Abstract
Family history is among the strongest known risk factors for prostate cancer (PCa). Emerging data suggest molecular subtypes of PCa, including two somatic genetic aberrations: fusions of androgen-regulated promoters with ERG and, separately, PTEN loss. We examined associations between family history and incidence of these subtypes in 44,126 men from the prospective Health Professionals Follow-up Study. ERG and PTEN status were assessed by immunohistochemistry. Multivariable competing risks models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between self-reported family history of PCa and molecular subtypes of disease. Thirteen percent of men had a positive family history of PCa at baseline. During a median follow-up of 18.5 years, 5,511 PCa cases were diagnosed. Among them, 888 were assayed for ERG status (47% ERG-positive) and 715 were assayed for PTEN loss (14% PTEN null). Family history was more strongly associated with risk of ERG-negative (HR: 2.15; 95%CI: 1.71-2.70) than ERG-positive (HR: 1.49; 95%CI: 1.13-1.95) disease (Pheterogeneity: 0.04). The strongest difference was among men with an affected father (HRERG-negative: 2.09; 95%CI: 1.64-2.66; HRERG-positive: 1.30; 95%CI: 0.96-1.76; Pheterogeneity: 0.01). Family history of PCa was positively associated with both PTEN null (HR: 2.10; 95%CI: 1.26-3.49) and PTEN intact (HR: 1.72; 95%CI: 1.39-2.13) PCa (Pheterogeneity: 0.47). Our results indicate that PCa family history may be positively associated with PCa in all ERG and PTEN subtypes, suggesting a role of genetic susceptibility in their development. It is possible that ERG-negative disease could be especially associated with positive family history.
Keywords: prostate cancer, TMPRSS2:ERG, PTEN, family history, molecular subtypes
INTRODUCTION
Family history of prostate cancer (PCa) is a well-established risk factor for PCa incidence.1 Men with an affected father have a more than two-fold greater risk of PCa and those with an affected brother have a more than three-fold greater risk.2 Furthermore, twin studies indicate that nearly 60% of the variability in PCa liability can be attributed to genetic factors,3,4 making PCa one of the most heritable malignancies.
The past several years have seen progress in defining molecular subtypes of PCa, yet no studies have evaluated the role of family history in specific subtypes of disease. In the most common known molecular subtype (i.e., roughly half of primary PCa),5 the oncogene ERG fuses with androgen-regulated promoter genes, most often TMPRSS2.6 While ERG status is unlikely prognostic by itself,7 several studies have shown that various risk factors are differentially associated with ERG-defined PCa.8–16 In particular, preliminary evidence suggests that there are distinct inherited genetic factors associated with the risk of ERG-positive vs. ERG-negative disease,8–10 lending plausibility to the hypothesis that family history could be differentially associated with the risk of ERG-defined disease.
Loss of phosphatase and tensin homolog (PTEN), a tumor suppressor gene, is another common molecular subtype of PCa. Complete PTEN loss is characteristic of approximately one-fifth of primary tumors,17,18 and it is associated with aggressive clinical features, occurring in nearly 50% of metastatic and castration-resistant disease.19–22 Given that family history is positively associated with fatal PCa,23 the evaluation of the role of family history in PCa with PTEN loss has the potential to clarify mechanisms and inform clinical counseling for the risk of aggressive disease. No data exist, however, regarding the inherited genetic susceptibility to PTEN-defined PCa.
Given the substantial heritability of PCa and the high prevalence of both ERG overexpression and PTEN loss, an association between family history and these molecular subtypes is both plausible and potentially valuable for prevention efforts in clinic. Utilizing data from the large prospective Health Professionals Follow-up Study (HPFS), we evaluated whether a positive PCa family history is differentially associated with the incidence of ERG- and/or PTEN-defined disease.
MATERIALS AND METHODS
Study population
The HPFS is an ongoing cohort of 51,529 U.S. male health professionals who were ages 40 to 75 at enrollment in 1986. Cohort data have been updated biennially via questionnaires concerning lifestyle factors, known or suspected contributors to chronic diseases, and various health outcomes. For these analyses, we restricted the cohort to the 47,158 men who responded to a question about family history of PCa on the 1990 questionnaire. We then excluded men who reported cancers other than nonmelanoma skin cancer prior to 1990 (n = 3,013), who were missing data on date of birth (n = 10), who were diagnosed with PCa but missing a diagnosis date (n = 7), or who had a date of death prior to a date of metastases (n = 2). The remaining 44,126 men comprised the study population for these analyses.
