The Biology of Cancer Health Disparities
Melanie Nix is a triple-negative breast cancer survivor.
Health-related differences in disease incidence and outcomes among distinct racial and ethnic groups, known as health disparities, are thought to reflect the interplay of socioeconomic factors, culture, diet, stress, the environment, and biology. The least understood of these factors is the role of biology. With the advent of advanced genomics and other molecular technologies and the growing sophistication of computational tools, an understanding of how biology contributes to health disparities and how biological factors interact with other relevant factors, such as diet and the environment, may finally be within our reach.
Some examples of early findings in this area of research are summarized below. These examples are from studies of men and women of African and European descent. Until fairly recently, the lack of large samples of germline DNA from individuals across a wide range of racial and ethnic groups for comparative purposes was a barrier to expanding this research.
Triple-Negative Breast Cancer in African American Women
From health statistics data, we have known for some time that African American women have a higher death rate from breast cancer than women of other racial and ethnic groups. Research reported within the past few years has revealed a higher prevalence of a poor prognosis molecular subtype of breast cancer, called the basal-like or triple-negative subtype (estrogen-receptor negative, progesterone-receptor negative, and HER2-protein negative), among African American women than among women of other racial and ethnic groups, especially among premenopausal women. However, the higher frequency of this poor prognosis subtype alone does not fully explain the poorer breast cancer survival rates among African American women. In a study reported in 2006, the 5-year relative survival of premenopausal women with advanced (stage III or IV) triple-negative breast cancer was 14 percent for African American women, compared with 37 percent for non-Hispanic white women and 38 percent for Hispanic women.
Some evidence suggests there could be biological differences between the triple-negative breast cancers that arise in African American women compared with those that arise in women of other racial and ethnic groups. Nearly 70 percent of the breast cancers that occur in BRCA1 gene mutation carriers are triple-negative. Several studies, however, have shown that the incidence of germline BRCA1 mutations is much lower among African American women diagnosed with triple-negative disease than among similar women of other races or ethnicities. In one study, 50 percent of white non-Ashkenazi Jewish women diagnosed with triple-negative breast cancer had a germline mutation in BRCA1, whereas fewer than 20 percent of African American women diagnosed with triple-negative disease did. These observations suggest another genetic mechanism or mechanisms could be at play in promoting triple-negative breast cancers in African American women.
Colorectal Cancer in African Americans
Colorectal cancer incidence and mortality are higher among African American men and women than among men and women of other racial and ethnic groups. To explore the possibility that tumor genetics might contribute to this disparity, an NCI-supported team of researchers sequenced paired germline and tumor DNA from more than 100 patients diagnosed with either late-stage or early-stage colorectal cancer. They identified 20 new genes that are significantly mutated in colorectal cancer. Fifteen of these genes appear to be preferentially associated with colorectal tumors that arise in African Americans, accounting for 41 percent of colorectal cancers in African Americans versus 15 percent of colorectal cancers in whites.
Mutations in three of the 15 genes, namely EPHA6, FLCN, and HTR1F, were found exclusively in colorectal cancers arising in African Americans. EPHA6 and FLCN are of particular interest because they belong to known oncogenic pathways. EPHA6 encodes a cell-surface receptor tyrosine kinase called ephrin type-A receptor 6, which is involved in cell signaling. The function of the protein encoded by FLCN, folliculin, is not yet known, but researchers believe it may act as a tumor suppressor. Based on their findings and other data, the researchers have proposed EPHA6 and FLCN as candidate colorectal cancer driver genes in African Americans.
Because the patient population in this study was drawn exclusively from northeastern Ohio, it will be necessary to confirm these findings in African American patients from other regions of the country. However, the results suggest that the tyrosine kinase activity of the EPHA6 protein may be a target for potential therapeutic drug development.
Prostate Cancer in African American Men
The incidence of prostate cancer among African American men is approximately 60 percent higher than among American men of European ancestry, and their mortality rate is two to three times higher. At the time of prostate cancer diagnosis, African American men typically present with more advanced disease than white men. Some evidence indicates that prostate cancer growth is faster and/or there is an earlier transition from latent to aggressive disease in African American men, which may explain, in part, the observation of more advanced disease at diagnosis. These features suggest that the biology of prostate cancer in African American men and white men may differ in important ways.
In support of this notion, genetic analyses conducted by NCI-funded researchers have identified multiple regions on the long arm of chromosome 8 (at 8q24) that are associated with susceptibility to prostate cancer. The researchers have proposed that genetic variation in these regions may explain up to 50 percent of the higher risk of prostate cancer observed among men of African descent.
Some of the same researchers have identified a second chromosomal region—this one on the long arm of chromosome 17 (at 17q21)—that is associated with increased prostate cancer risk among African American men compared with men of other populations. Approximately 5 percent of African American men carry a rare genetic variant in this region that appears to be associated with higher prostate cancer risk. This genetic variant has been found in less than 1 percent of men of other populations.
Ongoing research is aimed at understanding the functional consequences of these and other genetic variants that influence prostate cancer risk—not only among African American men but in all men. Only then will we have insights that have the potential to be translated into clinical benefit, including effective strategies for early detection and disease prevention.
Additional studies have identified epigenetic differences and differences in gene expression patterns and other molecular characteristics between the prostate tumors of African American men and white men. In one study, researchers found higher levels of a protein called Kaiso, a regulator of gene expression, in the nuclei of prostate cancer cells from African American men than in the nuclei of prostate cancer cells from white men. In the study, higher nuclear levels of Kaiso were associated with aggressive prostate cancer, and the protein was shown to decrease expression of E-cadherin, a tumor suppressor protein that functions as a cell–cell adhesion receptor. Loss of E-cadherin-mediated cell–cell adhesion has been implicated in the transition from noninvasive lesions to invasive, metastatic cancers.
Future Directions
Understanding the role that biology plays in cancer health disparities and the interplay of biological factors with other factors that contribute to differences in the cancer burden experienced by different populations must remain a research priority. As that understanding grows, new opportunities for prevention, early detection, and intervention will undoubtedly be revealed.
We must also continue to explore and find innovative ways to mitigate the effects of other factors apart from biology that contribute to cancer health disparities, such as limited access to and utilization of health care services, including cancer screening programs, and the ability to pay for care. The state of Delaware’s experiment to reduce racial disparities in colorectal cancer is a real-world example of what is possible.