The incidence rate of prostate cancer in African-American males is two times higher than Caucasian men and ten times higher than Japanese men. The geographical specificity of Y haplogroups implies that males from different ethnic groups undoubtedly have various Y lineages with different Y-chromosomal characteristics that may affect their susceptibility or resistance to such a male-specific cancer. To confirm this hypothesis we studied the Y-chromosomal haplogroups of 92 Japanese prostate cancer patients comparing them with randomly selected 109 unrelated healthy Japanese male controls who were confirmed to be residents of the same geographical area. Males could be classified using three binary Y-chromosome markers (sex-determining region Y (SRY), YAP, 47z) into four haplogroups DE, O2b*, O2b1, and untagged group. Our results confirmed that prostate cancer incidence varies among males from different Y-chromosome lineages. Males from DE and the untagged haplogroups are at a significantly higher risk to develop prostate cancer than O2b* and O2b1 haplogroups (P=0.01), odds ratio 2.17 and 95% confidence interval (1.16–4.07). Males from haplogroup DE are over-represented in the patient group showing a percentage of 41.3%. The underlying possible causes of susceptibility variations of different Y lineages for such a male-specific cancer tumorigenesis are discussed. These findings explain the lower incidence of prostate cancer in Japanese and other South East Asian males than other populations. To our knowledge, this is the first reliable study examining the association between prostate cancer and Y-chromosomal haplogroups, comparing prostate cancer patients with carefully selected matched controls.
Prostate cancer is a significant cause of morbidity and mortality in American males, and after lung cancer it is the second leading cause of their deaths; and it is the most commonly diagnosed form of cancer other than skin cancer. The American Cancer Society estimated that in the year 2005, 232 090 men will be newly diagnosed with prostate cancer and an estimated 30 350 deaths will be attributable to the disease.1, 2
Males from different ethnic origins and from different geographical areas of the world are at a conspicuous difference in their susceptibility for developing prostate cancer.3 The incidence rate of prostate cancer is two times higher in African-American men than Caucasian men, and 10 times higher than Japanese men who have one of the lowest incidence rates in the world. Epidemiological studies have shown that Japanese immigrants in the US have experienced an increase in prostate cancer incidence; however, they remain at a much lower risk than the American white men.3, 4, 5, 6
In addition to age, race, dietary, and environmental factors, the family history is a strong risk factor, indicating the importance of the role of genetics in the development of prostate cancer.6, 7, 8
Prostate cancer is genetically heterogeneous, and a variety of genetic changes have been identified on the way to find susceptibility genes or loci that share in the molecular mechanisms of development and progression of this disease. Based on genomewide scans, such susceptibility loci and genetic alterations were attributed to chromosomes, 1, 7, 8, 10, 12, 17, 18, 20, X, and the Y chromosome.9, 10, 11, 12, 13, 14
A large amount of data has been generated about alterations, aberrations, rearrangements, gain, or loss of Y-chromosome materials in prostate cancer using different techniques of molecular cytogenetics.15, 16, 17, 18, 19, 20
The simple fact that the Y chromosome and prostate cancer have male-specificity in common lead many researchers to investigate if there is Y involvement in such a male-specific cancer, however, yet there is no clear conclusions.21, 22, 23
Except for the pseudoautosomal region, all other Y-linked loci on the nonrecombining part of the Y chromosome are haploid and paternally inherited. Thus, Y-chromosome markers are transmitted as haplotypes from fathers to their sons throughout generations establishing patrilineages.24 There is high geographical specificity of Y haplotypes, which indicates that different ethnic groups certainly have very different Y lineages.25
We hypothesize that males from different Y-chromosome lineages may show variable degrees of susceptibility or resistance to the development of human cancers, particularly, cancers of male-specific organs, such as the testis and prostate.
In a previous study, we reported a method for haplogrouping analysis of the Japanese Y chromosomes. This method determines the DNA types by PCR-SSCP, PCR-RFLP, and PCR for three binary polymorphic loci, SRY+465, DXYS5Y (47z/StuI), and DYS287 (YAP), respectively, (Figure 1). By combining results of these three binary polymorphisms, Japanese Y chromosomes were classified into four haplogroups: I, II, III, and IV.26 Males from these different haplogroups exhibited male phenotypic differences, for example, spermatogenic ability.27
These binary haplogrouping method for classification of male populations is well-known worldwide; and according to the nomenclature of the Y-chromosome consortium (YCC), these haplogroups should get the names of DE for haplogroup II, O2b* for haplogroup III, and O2b1 for haplogroup IV.28 We will use the name of untagged when referring to Japanese haplogroup I, which is considered as the common pool from which other Y haplogroups have branched (Figure 2).