Consent and approval
The Institutional Review Board at the Harvard T.H. Chan School of Public Health approved this study. Response to the baseline questionnaire was considered implied consent. Written informed consent was obtained from each study participant to obtain medical records and archival tumor tissue.
Family history assessment
Questionnaires assessed family history of PCa in a father and/or brother (yes/no) in 1990, 1992, and 1996. Family history was considered time-variable, whereby men who initially reported no family history could change to have a positive family history over time. In 1996, participants were asked the age of their affected relatives at the time of diagnosis in five categories (<50, 50–59, 60–69, ≥70 years, unknown). As few relatives were diagnosed under the age of 50 years, we further categorized age of the relative at diagnosis (<60, ≥60 years, unknown).
Case ascertainment, tumor tissue cohort, and immunohistochemistry
PCa diagnoses and deaths were initially identified by self-report or next of kin, and confirmed with medical records, pathology reports, and the National Death Index. Medical records were reviewed to abstract information about clinical characteristics and disease progression. We were thus able to define the following categories of PCa diagnoses: high-grade cancer (Gleason score ≥4+3), low-grade cancer (Gleason score ≤3+4), and lethal disease (distant metastases at diagnosis or during follow-up, or PCa death during follow-up). A total of 5,511 PCa cases were diagnosed during the study period (i.e., between 1990 and 2009).
We collected archival tumor tissue from men who underwent radical prostatectomy (95%) or transurethral resection of the prostate (5%). Hematoxylin and eosin slides were reviewed by study pathologists to confirm PCa and to identify tumor areas for tissue microarray (TMA) construction. We constructed TMAs by sampling at least three 0.6 mm cores of tumor per case from the dominant nodule or nodule with highest Gleason pattern.
Archival tumor tissue was unavailable from some hospitals; hospitals destroy blocks after 10 years, and some do not release tissue outside of their institutions. In addition, tissue for men who were not treated with surgery was not assayed. Among men for whom tissue was available, ERG and PTEN status were measured by immunohistochemistry in a subset, as described in detail previously.7,24 A case was scored ERG-positive if at least one TMA core had positive ERG staining within PCa epithelial cells.7 A tissue core was considered to have PTEN protein loss if the intensity of cytoplasmic and nuclear staining was entirely lost (0+ intensity) or decreased (1+ intensity) across more than 10% of tumor cells compared with surrounding benign glands and/or stroma.24 Among the PCa cases with tissue available, ERG data were available for 888 men and PTEN data were available for 715 men.
Statistical Analysis
Person-time was calculated from the return date of the 1990 questionnaire until PCa diagnosis (regardless of the availability of ERG and PTEN assays), death from any cause, or end of follow-up. Because prostate tumor tissue was available for ERG and PTEN in cases diagnosed through 2009, we ended follow-up at that time. We used Cox proportional hazards models adjusted for age and calendar time to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the association between any family history of PCa and disease incidence (regardless of ERG or PTEN data availability). We also ran separate models for associations with father family history, brother family history, and earliest age at PCa diagnosis in any relative. Multivariable models were adjusted for Caucasian race (yes, no), height (≤68, >68-70, >70-72, >72 inches), body mass index (BMI) at age 21 (<20, 20-<22.5, 22.5-<25, 25+ kg/m2), current BMI (<21, 21-<25, 25-<30, 30+ kg/m2), physical activity (quintiles of metabolic equivalent task [MET] hours per week), smoking (never, former/quit >10 years ago, former/quit ≤10 years ago, current), history of diabetes (yes, no), prostate-specific antigen (PSA) testing in the two years prior to the questionnaire date (yes, no; lagged by one period to avoid counting diagnostic PSA tests as screening), total energy intake (quintiles), tomato sauce intake (quintiles), and coffee intake (none, <1, 1-<2, 2-<3, 3+ cups per day). Multivariable models for father family history were additionally adjusted for brother family history and vice versa.
To assess associations with PCa by ERG and, separately, PTEN status, we implemented an extension of Cox modeling as described by Lunn and McNeil.25 These competing risks models allowed for HR estimation for each molecular subtype of cancer versus no cancer. We examined whether associations between family history and PCa defined by ERG or PTEN status differed using likelihood ratio tests.26
Multivariable models were also fit for high-grade and low-grade PCa overall and by subtype. We were also powered to look at the risk of lethal disease for PCa overall.
P-values were calculated with two-sided tests with a significance threshold set at p<0.05. Analyses were performed in SAS Version 9.4 (SAS Institute Inc, Cary, NC).
Data Availability
The data that support the findings of this study are available on request. The data are not publicly available due to privacy or ethical restrictions.
