Androgen Metabolism Gene Polymorphisms, Associations with Prostate Cancer Risk and Pathological Characteristics: A Comparative Analysis between South African and Senegalese Men
Prostate cancer is the most common cancer in men in developed countries and the leading cause of mortality in males in less developed countries. African ethnicity is one of the major risk factors for developing prostate cancer. Pathways involved in androgen metabolism have been implicated in the etiology of the disease. Analyses of clinical data and CYP3A4, CYP3A5, and SRD5A2 genotypes were performed in South African White (120 cases; 134 controls), Mixed Ancestry (207 cases; 167 controls), and Black (25 cases; 20 controls) men, as well as in Senegalese men (86 cases; 300 controls). Senegalese men were diagnosed earlier with prostate cancer and had higher median PSA levels compared to South African men. Metastasis occurred more frequently in Senegalese men. Gene polymorphism frequencies differed significantly between South African and Senegalese men. The CYP3A4 rs2740574 polymorphism was associated with prostate cancer risk and tumor aggressiveness in South African men, after correction for population stratification, and the SRD5A2 rs523349 CG genotype was inversely associated with high-stage disease in Senegalese men. These data suggest that variants previously associated with prostate cancer in other populations may also affect prostate cancer risk in African men. 1. Introduction Prostate cancer is the most common cancer in men from industrialized developed countries, and worldwide, the second most common of all malignancies in men [1–3]. The highest rates of prostate cancer are observed in African-American men in the United States of America (USA) and Caribbean men of African descent [1, 4], while the highest disease-associated mortality rates are observed in less developed countries that include regions of the Caribbean, Sub-Saharan Africa, and South America [3]. These data lend support to the suggestion that the African ethnicity is one of the major risk factors for prostate cancer [5, 6]. Although comprehensive cancer registries are limited in Africa, available data indicate that prostate cancer accounts for approximately 10.6% and 4.8% of all cancers in males in Sub-Saharan Africa and North Africa, respectively [7]. In Southern Africa (South Africa) and Western Africa (Nigeria and Cameroon), prostate cancer is the most commonly diagnosed cancer in males; however, the incidence of prostate cancer in Southern Africa is double that observed in Western Africa [8]. The reported age-standardized rate of histologically diagnosed prostate cancer in South Africa is 74.4 per 100000 males in the White population (European ancestry), 48 per 100000 males in
References
[1]
J. Ferlay, H. R. Shin, F. Bray, D. Forman, C. Mathers, and D. M. Parkin, “Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008,” International Journal of Cancer, vol. 127, no. 12, pp. 2893–2917, 2010.
[2]
A. Jemal, F. Bray, M. M. Center, J. Ferlay, E. Ward, and D. Forman, “Global cancer statistics,” CA: A Cancer Journal for Clinicians, vol. 61, no. 2, pp. 69–90, 2011.
[3]
M. M. Center, A. Jemal, J. Lortet-Tieulent et al., “International variation in prostate cancer incidence and mortality rates,” European Urology, vol. 61, no. 6, pp. 1079–1092, 2012.
[4]
N. B. Delongchamps, A. Singh, and G. P. Haas, “Epidemiology of prostate cancer in Africa: another step in the understanding of the disease?” Current Problems in Cancer, vol. 31, no. 3, pp. 226–236, 2007.
[5]
E. A. Platz and E. Giovannucci, “Prostate cancer,” in Cancer Epidemiology and Prevention, D. Schottenfeld and J. F. Fraumeni, Eds., pp. 1128–1150, Oxford University Press, New York, NY, USA, 2006.
[6]
F. T. Odedina, T. O. Akinremi, F. Chinegwundoh et al., “Prostate cancer disparities in Black men of African descent: a comparative literature review of prostate cancer burden among Black men in the United States, Caribbean, United Kingdom, and West Africa,” Infectious Agents and Cancer, vol. 4, supplement 1, article S2, 2009.