The present study was conducted to explore if there is any association of Y-chromosome haplogroups with the occurrence of prostate cancer in Japanese men as a genotype/phenotype correlation study.
Samples' collection and DNA extraction
Prostate tissue samples were obtained from 92 prostate cancer Japanese patients and blood samples were obtained from 109 healthy control Japanese males to study their Y-chromosomal haplogroups. Seventy-three prostate cancer tissue specimens were obtained from frozen samples or archived paraffin embedded samples from both the urology and pathology departments of the Tokushima University School of Medicine. From Saint Marianna University hospital, Professor T Iwamoto provided 24 DNA samples derived from 24 different prostate cancer patients. Five samples were difficult to amplify because of the poor condition of their DNA. Hence, our study included 92 Japanese prostate cancer patients' samples. DNA of the control group was prepared from peripheral leukocytes of the 109 healthy blood donors, 90 control males were from Tokushima and the surrounding area of Shikoku Island, while 19 DNA samples of normal controls were collected at St Marianna University hospital, Kawasaki, Japan. Hence, a total of 109 Japanese healthy control males were included for the purpose of comparisons as matched controls randomly selected from males with a comparable age group and from the same area of residence of the studied prostate cancer cases (mean age±s.d. was 68±10.7 years, from Shinkuko Island, and Kawasaki, Japan). All samples were collected according to approved human subject protocols, and the ethical committee of The University of Tokushima School of Medicine, approved the study.
The control group was a mixture of a randomly selected group of healthy normal blood donors, and some comprised of benign prostatic hyperplasia (BPH) presenting at St Marianna University hospital, Kawasaki, Japan. All the participants were Japanese men who are living in the same geographical region from which the prostate cancer patients were derived from.
The control individuals had no current or previous diagnosis of prostate cancer. All the participants completed questionnaires administered by the medical team, covering medical, residential, occupational and smoking status. Among controls, the possibility of subclinical prostate cancer was ruled out by serum measurement of the prostate-specific antigen (PSA), (<4.0 ng/ml by Tandem-R assay; Hybritech Inc., San Diego, CA USA), physical and histological examination for those participants with BPH.
Pathological grading and clinical staging of the prostate cancer was determined according to the General Rule for Clinical and Pathological Studies on Prostate Cancer by the Japanese Urological Association and the Japanese Society of Pathology, which is based on the WHO criteria and the Gleason pattern. As for the grading, 29 patients (31.5%) were confirmed as well differentiated, 37 patients (40.2%) were diagnosed as moderately differentiated and 26 patients (28.3%) had poorly differentiated adenocarcinomas. Well, moderately, and poorly differentiated carcinoma generally corresponds to Gleason patterns 1–2, 3–4, and 5, respectively.29, 30
The clinical or pathological stage was determined by reviewing the medical records and classified using the Tumor-Node-Metastasis system. Prostate cancer was classified into the localized group consisting of T1-4N0M0 (stage A, B, or C by the Whitmore-Jewett system) tumors and the metastatic group consisting of T1–4N+M0–1 or T1–4N0–1M1 (stage D by the Whitmore-Jewett system) tumors.31 Regarding the clinical staging, seven cases (7.6%) were stage A, 25 cases (27.2%) were stage B, 21 cases (22.8%) were stage C and 39 cases (42.4%) were stage D.
Genomic DNA was prepared from the available prostate cancer specimens and blood samples according to the standard method.32
Haplogroup analysis of Y chromosomes was performed by the method reported previously.26 In brief, it determines the DNA types by PCR-SSCP, PCR-RFLP, and PCR, for three binary polymorphic loci, SRY, DXYS5Y (47z/Stu I), and DYS287 (YAP), respectively. By combinations of these three polymorphisms, Y chromosomes were classified into four haplogroups DE, O2b*, O2b1, and untagged, according to the nomenclature of the Y-chromosome consortium,28 (Figure 2).
The statistical significant differences among the matched cases and control groups were tested using Chi square test, and Fisher exact test with a probability of <0.05 as the cutoff point for significance. Also, test of proportion and odds ratios (OR) with its 95% confidence intervals (CI) were calculated when needed.