RESULTS
Table 1 describes the age-standardized characteristics of the study population by family history of PCa. More men with a known PCa family history were PSA screened in the prior two years (48% in 1994; 75% in 2004) than men without a family history (38% in 1994; 68% in 2004). There were no material differences in any other lifestyle, nutritional, or demographic characteristics between those with and without a PCa family history.
Table 1.
Age-standardized characteristics of the study population at baseline in 1990 by family history of PCa, the Health Professionals Follow-up Study
| PCa family history | ||
|---|---|---|
| Characteristic | No | Yes |
| N | 38,537 | 5,589 |
| Mean age, years (SD)a | 58.0 (9.6) | 58.2 (9.5) |
| Caucasian | 95.8% | 96.5% |
| Mean height, inches (SD) | 70.1 (2.7) | 70.2 (2.7) |
| Mean BMI at age 21 years, kg/m2 (SD) | 23.0 (2.9) | 22.9 (2.9) |
| Mean BMI, kg/m2 (SD) | 25.7 (3.4) | 25.7 (3.4) |
| Top quintile of physical activity (≥29.7 MET hours/week) | 19.9% | 21.0% |
| Smoking status | ||
| Never smoker | 44.3% | 46.6% |
| Past smoker quit >10 years | 31.7% | 31.2% |
| Past smoker quit ≤10 years | 9.6% | 8.7% |
| Current smoker | 8.3% | 8.0% |
| Smoking unknown | 6.1% | 5.5% |
| History of diabetes | 4.4% | 4.0% |
| PSA screeningb | ||
| 1994 | 38.1% | 48.2% |
| 2004 | 67.7% | 75.2% |
| Mean total energy intake, kcal/day (SD) | 1,953 (558) | 1,972 (554) |
| Mean tomato sauce intake, servings/day (SD) | 0.1 (0.1) | 0.1 (0.1) |
| Mean coffee intake, cups/day (SD) | 1.9 (1.7) | 1.9 (1.7) |
| Father with PCa | – | 80.6% |
| Brother(s) with PCa | – | 23.6% |
| Earliest age at family member PCa diagnosis | ||
| Age <60 years | – | 7.9% |
| Age 60+ years | – | 60.0% |
| Age unknown | – | 32.1% |
Abbreviations: BMI, body mass index; MET, metabolic equivalent task; PCa, prostate cancer; PSA, prostate-specific antigen; SD, standard deviation
Value is not age-standardized
Reported having a PSA test in the two years before the questionnaire date
During a median follow-up of 18.5 years, 697,872 person-years were accrued and 5,511 incident PCa cases were diagnosed (Table 2). Among them, 888 were assayed for ERG status (47% ERG-positive) and 715 were assayed for PTEN status (14% PTEN null). Men assayed for a molecular marker were more likely to be diagnosed in earlier years, to be younger at diagnosis, and to have more information regarding their clinical characteristics. Previous studies from our group suggest that statistically accounting for differences between cases with and without molecular marker information does not materially change results.11,12
Table 2.
Age-standardized characteristics of participants with PCa by ERG and PTEN status, the Health Professionals Follow-up Study, 1990-2009
| Cases by ERG status | Cases by PTEN status | |||||
|---|---|---|---|---|---|---|
| Characteristic | Positive | Negative | Unavailable | Null | Intact | Unavailable |
| N | 417 | 471 | 4,623 | 100 | 615 | 4,796 |
| Mean age at diagnosis, years (SD)a | 65.2 (6.1) | 66.2 (5.7) | 70.9 (7.5) | 66.4 (6.3) | 65.7 (5.9) | 70.7 (7.5) |
| Year of diagnosis | ||||||
| 1990-1994 | 34.7% | 27.9% | 21.5% | 32.9% | 26.0% | 22.3% |
| 1995-1999 | 36.3% | 33.1% | 25.3% | 39.8% | 28.6% | 26.4% |
| 2000-2004 | 15.0% | 25.2% | 30.4% | 16.9% | 26.3% | 29.4% |
| 2005-2009 | 14.0% | 13.7% | 22.8% | 10.4% | 19.0% | 21.9% |
| Mean PSA at diagnosis (SD)b | 9.9 (10.8) | 10.0 (11.1) | 15.5 (117) | 9.4 (7.8) | 9.9 (11.2) | 15.4 (116) |
| % Missing | 5.6% | 9.5% | 16.0% | 13.9% | 6.8% | 15.8% |
| TNM clinical stage | ||||||
| T1 / T2b | 93.4% | 96.0% | 92.8% | 92.1% | 96.0% | 92.9% |