[7]
D. M. Parkin, F. Sitas, M. Chirenje, L. Stein, R. Abratt, and H. Wabinga, “Part I: cancer in indigenous Africans-burden, distribution, and trends,” The Lancet Oncology, vol. 9, no. 7, pp. 683–692, 2008.
[8]
A. Jemal, F. Bray, D. Forman et al., “Cancer burden in Africa and opportunities for prevention,” Cancer, vol. 118, no. 18, pp. 4372–4384, 2012.
[9]
E. de Wit, W. Delport, C. E. Rugamika et al., “Genome-wide analysis of the structure of the South African Coloured Population in the Western Cape,” Human Genetics, vol. 128, no. 2, pp. 145–153, 2010.
[10]
N. Mqoqi, P. Kellett, F. Sitas, and M. Jula, “Incidence of histologically diagnosed cancer in South Africa, 1998-1999,” in National Cancer Registry Johannesburg, National Cancer Registry of South Africa, 2004.
[11]
C. F. Heyns, S. Mathee, A. Isaacs, A. Kharwa, P. M. de Beer, and M. A. Pretorius, “Problems with prostate specific antigen screening for prostate cancer in the primary healthcare setting in South Africa,” BJU International, vol. 91, no. 9, pp. 785–788, 2003.
[12]
C. F. Heyns, M. Fisher, A. Lecuona, and A. van der Merwe, “Prostate cancer among different racial groups in the western cape: presenting features and management,” South African Medical Journal, vol. 101, no. 4, pp. 267–270, 2011.
[13]
S. M. Gueye, C. M. Zeigler-Johnson, T. Friebel et al., “Clinical characteristics of prostate cancer in African Americans, American whites, and Senegalese men,” Urology, vol. 61, no. 5, pp. 987–992, 2003.
[14]
C. M. Zeigler-Johnson, H. Rennert, R. D. Mittal et al., “Evaluation of prostate cancer characteristics in four populations worldwide,” The Canadian Journal of Urology, vol. 15, no. 3, pp. 4056–4064, 2008.
[15]
L. Niang, C. N. Kouka, M. Jalloh, and S. M. Gueye, “Screening for prostate cancer by digital rectal examination and PSA determination in Senegal,” ISRN Oncology, vol. 2011, Article ID 943704, 4 pages, 2011.
[16]
M. C. Parkinson, “Pre-neoplastic lesions of the prostate,” Histopathology, vol. 27, no. 4, pp. 301–311, 1995.
[17]
R. A. Kittles, W. Chen, R. K. Panguluri et al., “CYP3A4-V and prostate cancer in African Americans: causal or confounding association because of population stratification?” Human Genetics, vol. 110, no. 6, pp. 553–560, 2002.
[18]
S. J. Plummer, D. V. Conti, P. L. Paris, A. P. Curran, G. Casey, and J. S. Witte, “CYP3A4 and CYP3A5 genotypes, haplotypes, and risk of prostate cancer,” Cancer Epidemiology Biomarkers and Prevention, vol. 12, no. 9, pp. 928–932, 2003.
[19]
C. Zeigler-Johnson, T. Friebel, A. H. Walker et al., “CYP3A4, CYP3A5, and CYP3A43 genotypes and haplotypes in the etiology and severity of prostate cancer,” Cancer Research, vol. 64, no. 22, pp. 8461–8467, 2004.
[20]
A. Stone, L. D. Ratnasinghe, G. L. Emerson et al., “CYP3A43 Pro340 Ala polymorphism and prostate cancer risk in African Americans and Caucasians,” Cancer Epidemiology Biomarkers and Prevention, vol. 14, no. 5, pp. 1257–1261, 2005.
[21]
T. R. Rebbeck, H. Rennert, A. H. Walker et al., “Joint effects of inflammation and androgen metabolism on prostate cancer severity,” International Journal of Cancer, vol. 123, no. 6, pp. 1385–1389, 2008.
