Camille Ragin, PhD, MPH
Office Phone: 215-728-1148
African Caribbean Cancer Consortium (AC3) (www.ac3online.org): Study of gene x environment interactions to addressing the burden of cancer in populations of African descent
The AC3 is a multi-institutional collaborative network that focuses on studies of cancer risk and outcomes among populations of African ancestry (African-American, African and Caribbean).
- Promote collaboration between cancer health disparities researchers in our AC3 network
- Promote diversity in cancer research through training
- Develop and conduct pooled and/or multi-centered studies for the investigation of cancer in Black populations
Recognizing the public health significance of cancer in populations of African origin, and socio-cultural factors that influence disparities in health outcomes, we have provided the platform in the AC3 to report not only country-level findings but fostered collaborative research by pooling data to generate sample sizes sufficient to examine genetic and environmental contributions in carcinogenesis among populations of African origin. Our working group focuses on investigating gene x environment interactions.Top
Our AC3 studies:
Since 2009, AC3 has conducted studies of biomarkers of susceptibility to and outcomes from prostate cancer among men of African ancestry; cervical human papillomavirus (HPV) infections in Black women from the US, Jamaica, Tobago and the Bahamas and assessments of knowledge, perception and attitudes of HPV and the HPV vaccine in the US, and Bahamas and many others. These studies were initiated 1) to generate indigenous data from the Caribbean populations 2) to allow us to evaluate the contribution of culture, attitudes and lifestyle in cancer risk by comparing native Caribbean, African-Americans and immigrant populations.
Our community efforts:
AC3 has conducted community education and research information sessions to the community since its conception in 2006. The experiences gained from this approach have provided us with a successful model that can be applied in our population-based health disparities research studies. We have provided the community not only with information about the importance of incorporating cancer prevention practice and screening into their lifestyle but also these information sessions were designed to provide the community members with a better understanding of the importance of cancer disparities research and the value of participating in research studies. This approach over the years has led to an overwhelming acceptance of the research study, thus providing us with the ability to recruit more than the targeted number of study participants. We successfully adapted this approach to cancer-related studies in the Caribbean, the “Tobago Cervical and Oral Cancer Research Study”, as well as the “Healthy People Project,” which was conducted in collaboration with Dr. Emanuela Taioli M.D., Ph.D. at the University of Pittsburgh. We have recently launched a new effort through our Philadelphia community-research network partnership, the “Cancer Prevention Project of Philadelphia (CAP3),” which serves as a pipeline project for our population-based molecular epidemiology research studies.Top
Our training efforts:
Through research skills training sessions during our AC3 meetings, we have embarked on developing and strengthening population-based cancer research and cancer registration in the Caribbean to facilitate stronger collaborative research studies. We also provide research training opportunities in our lab to undergraduate and graduate students where they learn molecular biology techniques, epidemiology study designs and applications. See interns on People page.Top
Racial disparities in head and neck squamous cell carcinoma
Squamous cell carcinoma of the head and neck refers to a variety of malignant tumors arising from the oral cavity and upper aerodigestive tract. The primary risk factors for head and neck cancer are tobacco and alcohol use, and more recently HPV has been defined as an independent risk factor for oropharyngeal tumors. Typical genetic features of tobacco- and alcohol-related head and neck tumors involve mutations in the TP53, gene amplification at chromosome 11q13 and loss of p16 protein expression. In our lab we have used a molecular approach and evaluated the relationship between HPV DNA status and genetic alterations in TP53, 11q13 and p16 protein expression. This pilot study showed that HPV-positive tumors were more likely to express in combination wild-type TP53, high levels of p16 protein and no gene amplification at chromosome 11q13. These results provided us with indirect evidence that the infection may have occurred at an earlier time point in the carcinogenic process. Another interesting observation is that the head and neck tumors included in our analysis were first primaries from various sites within the oral cavity and pharynx, and this distinct molecular phenotype was present not only in oropharynx tumors but also in the oral cavity.
Racial disparities among patients with head and neck squamous cell carcinoma (HNSCC) have remained unchanged for more than three decades. Persons of African ancestry have a higher incidence of oral cavity and pharynx tumors compared to persons of European ancestry (NCI SEER: age-adjusted incidence rates 1975-2009: 13.4 vs. 11.9 per 100,000, respectively). Similarly for larynx cancers, the incidence is higher among Black Americans compared to White Americans (NCI SEER: age-adjusted incidence rates 1975-2009: 6.8 vs. 4.4 per 100,000 respectively). Notably, Black patients consistently have lower five-year survival rates as compared to White patients (oral cavity and pharynx: 45% vs. 67%, respectively; larynx: 51% vs. 65%).