| T3b | 4.7% | 2.0% | 2.8% | 2.3% | 3.3% | 2.8% |
| T4 / N1 / M1b | 1.9% | 2.0% | 4.4% | 5.6% | 0.7% | 4.3% |
| % Missing | 0.0% | 0.0% | 11.8% | 0.0% | 0.0% | 11.5% |
| Gleason grade | ||||||
| Gleason 2-6b | 58.1% | 59.0% | 61.5% | 33.1% | 60.5% | 61.7% |
| Gleason 3+4b | 19.1% | 16.9% | 16.1% | 21.0% | 17.9% | 16.1% |
| Gleason 4+3b | 12.0% | 12.6% | 7.5% | 17.4% | 12.8% | 7.5% |
| Gleason 7, breakdown unknownb | 1.5% | 0.7% | 3.7% | 3.7% | 0.2% | 3.6% |
| Gleason 8-10b | 9.3% | 10.8% | 11.2% | 24.8% | 8.7% | 11.0% |
| % Missing | 0.0% | 0.1% | 15.3% | 0.0% | 0.1% | 14.8% |
| Lethal PCa | 9.6% | 8.8% | 14.2% | 24.8% | 5.0% | 14.1% |
| Family history of PCa | 21.6% | 21.8% | 20.0% | 25.7% | 19.8% | 20.2% |
| Father with PCa | 14.3% | 16.7% | 15.4% | 14.8% | 15.2% | 15.5% |
| Brother(s) with PCa | 8.5% | 6.2% | 5.9% | 12.3% | 5.5% | 6.0% |
| Earliest age at family member PCa diagnosisc | ||||||
| Age <60 years | 14.0% | 5.9% | 10.3% | 15.3% | 5.3% | 10.5% |
| Age 60+ years | 59.1% | 63.2% | 63.1% | 58.6% | 63.7% | 63.0% |
| Age unknown | 26.9% | 30.8% | 26.6% | 26.1% | 31.0% | 26.5% |
Abbreviations: PCa, prostate cancer; PSA, prostate-specific antigen; SD, standard deviation
Value is not age-standardized
Values are among those with data available
Among cases with a positive family history of PCa
Multivariable results for associations between family history of PCa and incidence of PCa overall and by molecular marker status are presented in Table 3; results from age- and calendar time-adjusted models were materially similar (data not shown). A positive family history was associated with a higher incidence of overall PCa (HR: 1.68; 95% CI: 1.56, 1.80), as well as both high- and low-grade disease. There was also suggestive evidence that men may have an even greater increased incidence of PCa if a family member was diagnosed before age 60: (HR: 2.22; 95% CI: 1.84, 2.68). Results for lethal PCa (HR: 1.65; 95% CI: 1.35, 2.02) were comparable with those for overall PCa.
Table 3.
Multivariable hazard ratios (HR) and 95% confidence intervals (CI) for the incidence of PCa, overall and by ERG and PTEN status, the Health Professionals Follow-up Study, 1990-2009
| PCa Overall | By ERG Status | By PTEN Status | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| N cases | HR (95% CI)a | N Cases | HR (95% CI)a | N Cases | HR (95% CI)a | |||||
| ERG+ | ERG− | ERG+ | ERG− | PTEN Null | PTEN Intact | PTEN Null | PTEN Intact | |||
| Total PCa | 5,511 | 417 | 471 | 100 | 615 | |||||
| Family history of PCa | ||||||||||
| No | 4,554 | 1 (ref) | 354 | 375 | 1 (ref) | 1 (ref) | 80 | 509 | 1 (ref) | 1 (ref) |
| Yes | 957 | 1.68 (1.56, 1.80) | 63 | 96 | 1.49 (1.13, 1.95) | 2.15 (1.71, 2.70) | 20 | 106 | 2.10 (1.26, 3.49) | 1.72 (1.39, 2.13) |
| Pheterogeneity | 0.04 | 0.47 | ||||||||
| Father with PCa | ||||||||||
| No | 4,738 | 1 (ref) | 368 | 388 | 1 (ref) | 1 (ref) | 86 | 525 | 1 (ref) | 1 (ref) |
| Yes | 773 | 1.65 (1.53, 1.78) | 49 | 83 | 1.30 (0.96, 1.76) | 2.09 (1.64, 2.66) | 14 | 90 | 1.60 (0.88, 2.91) | 1.63 (1.30, 2.05) |
| Pheterogeneity | 0.01 | 0.96 | ||||||||
| Brother(s) with PCa | ||||||||||
| No | 5,279 | 1 (ref) | 402 | 455 | 1 (ref) | 1 (ref) | 94 | 597 | —b | —b |
| Yes | 232 | 1.51 (1.32, 1.73) | 15 | 16 | 1.96 (1.16, 3.29) | 1.71 (1.03, 2.86) | 6 | 18 | ||
| Pheterogeneity | 0.72 | |||||||||
| Earliest age at family member PCa diagnosis | ||||||||||
| No family history | 4,400 | 1 (ref) | 332 | 361 | 1 (ref) | 1 (ref) | 75 | 489 | —b | —b |
| Age <60 years | 114 | 2.22 (1.84, 2.68) | 11 | 9 | 2.58 (1.42, 4.72) | 2.40 (1.22, 4.74) | 3 | 10 | ||