The present study investigated the relationship between Y haplogroups and the incidence of prostate cancer among Japanese males who are classified into four haplogroups according to a previous study.26 From these haplogroups, DE and untagged are commonly distributed all over the world, while O2b* and O2b1 are confined to the East Asian populations of Korea and Japan and small parts of China. Haplogroup DE is absent in all Asian populations except for Japanese population where frequencies that range from 20 to 35% were detected in different Japanese geographical areas.33, 34
We conducted this study on Japanese prostate cancer patients and compared them to control Japanese males from the same geographical area to eliminate any chance of racial differences. The racial composition of the groups under study is important when considering whether particular alleles at a certain locus or composed haplotype predispose to development of certain disorder.
Our results demonstrated that the incidence of prostate cancer varies among the four main Japanese Y haplogroups.
On comparison to the untagged haplogroup, males with haplogroup DE were more susceptible for developing prostate cancer showing over-representation 41.3% of prostate cancer group, while males from haplogroup O2b* and O2b1 lineages were at a much lower risk than the other haplogroups with under-representation (21.7), (Table 1).
As the haplogroups of O2b* and O2b1 are considered as East Asian-specific haplogroups, we classified Japanese males (patients and controls) into two major haplogroups, Asian-specific haplogroups (O2b* and O2b1) and haplogroups shared with other continents male populations (untagged and DE). Then, we compared these two major groups using the χ2 test, which indicated that the occurrence of prostate cancer in males from Y haplogroups O2b* and O2b1 is significantly lower (P=0.01) than that of males from haplogroups DE and the untagged lineages who showed an OR of 2.17 with a 95% CI of (1.16–4.07), (Table 2). These findings explain the lower incidence of prostate cancer in male population of Japan and other southeast Asian countries than other populations.
The Y chromosome is a gene-poor chromosome that is thought to have only the genes that are preferable to male phenotype and factors specific for growth advantage and spermatogenesis.35
Many recent studies proposed that Y chromosome may have other determining genes for the male phenotype.36, 37, 38 A number of diverse phenotypes have been attributed to the Y chromosome, including stature,39 aggression,40 handedness,41 tooth size,42 cerebral asymmetry,43 alcohol dependence,44 high blood pressure,45 spermatogenic ability,27, 46 and adult height.47
Researchers have been trying to investigate if there is Y involvement in tumorigenesis of male-specific cancers depending on the fact that the Y chromosome together with prostate and testicular cancers has male-specificity in common. Recently, studies trying to establish a relationship between Y haplotypes and such male-specific cancers started to appear in the literature.48, 49
It is hypothesized that males from different Y lineages have characteristically different Y chromosomes and the high geographical specificity of Y haplotypes indicates that different ethnic groups certainly have very different Y lineages.25
We hypothesize that males from different Y-chromosome lineages have different Y-chromosomal structures, which is ultimately responsible for the variable degrees of susceptibility to or resistance for the development of human cancers, particularly, cancers of male-specific organs, such as the testis and prostate.
This hypothesis is supported by many epidemiological studies showing that males from different racial groups and from different geographical areas of the world vary regarding their susceptibility to develop prostate cancer. In addition, these studies emphasized the role of genetics in the development of prostate cancer beside the other factors such as age, race, dietary, and environmental factors.3, 6, 7, 50
However, till now, there are no reliable studies examining associations between cancers and Y haplotypes have yet been performed. Studies of haplotypes among prostate and testicular cancer patients (male-specific cancers) compared with carefully selected controls seem worthwhile.25
Our findings indicate that the incidence of prostate cancer in males from Y haplogroups DE and untagged is significantly higher than that of males from haplogroups O2b* and O2b1 (P=0.01). Japanese males from Y haplogroups DE and untagged showed a higher incidence rate (78.3%) of all the prostate cancer cases.
Males from haplogroup DE were over-represented (41.3%) in the prostate cancer group compared with the proportion of (27.5%) males from the same haplogroup in the matched controls. In contrary to this, haplogroups O2b* and O2b1 were under represented in the prostate cancer group (21.7%) compared with the (37.6%) in the control group (Table 1).
These results indicate that males from haplogroups O2b* and O2b1 are at a much lower risk for developing prostate cancer than those from other haplogroups, whereas males from haplogroup DE show more susceptibility for developing the disease.
Interestingly, we found that Japanese haplogroup DE males have the highest incidence of prostate cancer among males from different haplogroups in Japan. These Y chromosomes with haplogroup DE are characterized by having the YAP insertion polymorphism, that is YAP+ chromosomes. This haplogroup is rare in all East Asian populations except for Japanese who showed prevalence rates of about 30% for DE haplogroup.26, 34 Such YAP+ chromosomes are present in African-American and Caucasian populations in rates of about 80 and 20%, respectively.33 However, the incidence of prostate cancer in African-American males (142/100 000) is 10 times higher than that in Japanese (14/100 000) men. The incidence rates in the present study, within each haplogroup of Japanese males can highlighten the possible causes of such variations. Only haplogroup DE of the Japanese population are showing comparable prevalence rate with that of African-Americans who share them the same haplogroup. This implies that haplogroup DE males are at a higher risk for developing prostate cancer than other males.
