Abstract
It is well established that African Americans exhibit higher incidence, higher mortality, and more aggressive forms of some cancers, including those of breast, prostate, colon, stomach, and cervix. Here we examine the ancestral haplotype of the TRPV6 calcium channel as a putative genomic factor in this racial divide. The minor (ancestral) allele frequency is 60% in people of African ancestry, but between 1% and 11% in all other populations. Research on TRPV6 structure/function, its association with specific cancers, and the evolutionary-ecological conditions that impacted selection of its haplotypes are synthesized to provide evidence for TRPV6 as a germline susceptibility locus in cancer. Recently elucidated mechanisms of TRPV6 channel deactivation are discussed in relation to the location of the allele favored in selection, suggesting a reduced capacity to inactivate the channel in those who have the ancestral haplotype. This could result in an excessively high cellular Ca2+, which has been implicated in cancer, for those in settings where calcium intake is far higher than in their ancestral environment. A recent report associating increasing calcium intake with a pattern of increase in aggressive prostate cancer in African-American but not European-American men may be related. If TRPV6 is found to be associated with cancer, further research would be warranted to improve risk assessment and examine interventions with the aim of improving cancer outcomes for people of African ancestry.
Highlights
It is well established that African Americans exhibit higher incidence, higher mortality, and more aggressive forms of some cancers, including those of breast, prostate, colon, stomach, and cervix
It has been suggested that a combination of factors including social determinants of health, access to health care, biological factors including genomics, and patterns of research lead to racial disparities in cancer outcomes [4]
The proportion of cases diagnosed with aggressive prostate cancer [as determined using the National Comprehensive Cancer Network (NCCN) risk stratification scheme] was found to increase with increasing total calcium intake in AA men but not in European ancestry (EA) men (Fig. 1)
Summary
African Americans (AA) are residents of the United States, typically with an admixture of Sub-Saharan African and European ancestry [1]. The disparity in cancer outcomes between AAs and Americans of European ancestry (EA) has been a cause for concern in recent years. Centers for Disease Control and Prevention age-adjusted death rates per 100,000 for AAs from prostate cancer (14.3) indicate mortality twice as high as for EAs (7.4). The breast cancer death rate for AAs (16.4) is high compared with that of EAs Pancreatic cancer is disproportionately higher (13.3) than in EAs (10.9) [2]. Colorectal cancer mortality in AAs (18.9) is alarmingly high compared with that of EAs (13.8). In these cancers, TRPV6 is upregulated—highly so for breast and prostate cancers, where TRPV6 inhibition is under study as a potential therapeutic strategy. Expression level has been linked to tumor progression and has been proposed as a prognostic marker [3]
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