| Age 60+ years | 693 | 1.76 (1.62, 1.91) | 49 | 65 | 1.65 (1.22, 2.22) | 1.99 (1.53, 2.60) | 15 | 73 | ||
| Age unknown | 304 | 1.57 (1.40, 1.77) | 25 | 36 | 1.65 (1.09, 2.48) | 2.25 (1.59, 3.17) | 7 | 43 | ||
| Pheterogeneity | 0.57 | |||||||||
| High grade PCa (Gleason ≥4+3) | 1,207 | 181 | 213 | 76 | 269 | |||||
| Family history of PCac | ||||||||||
| No | 997 | 1 (ref) | 144 | 177 | 1 (ref) | 1 (ref) | 59 | 219 | 1 (ref) | 1 (ref) |
| Yes | 210 | 1.68 (1.44, 1.96) | 37 | 36 | 2.14 (1.48, 3.10) | 1.75 (1.21, 2.53) | 17 | 50 | 2.43 (1.39, 4.26) | 1.94 (1.41, 2.66) |
| Pheterogeneity | 0.45 | 0.49 | ||||||||
| Father with PCac | ||||||||||
| No | 1,039 | 1 (ref) | 155 | 182 | 1 (ref) | 1 (ref) | 65 | 228 | 1 (ref) | 1 (ref) |
| Yes | 168 | 1.64 (1.39, 1.94) | 26 | 31 | 1.62 (1.06, 2.48) | 1.69 (1.14, 2.51) | 11 | 41 | 1.64 (0.83, 3.26) | 1.75 (1.24, 2.47) |
| Pheterogeneity | 0.89 | 0.87 | ||||||||
| Brother(s) with PCac | ||||||||||
| No | 1,154 | 1 (ref) | 169 | 208 | —b | —b | 70 | 259 | —b | —b |
| Yes | 53 | 1.57 (1.18, 2.08) | 12 | 5 | 6 | 10 | ||||
| Pheterogeneity | ||||||||||
| Low grade PCa (Gleason ≤3+4) | 3,434 | 235 | 253 | 24 | 344 | |||||
| Family history of PCac | ||||||||||
| No | 2,808 | 1 (ref) | 209 | 195 | 1 (ref) | 1 (ref) | 21 | 290 | —b | —b |
| Yes | 626 | 1.73 (1.58, 1.89) | 26 | 58 | 1.04 (0.69, 1.58) | 2.39 (1.77, 3.22) | 3 | 54 | ||
| Pheterogeneity | 0.001 | |||||||||
| Father with PCac | ||||||||||
| No | 2,928 | 1 (ref) | 212 | 203 | 1 (ref) | 1 (ref) | 21 | 297 | —b | —b |
| Yes | 506 | 1.67 (1.52, 1.84) | 23 | 50 | 1.06 (0.69, 1.65) | 2.31 (1.69, 3.16) | 3 | 47 | ||
| Pheterogeneity | 0.004 | |||||||||
| Brother(s) with PCac | ||||||||||
| No | 3,286 | 1 (ref) | 232 | 243 | —b | —b | 24 | 337 | —b | —b |
| Yes | 148 | 1.61 (1.36, 1.91) | 3 | 10 | 0 | 7 | ||||
| Pheterogeneity | ||||||||||
Abbreviations: CI, confidence interval; HR, hazard ratio; PCa, prostate cancer
Models adjusted for age, calendar time, Caucasian race (yes, no), height (≤68, >68-70, >70-72, >72 inches), body mass index (BMI) at age 21 years (<20, 20-<22.5, 22.5-<25, 25+ kg/m2), current BMI (<21, 21-<25, 25-<30, 30+ kg/m2), physical activity (quintiles of metabolic equivalent task [MET] hours per week), smoking (never, former / quit >10 years ago, former / quit ≤10 years ago, current), history of diabetes (yes, no), prostate-specific antigen (PSA) testing in the two years prior to the questionnaire date (yes, no; lagged by one period to avoid counting diagnostic PSA tests as screening), total energy intake (quintiles), tomato sauce intake (quintiles), and coffee intake (none, <1, 1-<2, 2-<3, 3+ cups per day); models for father family history were additionally adjusted for brother family history and vice versa
Sample size insufficient to yield meaningful results
Of any grade
Family history of PCa was associated with the incidence of ERG-positive (HR: 1.49; 95% CI: 1.13, 1.95) PCa and even more so ERG-negative (HR: 2.15; 95% CI: 1.71, 2.70) PCa (Pheterogeneity: 0.04). The strongest difference was among men with an affected father (HRERG-negative: 2.09; 95% CI: 1.64-2.66; HRERG-positive: 1.30; 95% CI: 0.96–1.76; Pheterogeneity: 0.01). These results were seemingly driven by the association of having an affected father with the incidence of low-grade ERG-negative PCa (HR: 2.31; 95% CI: 1.69-3.16). Indeed, family history overall was more strongly associated with low-grade ERG-negative disease (HR: 2.39; 95% CI: 1.77, 3.22) than low-grade ERG-positive disease (HR: 1.04; 95% CI: 0.69, 1.58; Pheterogeneity: 0.001).
