variants may well contribute to BC incidence in Tanzania. Thus, the identification of frequent variants in BRCA1/2 genes will enable implementation of rapid, inexpensive population-specific BRCA1/2 genetic testing, particularly for triple-negative BC patients known for their high prevalence in Tanzania. This will, in turn, greatly contributes to provide effective therapeutic strategies.

Implication of Soluble HLA-G and HLA-G +3142G/C Polymorphism in Breast Cancer Patients Receiving Adjuvant Therapy in Tanzania.

BACKGROUND: During cancer growth, immunosuppressive microenvironment is created that enables tumour cells to evade an eliminative immune response and hence manage to grow into malignancy. HLA-G, existing as either membrane-bound (mHLA-G) or soluble (sHLA-G) molecule is thought to be immunosuppressive and produced more by tumor cells. The +3142G/C polymorphism in HLA-G gene affects its expression, and G allele is considered to be a protective mutant allele associated with less expression of HLA-G. The implication of HLA-G in cancer development has been reported in different cancers and populations. But, its implication in most African populations has not yet been investigated. The aim of this study was to determine the possible associations of soluble HLA-G and HLA-G +3142G/C SNP with breast cancer. MATERIALS AND METHODS: 75 breast cancer patients and 84 normal controls were recruited in this study. The genotyping of HLA-G +3142G/C polymorphism was determined by LightSNiP typing assay using quantitative Real-Time PCR and sHLA-G levels were determined by ELISA. RESULTS: The sHLA-G levels were significantly lower in breast cancer patients than in controls (p<0.001). Also, they were significantly lower in mastectomized patients compared to non-mastectomized patients (p=0.018). The ROC analysis revealed a significant ability of sHLA-G to differentiate breast cancer patients versus normal controls (AUC=0.697, 95% CI= 0.619-0.767, p<0.001) and identify mastectomized patients (AUC=0.667, 95% CI= 0.549 to 0.772, p=0.041). The assessment of +3142G/C polymorphism revealed a relatively similar distribution of frequencies of genotypes and alleles between breast cancer patients and normal controls (p>0.05) and was neither associated with sHLA-G levels. CONCLUSION: While the +3142G/C SNP was found not to be relevant to breast cancer, the changes of sHLA-G levels in response to medical interventions such as mastectomy may be translated into its potential prognostic utility for breast cancer. More studies are needed to provide clear evidence of sHLA-G as a diagnostic and prognostic marker of breast cancer in Tanzania.
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