[22]
J. M. Jaffe, S. B. Malkowicz, A. H. Walker et al., “Association of SRD5A2 genotype and pathological characteristics of prostate tumors,” Cancer Research, vol. 60, no. 6, pp. 1626–1630, 2000.
[23]
M. S. Cicek, D. V. Conti, A. Curran et al., “Association of prostate cancer risk and aggressiveness to androgen pathway genes: SRD5A2, CYP17, and the AR,” Prostate, vol. 59, no. 1, pp. 69–76, 2004.
[24]
V. M. Hayes, G. Severi, E. J. D. Padilla et al., “5α-reductase type 2 gene variant associations with prostate cancer risk, circulating hormone levels and androgenetic alopecia,” International Journal of Cancer, vol. 120, no. 4, pp. 776–780, 2007.
[25]
C. Neslund-Dudas, C. H. Bock, K. Monaghan et al., “SRD5A2 and HSD3B2 polymorphisms are associated with prostate cancer risk and aggressiveness,” Prostate, vol. 67, no. 15, pp. 1654–1663, 2007.
[26]
C. Paz-y-Mi？o, T. Witte, P. Robles, W. Llumipanta, M. Díaz, and M. Arévalo, “Association among polymorphisms in the steroid 5α-reductase type II (SRD5A2) gene, prostate cancer risk, and pathologic characteristics of prostate tumors in an Ecuadorian population,” Cancer Genetics and Cytogenetics, vol. 189, no. 2, pp. 71–76, 2009.
[27]
P. Fernandez, P. D. de Beer, L. D. van der Merwe, and C. F. Heyns, “Genetic variations in androgen metabolism genes and associations with prostate cancer in South African men,” South African Medical Journal, vol. 100, no. 11, pp. 741–745, 2010.
[28]
C. M. Zeigler-Johnson, A. H. Walker, B. Mancke et al., “Ethnic differences in the frequency of prostate cancer susceptibility alleles at SRD5A2 and CYP3A4,” Human Heredity, vol. 54, no. 1, pp. 13–21, 2002.
[29]
P. Fernandez, P. M. de Beer, L. van der Merwe, and C. F. Heyns, “COX-2 promoter polymorphisms and the association with prostate cancer risk in South African men,” Carcinogenesis, vol. 29, no. 12, pp. 2347–2350, 2008.
[30]
M. L. Freedman, D. Reich, K. L. Penney et al., “Assessing the impact of population stratification on genetic association studies,” Nature Genetics, vol. 36, no. 4, pp. 388–393, 2004.
[31]
A. B. Spurdle, B. Goodwin, E. Hodgson et al., “The CYP3A4* 1B polymorphism has no functional significance and is not associated with risk of breast or ovarian cancer,” Pharmacogenetics, vol. 12, no. 5, pp. 355–366, 2002.
[32]
N. M. Makridakis, R. K. Ross, M. C. Pike et al., “Association of mis-sense substitution in SRD5A2 gene with prostate cancer in African-American and Hispanic men in Los Angeles, USA,” The Lancet, vol. 354, no. 9183, pp. 975–978, 1999.
[33]
N. Makridakis, R. K. Ross, M. C. Pike et al., “A prevalent missense substitution that modulates activity of prostatic steroid 5α-reductase,” Cancer Research, vol. 57, no. 6, pp. 1020–1022, 1997.
[34]
V. Petrow, “The dihydrotestosterone (DHT) hypothesis of prostate cancer and its therapeutic implications,” Prostate, vol. 9, no. 4, pp. 343–361, 1986.
[35]
K. Stefflova, M. C. Dulik, A. A. Pai et al., “Evaluation of group genetic ancestry of populations from Philadelphia and Dakar in the context of sex-biased admixture in the Americas,” PLoS ONE, vol. 4, no. 11, Article ID e7842, 2009.