Fourteen percent of cases were PTEN null. Analyses of family history and incidence of PCa by PTEN status found similar positive associations for both PTEN null and intact disease (Pheterogeneity: 0.47). Analyses restricted to subtypes combining both PTEN status and Gleason grade were largely underpowered for meaningful analysis.
DISCUSSION
To the best of our knowledge, this is the first study to evaluate associations between PCa family history and disease incidence by ERG and PTEN status. Our results suggest that family history contributes to the incidence of PCa across the four molecular subtypes. They also indicate the possibility that family history may contribute most strongly to the incidence of ERG-negative PCa, particularly of the low-grade variety.
Twin studies have shown that PCa is among the most heritable cancers,3,4 and array-based analyses suggest that common genetic variants explain over 33% of PCa heritability.27 It is thus unsurprising that we found a family history of PCa to be associated with the incidence of PCa overall and with the incidence of each molecular subtype of disease. There is, however, evidence to suggest that the genetic factors that contribute to the incidence of TMPRSS2:ERG-positive versus -negative PCa are distinct. One genome-wide linkage analysis revealed several loci that were suggestive of linkage to TMPRSS2:ERG-positive PCa.8 In addition, two studies published in 2016, including one from our group, produced evidence of individual germline variants differentially associated with PCa defined by fusion status.9,10 Our group further found that shorter CAG repeats in androgen receptor are specifically associated with the development of ERG-positive PCa.28 It should also be noted that the prevalence of the fusion varies across ancestries, suggesting a role for genetics in its development; prevalence of TMPRSS2:ERG is higher for Caucasians (~50%) than for individuals of African (16–30%) and Asian (16–30%) descent.7,29–31 Multi-ancestry genome-wide association studies of PCa defined by molecular subtypes have the potential to more comprehensively elucidate the genetic factors that contribute to the subtypes.
Lifestyle may also play a role in the development of PCa defined by TMPRSS2:ERG.11–16 For example, lycopene consumption from tomato products has been shown to be inversely associated with ERG-positive but not ERG-negative disease,11 and two studies have shown obesity to be associated with a reduced risk of developing TMPRSS2:ERG-positive PCa.12,13 Given that families often share lifestyle exposures, the association between a family history of PCa and molecular subtypes of PCa could operate through environment.
We found some suggestive evidence that a family history of PCa may be more strongly associated with ERG-negative than ERG-positive PCa. A possible explanation stems from the association between a family history of PCa and increased PSA screening.32–34 While PSA screening does not seem to wholly account for the association between a family history of PCa and PCa risk,1,34,35 its increased adoption among men with a family history of PCa means that such men are more likely to be diagnosed with lower stage disease.36–38 Given that the TMPRSS2:ERG gene fusion is associated with higher stage PCa,7 it is perhaps unsurprising that we found a family history of PCa to be more strongly associated with ERG-negative disease. It is also possible that ERG-negative PCa is more heritable than ERG-positive PCa and/or that lifestyle risk factors shared by families more strongly affect ERG-negative disease. Regardless of the underlying reason, ours is the first study to show a differential association for PCa family history with PCa defined by ERG status. Fewer explanations come to mind regarding a possible differential association for family history in a father and ERG-defined PCa, or, more accurately, the lack of such a differential association for family history in a brother. The most likely is perhaps insufficient power.
