Temidayo O. Ogundiran

Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer.

We carried out a genome-wide association study of breast cancer predisposition with replication and refinement studies involving 6,145 cases and 33,016 controls and identified two SNPs (rs4415084 and rs10941679) on 5p12 that confer risk, preferentially for estrogen receptor (ER)-positive tumors (OR = 1.27, P = 2.5 × 10−12 for rs10941679). The nearest gene, MRPS30, was previously implicated in apoptosis, ER-positive tumors and favorable prognosis. A recently reported signal in FGFR2 was also found to associate specifically with ER-positive breast cancer.

Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.

We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor α (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case∶control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2×10−3), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9×10−4) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9×10−7), was without significant heterogeneity between ancestries (Phet = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.

Parity and breastfeeding are protective against breast cancer in Nigerian women

As the relation between reproductive factors and breast cancer risk has not been systematically studied in indigenous women of sub-Saharan Africa, we examined this in a case–control study in Nigeria. In-person interviews were conducted using structured questionnaires to collect detailed reproductive history in 819 breast cancer cases and 569 community controls between 1998 and 2006. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI). Compared with women with menarcheal age <17 years, the adjusted OR for women with menarcheal age ⩾17 years was 0.72 (95% CI: 0.54–0.95, P=0.02). Parity was negatively associated with risk (P-trend=0.02) but age at first live birth was not significant (P=0.16). Importantly, breast cancer risk decreased by 7% for every 12 months of breastfeeding (P-trend=0.005). It is worth noting that the distribution of reproductive risk factors changed significantly from early to late birth cohorts in the direction of increasing breast cancer incidence. Our findings also highlight the heterogeneity of breast cancer aetiology across populations, and indicate the need for further studies among indigenous sub-Saharan women.

Emerging breast cancer epidemic: evidence from Africa

Cancer is an increasingly important public health problem in developing countries, including Africa [1]. As public and professional awareness of the cancer problem has grown, so has interest in the pattern of disease presentation, its epidemiology and treatment outcome. To date, however, there has been limited research about breast cancer in Africa. In the absence of systematic population-based cancer registration, most information has come from small clinical and pathology case series and the bias inherent in these types of studies has influenced current understanding of the pattern and characteristics of breast cancer in Africa. In this communication, we review the evidence for an emerging epidemic of breast cancer in Africa, its risk factors and likely future course. We conclude that, despite limited data, rising incidence of breast cancer is being driven by increasing life expectancy, improved control of infectious diseases, and changing lifestyle, diet, physical activity and obstetric practices. We also review current beliefs about hormone receptor subtypes of breast cancer in Africa and suggest that this is probably not systematically different from the pattern in other populations after adjusting for factors such as age and that the reported differences are related to poor tissue handling and laboratory processing practices.

Waist–hip ratio and breast cancer risk in urbanized Nigerian women

BackgroundThe aim of this study was to examine the relationship between waist–hip ratio and the risk of breast cancer in an urban Nigerian population.MethodsBetween March 1998 and August 2000, we conducted a case–control study of hospital-based breast cancer patients (n = 234) and population-based controls (n = 273) using nurse interviewers in urban Southwestern Nigeria.ResultsMultivariable logistic regression showed a significant association between the highest tertile of waist–hip ratio and the risk of breast cancer (odds ratio= 2.67, 95% confidence interval = 1.05–6.80) among postmenopausal women. No association was found in premenopausal women.ConclusionThe present study, the first in an indigenous African population, supports other studies that have shown a positive association between obesity and breast cancer risk among postmenopausal women.

Voluntary Participation and Informed Consent to International Genetic Research

OBJECTIVES We compared voluntary participation and comprehension of informed consent among individuals of African ancestry enrolled in similarly designed genetic studies of hypertension in the United States and Nigeria. METHODS Survey questionnaires were used to evaluate factors associated with voluntariness (the number of people volunteering) and understanding of the studys genetic purpose. A total of 655 individuals (United States: 348; Nigeria: 307) were interviewed after participation in the genetic studies. RESULTS Most US respondents (99%), compared with 72% of Nigerian respondents, reported being told the study purpose. Fewer than half of the respondents at both sites reported that the study purpose was to learn about genetic inheritance of hypertension. Most respondents indicated that their participation was voluntary. In the United States, 97% reported that they could withdraw, compared with 67% in Nigeria. In Nigeria, nearly half the married women reported asking permission from husbands to enroll in the hypertension study; no respondents sought permission from local elders to participate in the study. CONCLUSIONS Our findings highlight the need for more effective approaches and interventions to improve comprehension of consent for genetic research among ethnically and linguistically diverse populations in all settings.

