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Prostate cancer is a pathological condition of aberrant growth in prostate gland present in males. The cancer is slow-growing and occurs in the fifth decade of life, due to which patients generally die due to other causes than malignancy like heart or circulatory disease, pneumonia or old age. Prostate cancer may cause pain, discomfort in passing urine, and problems in sexual intercourse or erectile dysfunction. Albeit cancer of the prostate is a slow-growing one, cases of early-onset and aggressive tumors have also been observed.
Prostate cancer is usually diagnosed symptomatically, by physical examination, prostate specific antigen test or a biopsy. These tests rely on the expression of tumor biomarkers typically associated with prostate malignancy. The disease can be treated to an extent by various modalities like surgery, radiation therapy and proton therapy apart from hyperthermia and chemotherapy. CT and bone scans are usually included as recurrent procedures to determine metastasis.
Several factors have been attributed to prostate cancer such as diet, medication, viral or bacterial infections, and genetics. Men with one first degree relative with this condition have a twofold risk of developing cancer while men two first degree relatives with prostate cancer have fivefold risk in developing the cancer. Twin studies in Scandinavian population have confirmed a 40 % influence of genetics in development of prostate cancer (1). This article reviews the various genetic polymorphisms associated with prostate cancer.
Single Nucleotide Polymorphism (SNP) is the polymorphism in a single base of an allele of a certain gene that may attribute to risk of developing a diseased phenotype, in more than one percent of the population. No single genes have been reported to responsible for the cancer but several different genes that when altered implicate the same. Most common mutations have been described in BRCA1and BRCA2 that have confirmed associations with breast and ovarian cancer pathophysiologies (2). Another gene called RNASEL is shown to be mutated implicating to prostate cancer development. The gene encodes an enzyme 2-5A-dependent ribonuclease that participates in antiviral and antiproliferative mechanisms (3). Mutations in this gene have resulted in the allele Hereditary Prostate Cancer 1 (HPC1) related with prostate cancer (4).
Prostate cancer broadly surfaces via two mechanisms: androgen dependent pathway and androgen independent pathway. A gene TMPRSS2 is shown to be upregulated in androgen dependent pathway overexpressed by angrogenic hormones (5). The gene encodes for the enzyme transmembrane protease, serine 2 and the fusion of this gene with another encoding the transcriptional factors ERG and ETV1 that are most commonly associated with prostate carcinogenesis (6).
Another gene MSMB shown to exhibit SNP at 10q11 locus is associated with prostate cancer development has been reported by Chang et al (7). The study has found two separate SNPs within the 65kb genomic region of 10q11 locus separated by a recombination hotspot. The SNP in promoter region of MSMB gene showed only 13 percent of promoter activity while a novel SNP in the second locus NCOA4 that mechanized by enhancing transcriptional activity of androgen receptor contributing to prostate carcinogenesis.
Yet another study has reported the influence of selenoprotein P with prostate cancer (PC) risk. This plasma carrier is severely down expressed in PC tumors and cell lines. This has further been shown to be caused due to presence of SNP within its gene, SEPP1- Ala234. This mutation causes disconcert in functionality of other antioxidant moieties such as mitochondrial superoxide dismutase (SOD2) that shows single nucleotide polymorphism at 16th position, Ala16Val. Men homozygous for the SNP at SEPP1 gene and SOD2-Ala16+ depicted a higher risk of prostate cancer than those who were SOD2-Val16 homozygotes. In addition, SOD2-Ala16+ men homozygous for SEPP1-Ala234 showed a doubled risk of prostate cancer and this interaction was more pronounced in ever-smokers. This is because smokers tend to produce higher mitochondrial H2O2 that they cannot eliminate, thus increasing risk of tumor generation (8). A related study (9) has reported SNPs in six selenoprotein genes, GPX1, GPX2, GPX3, GPX4 and TXNRD1 apart from the already known SEPP1. These genes facilitate antioxidant defenses and dysfunctioning surfaces sue to SNP at coding region, intron-exon borders and flanking untranslated regions (UTR). The study emphasizes suggestive correlation between SNP at GPX1 at 3p21 locus and prostate cancer risk.
Transcription factor-7 like-2 (TCF7L2) is associated with Wnt/ß-catenin signaling pathway that when aberrant has proven to be implicated in diabetes. A study examined the influence of this mutated gene in establishment of prostate cancer. Though previous reports of this gene mutation has been confirmed with breast cancer progression, the finding reported inconclusive in placing a direct correlation between TCF7L2 and tumor initiation or prostate-cancer specific mortality (10).
There are many other similar studies been conducted on prostate cancer specific mortality and single nucleotide polymorphisms in several genes like CYP17, CYP3A4, CYP19A1, SDR5A2, IGF1, IGFBP3 to name a few (11).
Inherited prostate cancer generally proves to be more aggressive since patients carry a genetic predisposition to the diseased condition attributed to the presence of the particular SNP allele. In either case, a heterozygote patient has better clinical prognosis than a homozygote with the disease showing lesser morbidity in the former. Alternatively, patients can become susceptible to the disease due to infection with certain microorgansisms and viruses. A certain study examined the role of ELAC2 gene with risk of prostate cancer (12).
A novel study has reported the role of a variant of COX2 in association with prostate cancer risk. The report also supplements dietary intake of long chain omega 3 polyunsaturated fatty acids that can reverse the risk of prostate cancer if the latter is not included or in low amounts (13).
Such studies thus highlight that though a diseased phenotype is an attribute of the genetic makeup of an individual, the environment and dietary supplements also closely influence the manifestation and management of the same. Identifying the genotype of an individual to list the number of individuals with a greater risk of prostate cancer is important and this in turn can help decipher dietary charts for such patients with the idea to increase prognosis and enhance management of prostate cancer, especially in cases where it is aggressive or develops early in life.
Summary
The following are the SNPs discussed in this article are as summarized below:
1. BRCA1 and BRCA2
2. HPC1 allele within the gene RNASEL
3. TMPRSS2
4. 5’ region of MSMB and NCOA4 genes at locus 10q11
5. Ala234 SNP within the SEPP1 gene
6. Ala16Val SNP within the SOD2 gene
7. GPX1 at 3p21 locus
8. CYP17 and IGF-1
9. elac homolog 2 within the ELAC2 gene in E. coli
10. +6364 A>G within the COX2 gene
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