Like TMPRSS2:ERG, the frequency of PTEN loss in PCa differs by ancestry, wherein it is lower for African-Americans than for Caucasians.39 Beyond ancestral differences, little evidence exists regarding the heritability of PTEN loss. Ours is the first study to investigate the relationship between family history and PCa defined by PTEN loss. We found that family history was positively associated with both PTEN intact and PTEN null tumor status. There could be several reasons for the lacking differential association. Many mechanisms may lead to PTEN alterations, including mutations,40,41 epigenetic changes,42 microRNA regulation,43,44 and post-translational modifications.45 Some PTEN loss may thus be hereditary while other PTEN loss occurs as a result of alternative mechanisms. PTEN loss may even occur subsequent to other genomic alterations, including the TMPRSS2:ERG fusion.46 Additional research is warranted to determine whether family history plays a role in PTEN loss.
This study had some limitations. Given that the HPFS largely consists of Caucasian men and that the prevalence of ERG and PTEN vary by race/ethnicity, results are not generalizable to all racial/ethnic groups. We also acknowledge that most cases assayed for ERG and/or PTEN status were treated with radical prostatectomy, and thus not representative of all men diagnosed with PCa. We found, however, that cases assayed for molecular markers did not substantially differ from other cases with respect to the majority of clinical and demographic characteristics (e.g., stage, Gleason score, and PSA at diagnosis). It is also reassuring that the prevalence of family history was similar among those with and without tissue biomarker data. In addition, two previous studies showed that the use of inverse probability weighting to account for differences between men with and without ERG status available did not materially change results.11,12 ERG and PTEN status were not available for family members diagnosed with PCa, as these data are not collected in clinical practice. Such information would have provided important data on the heritability of specific subtypes. Lastly, our study was limited by small sample sizes for ERG and PTEN status on rare subsets of PCa.
This study also had several strengths. We utilized longitudinal data from a prospective and well-annotated cohort with ample covariate data to adjust for potential confounders. It is also critical that we had access to a tumor biorepository for assaying ERG and PTEN status given that such data are unavailable from pathology reports. Whereas most epidemiological evaluations are only able to investigate ERG and PTEN status with respect to disease progression,47–50 our data permitted the assessment of risk factors for development of PCa defined by ERG and PTEN status. In addition, the PCa subtypes in our study were centrally assessed and clinically validated by pathologists, reducing the likelihood of misclassification.
In summary, this is the first study to examine the associations of family history of PCa with respect to ERG and PTEN status. We found evidence suggesting that family history is associated with PCa across molecular subtypes, which indicates that genetic variants may play a key role in the development of PCa irrespective of TMPRSS2:ERG and PTEN status. Our results also imply the possibility that family history may play the largest role in the development of ERG-negative PCa. Additional research is necessary to validate our findings and to further explore the contributions of heritability and environment to the development of molecular subtypes of PCa. Investigators conducting genome-wide association studies might consider integrating data on molecular subtypes to inform the heritability of PCa.
Novelty and Impact:
Despite data suggesting molecular subtypes of prostate cancer, little is known about their heritability. We investigated associations between family history of prostate cancer and incidence of prostate cancer defined by fusions of androgen-regulated promoters with ERG and, separately, PTEN loss. Our results indicate that family history may be positively associated with prostate cancer in all ERG and PTEN subtypes, suggesting a role of genetic susceptibility. It is possible that ERG-negative disease may be especially associated.
ACKNOWLEDGMENTS
We would like to thank the participants and staff of the HPFS for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.
FUNDING
This work was supported by the National Institutes of Health (grant numbers R01CA136578, R01CA141298, P50 CA090381, U01CA167552, R25CA112355 to REG, T32 CA09001 to TUA, CHP, EME) ; the Prostate Cancer Foundation Young Investigators Awards (to LAM, TL); the American Cancer Society – Ellison Foundation Postdoctoral Fellowship (PF-14-140-01-CCE to TUA); and the Office of the Assistant Secretary of Defense for Health Affairs under (Award No. W81XWH-14-1-0250 to EME).