Evaluation of 19 susceptibility loci of breast cancer in women of African ancestry

Multiple breast cancer susceptibility loci have been identified in genome-wide association studies (GWAS) in populations of European and Asian ancestry using array chips optimized for populations of European ancestry. It is important to examine whether these loci are associated with breast cancer risk in women of African ancestry. We evaluated 25 single nucleotide polymorphisms (SNPs) at 19 loci in a pooled case-control study of breast cancer, which included 1509 cases and 1383 controls. Cases and controls were enrolled in Nigeria, Barbados and the USA; all women were of African ancestry. We found significant associations for three SNPs, which were in the same direction and of similar magnitude as those reported in previous fine-mapping studies in women of African ancestry. The allelic odds ratios were 1.24 [95% confidence interval (CI): 1.04-1.47; P = 0.018] for the rs2981578-G allele (10q26/FGFR2), 1.34 (95% CI: 1.10-1.63; P = 0.0035) for the rs9397435-G allele (6q25) and 1.12 (95% CI: 1.00-1.25; P = 0.04) for the rs3104793-C allele (16q12). Although a significant association was observed for an additional index SNP (rs3817198), it was in the opposite direction to prior GWAS studies. In conclusion, this study highlights the complexity of applying current GWAS findings across racial/ethnic groups, as none of GWAS-identified index SNPs could be replicated in women of African ancestry. Further fine-mapping studies in women of African ancestry will be needed to reveal additional and causal variants for breast cancer.

Obesity and height in urban Nigerian women with breast cancer.

PURPOSE To examine the relationship between obesity, height, and breast cancer in an urban Nigerian population. METHODS Between March 1998 and August 2000, we conducted a case-control study of hospital-based breast cancer patients (n = 234) and population-based controls (n = 273) using nurse interviewers in urban Southwestern Nigeria. RESULTS The study did not find a significant association between obesity (BMI >/= 30) and breast cancer among all women (OR = 1.51, 95% CI = 0.87-2.62) pre- (OR = 1.21, 95% CI = 0.56-2.60) and post-menopausal breast cancer patients (OR = 1.82, 95% CI = 0.78-4.31) in multivariate logistic regression analysis, while increasing height was positively associated with the risk of breast cancer among all women (OR = 1.05, 1.01 - 1.08), pre- (1.06, 1.01-1.10) and post-menopausal women (1.07, 1.01-1.13) for each cm. Age, irregular period, and early age of onset of periods were also found to be significantly associated with breast cancer risk. CONCLUSION This study failed to demonstrate an association between breast cancer risk and obesity while showing that height is positively associated with risk of breast cancer in urbanized Nigerian women.

Complete allelic analysis of BRCA1 and BRCA2 variants in young Nigerian breast cancer patients

Breast cancer is a leading cause of cancer deaths among women, and is expected to claim the lives of nearly 40 000 individuals in the USA each year (American Cancer Society Breast Cancer Facts and Figures 2003–2004 ). Only 5–10% of breast cancers are associated with mutations in the susceptibility genes BRCA1 and BRCA2 . However, in cases associated with strong family history, mutation rates are higher, ranging from 16% to 26% for BRCA1 1–3 and from 7% to 13% for BRCA2 .2,3 However, many breast cancer patients with strong family histories have no obvious mutations in BRCA1 /2. While there is an active search for other breast cancer susceptibility genes, it is possible that the true contributions of BRCA1 and BRCA2 to early onset breast cancer have been underestimated. Indeed, one study has shown that only 63% of breast cancer families linked to BRCA1 are associated with detectable mutations in BRCA1 .4 Several reasons for this discrepancy are possible. For example, mutations in BRCA1 promoter sequences might be undetectable by current detection techniques. Additionally, inherited genomic rearrangements that inactivate BRCA1 and BRCA2 but cannot be detected by conventional polymerase chain reaction (PCR) based assays have been reported.5,6,7,8,9,10 Finally, it is possible that some genetic variants previously dismissed as “unclassified variants” or “polymorphisms” may have hitherto underappreciated effects on protein synthesis or function. Most studies of BRCA1 and BRCA2 associated breast cancers have focused on white populations, yet several observations suggest that there might be a genetic component to breast cancer susceptibility in families of African ancestry.11 Breast cancer is less common in African populations than in other populations but, when it does occur, it is characterised by an early age of onset and a higher mortality.12–14 Additionally, …

High prevalence of BRCA1 and BRCA2 mutations in unselected Nigerian breast cancer patients

Inherited mutations in the BRCA1 and BRCA2 genes are the strongest genetic predictors of breast cancer and are the primary causes of familial breast/ovarian cancer syndrome. The frequency, spectrum and penetrance of mutant BRCA1/BRCA2 alleles have been determined for several populations, but little information is available for populations of African ancestry, who suffer a disproportionate burden of early onset breast cancer. We have performed complete sequence analysis of all BRCA1 and BRCA2 exons and intron–exon boundaries for 434 Nigerian breast cancer patients from the University College Hospital in Ibadan, Nigeria. In contrast to previous suggestions that BRCA1/BRCA2 mutation frequencies are low or undetectable in African American populations, we find that Nigerian breast cancer patients have an exceptionally high frequency of BRCA1 and BRCA2 mutations (7.1 and 3.9%, respectively). Sixteen different BRCA1 mutations were detected, seven of which have never been reported previously, while thirteen different BRCA2 mutations were seen, six of which were previously unreported. Thus, our data support enrichment for genetic risk factors in this relatively young cohort. To improve breast cancer outcomes, we suggest that family‐based models of risk assessment and genetic counseling coupled with interventions to reduce breast cancer risk should be broadly disseminated in Nigeria and other underserved and understudied populations.