Although studies of racial disparities in HNSCC have been conducted, many suggest that the observed differences may be related to barriers to care and screening; but we have shown that the differences may be independent of these factors. After matching on age and smoking-dose (pack-years) and adjusting for socioeconomic and insurance status, any tobacco and alcohol use, any family history of cancer, gender, and age, we observed that Black oral cavity cancer patients were more likely than Whites to be diagnosed with advanced-stage disease (AdjOR = 3.60, 0.97–13.41). Similarly, Black larynx cancer patients were more likely than Whites to be diagnosed with positive lymph nodes (AdjOR = 2.26, 0.92–5.61) and Black patients were more likely than White patients to develop second primaries, recurrences or metastasis (AdjHR = 1.47, 0.99-2.18). We believe that genetic and environmental risk factors and their interaction may contribute to the higher incidence of head and neck cancer in Black Americans. Although a large number of studies evaluating gene-environment interactions in HNSCC have been conducted, many include smaller numbers of African-American/Black subjects compared to Caucasians, and were unable to report meaningful results related to race due to poor statistical power. Therefore, large studies that evaluate gene-environment interactions and head and neck cancer risk among African-Americans/Blacks are warranted. To address racial disparities in head and neck cancer risk and outcomes, our lab focuses on these types of studies through comparisons between African-American/Black and Caucasian populations. We are currently evaluating the interactions of tobacco/alcohol exposure and genetic variations in genes involved in these metabolic pathways in order to understand how these interactions contribute to the differences in cancer risk and outcome between Black and White populations.Top
Gene x environment interactions and prostate cancer risk in Black men
It is well documented that there is a disproportionate burden of prostate cancer among not only African-American men but also Black men from other parts of the world. Furthermore, the prostate cancer death rate among African-American males is higher than US males of European descent, and higher death rates have been reported in other populations of African descent in the Caribbean islands and Africa. Few studies have explored gene x environment interactions and prostate cancer among men of African ancestry. In our lab we have shown that among all of the case-control studies that investigated the association of genetic polymorphisms and cancer risk among Black populations, only a few genes have been evaluated for prostate cancer. Furthermore, for each single nucleotide polymorphism (SNP) only 1-2 studies were conducted with the exception of CYP3A4 A293G and CYP17 5’ UTR polymorphisms. Our meta analysis showed marginal statistically significant associations were observed for CYP3A4 A293G and CYP17 5’UTR polymorphisms and prostate cancer. The Black population included in these studies was predominantly African-American and there was little representation of Black men from the Caribbean and Africa. To further investigate these associations, we are performing a pooled analysis of these SNPs and are genotyping for the first time cases and controls from the Caribbean for inclusion in this analysis.
Our recent study of GSTM1 polymorphisms and prostate cancer risk offers a classic example of gene x environment interactions. Studies in populations of European descent have demonstrated that a genetic variation in the GSTM1 gene resulting in a deletion is associated with an increased risk of prostate cancer among smokers and this risk increases with smoking dose. Therefore, we conducted a multi-institutional analysis of prostate cancer risk to evaluate the association of GSTM1 deletion among Black men and found that GSTM1 genotype modifies the effect of tobacco exposure on prostate cancer risk for African-American men but not for Black Caribbean men. Our findings suggest that other environmental factors unique to Caribbean men may contribute to prostate cancer risk.Top
Gender disparities in lung cancer: investigating the role of HPV
Cigarette smoking is the primary risk factor for lung cancer and there are gender differences in the relationship between smoking and lung cancer, as well as response to therapy. In contrast to males, lung cancer mortality rates in women have been on the increase for the past three decades. This observation may be attributed to the changing pattern of tobacco use in women. Many have also questioned whether women are more susceptible to tobacco exposure, but the findings from these studies have not been consistent.
Human Papillomavirus (HPV) causes cervical cancer in women and is associated with most other anogenital cancers as well as oropharngeal cancers in both men and women. Some studies have suggested that HPV may also be associated with a subset of lung tumors, although an etiologic link has not been firmly established. A few studies support the carcinogenic role of HPV in lung cancer by showing that the virus is present the tumor cells and not in the adjacent normal epithelium. Furthermore, studies have reported evidence that the HPV E6 and E7 oncogenes are expressed in lung carcinomas. Due to the recent FDA approval of the HPV vaccine which prevents infections from the most common oncogenic HPV types (HPV 16 and 18), the potential significance of HPV infections in lung tumors needs to be further investigated.
We performed a meta-analysis of all published articles to determine the prevalence of HPV in invasive lung cancers. Although the viral DNA has been variably detected, in about 0 -78% of tumors, HPV16 and HPV18, the most common types etiologically linked to cervical cancers were most predominant in lung tumors. Furthermore our lab and others have suggested that HPV may play a role in the development of second primary lung cancers in women who had a first diagnosis of cervical cancer. It is not yet clear, whether HPV may contribute to the gender differences in lung cancer development, since an etiologic role has not been firmly established. First, we are performing a global multi-institutional pooled analysis of cross-sectional studies that have evaluated HPV in lung tumors in order to characterize the patients with HPV-positive lung cancer and to test whether the prevalence differs across levels of smoking status and gender. Secondly, we are using a molecular biology approach to evaluate HPV-positive lung tumors in order to determine whether HPV might be etiologically linked. We expect that this work will provide us with a better understanding of the role of HPV in the disease and also of gender-specific differences in lung cancer development.Top