These findings lead us to think, conceivably, that the Y chromosome bears oncogenes and/or tumor-suppressor genes, which act at different stages of tumorigenesis. One cancer predisposition locus has been assigned to the Y chromosome for gonadoblastoma in females with XY gonadal dysgenesis or 45, X/46, XY mosaicism, suggesting the existence of a Y-chromosomal oncogene. Detailed Y mapping provided a pool of candidate genes for gonadoblastoma and defined a critical GBY region that contains the TSPY gene family, whose function is unclear.37, 51 Recent studies provide circumstantial evidence supporting a role for the TSPY as an oncogene. TSPY has preferential expression in the epithelial cells of prostate cancer and its expression is upregulated in responsive prostatic cell line, LNCaP, with stimulation by androgen.52 The involvement of TSPY in cell proliferation and tumorigenesis is reinforced by its strong homology with the SET oncogene on 9q34, a cyclin B-binding protein.51, 53 As the TSPY is a polymorphic multicopy gene (20–40 copies),54 we can infer that its function is determined by the number of copies existing on the Y chromosome, and this copy number varies among males from different Y-chromosomal lineages, suggesting different degrees of susceptibility to its proto-oncogenic activity.
Moreover, the TSPY expression appears to depend on the spermatogenic activity and a proper hormonal environment (male androgen hormones);52 and the androgen receptor (AR) plays a critical role in the development and progression of prostate cancer, with most prostate cancers dependent upon androgens for their growth and responding to therapies that decrease androgen level.55, 56
The SRY (sex-determining region Y) gene has been found to interact with and negatively regulate AR transcriptional activity. Transient expression of SRY in LNCaP prostate cancer cells repressed expression of an androgen-dependent PSA reporter gene and stable SRY expression repressed the endogenous PSA gene.57 Therefore, the SRY function of negative AR regulation suggests that its loss in prostate cancer may augment the AR activity required for growth of prostate cancer and for oncogenic activity of TSPY gene.
In fact, Japanese Y haplogroups O2b* and O2b1 differ than those from haplogroups DE and the untagged in their SRY gene only, where the former have a new allele of the SRY gene caused by a polymorphism in the coding sequence of the SRY gene raised by a (C-to-T) transition in the codon 155.26 Those SRY polymorphic variants may differ in their interaction and negative regulation of AR transcriptional activities.
Based on the above discussions, our results can be interpreted in a way that Japanese males with haplogroups O2b* and O2b1 have Y chromosomes that are different in structure than those from haplogroups DE and untagged. Instantly, males from Y-chromosomal lineages O2b* and O2b1 may have genes or DNA sequences, working as tumor-suppressor factors making them resistant for developing this male-specific cancer, prostate cancer. Alternatively, they may lack a locus or DNA sequence that is present on Y chromosomes of haplogroups DE and untagged with oncogenic-like activity, making the DE and untagged haplogroups more susceptible for developing prostate cancer.
In conclusion, males from different Y-chromosome lineages may have different susceptibilities to tumorigenesis; some males are at high risk, whereas others may show resistance. In other words, different Y-chromosomal structures may interfere with the vulnerability for human cancers, especially male-specific cancers. These findings explain on genetic basis why do Japanese males have a lower risk for developing prostate cancer than African-American and Caucasian males, a fact that was reported in many previous reports and was incompletely explained in terms of dietary and environmental backgrounds.6, 50, 58, 59
Similar studies should be performed using different population groups comparing their prostate cancer individuals' Y-chromosomal structure to that of their carefully selected controls, which will help in confirming the current data.
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We would like to thank all the physicians, urologists and pathologists of different university and municipal hospitals in Shikoku Island for providing samples and clinical information. Also, many thanks are due to Miss Tsuji K., Unemi Y and Endo A for their excellent technical assistance.
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Ewis, A., Lee, J., Naroda, T. et al. Prostate cancer incidence varies among males from different Y-chromosome lineages. Prostate Cancer Prostatic Dis 9, 303–309 (2006). https://doi.org/10.1038/sj.pcan.4500876
- prostate cancer
- Y-chromosome lineages
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