Abbreviations Used:
- BMI
body mass index
- CI
confidence interval
- HR
hazard ratio
- HPFS
Health Professionals Follow-up Study
- PTEN
phosphatase and tensin homolog
- PCa
prostate cancer
- PSA
prostate-specific antigen
- TMA
tissue microarray
Footnotes
Conflicts of Interest: PWK does not have a conflict of interest, but it is his policy to report any and all disclosures as an author on a paper. To that end, as of July 10, 2019, he reports the following disclosures for the last 24-month period: he has investment interest in Context Therapeutics LLC, DRGT, Placon, Seer Biosciences, and Tarveda Therapeutics; he is a company board member for Context Therapeutics LLC; he is a consultant/advisory board member for Bavarian Nordic Immunotherapeutics, DRGT, GE Healthcare, Janssen, New England Research Institutes, Inc., OncoCellMDX, Progenity, Sanofi, Seer Biosciences,Tarveda Therapeutics, and Thermo Fisher; and he serves on data safety monitoring boards for Genentech/Roche and Merck. All other authors have no potential conflicts of interest to disclose.
REFERENCES
- 1.Barber L, Gerke T, Markt SC, Peisch SF, Wilson KM, Ahearn T, Giovannucci E, Parmigiani G, Mucci LA. Family History of Breast or Prostate Cancer and Prostate Cancer Risk. Clin Cancer Res 2018;24:5910–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Schaid DJ. The complex genetic epidemiology of prostate cancer. Hum Mol Genet 2004;13 Spec No 1:R103–21. [DOI] [PubMed] [Google Scholar]
- 3.Hjelmborg JB, Scheike T, Holst K, Skytthe A, Penney KL, Graff RE, Pukkala E, Christensen K, Adami HO, Holm NV, Nuttall E, Hansen S, Hartman M, Czene K, Harris JR, Kaprio J, Mucci LA. The heritability of prostate cancer in the Nordic Twin Study of Cancer. Cancer Epidemiol Biomarkers Prev 2014;23:2303–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Mucci LA, Hjelmborg JB, Harris JR, Czene K, Havelick DJ, Scheike T, Graff RE, Holst K, Moller S, Unger RH, McIntosh C, Nuttall E, Brandt I, Penney KL, Hartman M, Kraft P, Parmigiani G, Christensen K, Koskenvuo M, Holm NV, Heikkila K, Pukkala E, Skytthe A, Adami HO, Kaprio J. Familial risk and heritability of cancer among twins in Nordic countries. JAMA 2016;315:68–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.The molecular taxonomy of primary prostate cancer. Cell 2015;163:1011–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Tomlins SA, Laxman B, Varambally S, Cao X, Yu J, Helgeson BE, Cao Q, Prensner JR, Rubin MA, Shah RB, Mehra R, Chinnaiyan AM. Role of the TMPRSS2-ERG gene fusion in prostate cancer. Neoplasia 2008;10:177–88. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Pettersson A, Graff RE, Bauer SR, Pitt MJ, Lis RT, Stack EC, Martin NE, Kunz L, Penney KL, Ligon AH, Suppan C, Flavin R, Sesso HD, Rider JR, Sweeney C, Stampfer MJ, Fiorentino M, Kantoff PW, Sanda MG, Giovannucci EL, Ding EL, Loda M, Mucci LA. The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: a cohort study and meta-analysis. Cancer Epidemiol Biomarkers Prev 2012;21:1497–509. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Hofer MD, Kuefer R, Maier C, Herkommer K, Perner S, Demichelis F, Paiss T, Vogel W, Rubin MA, Hoegel J. Genome-wide linkage analysis of TMPRSS2-ERG fusion in familial prostate cancer. Cancer Res 2009;69:640–6. [DOI] [PubMed] [Google Scholar]
- 9.Luedeke M, Rinckleb AE, FitzGerald LM, Geybels MS, Schleutker J, Eeles RA, Teixeira MR, Cannon-Albright L, Ostrander EA, Weikert S, Herkommer K, Wahlfors T, Visakorpi T, Leinonen KA, Tammela TLJ, Cooper CS, Kote-Jarai Z, Edwards S, Goh CL, McCarthy F, Parker C, Flohr P, Paulo P, Jeronimo C, Henrique R, Krause H, Wach S, Lieb V, Rau TT, Vogel W, Kuefer R, Hofer MD, Perner S, Rubin MA, Agarwal AM, Easton DF, Al Olama AA, Benlloch S, Hoegel J, Stanford JL, Maier C. Prostate cancer risk regions at 8q24 and 17q24 are differentially associated with somatic TMPRSS2:ERG fusion status. Hum Mol Genet 2016;25:5490–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Penney KL, Pettersson A, Shui IM, Graff RE, Kraft P, Lis RT, Sesso HD, Loda M, Mucci LA. Association of prostate cancer risk variants with TMPRSS2:ERG status: evidence for distinct molecular subtypes. Cancer Epidemiol Biomarkers Prev 2016;25:745–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Graff RE, Pettersson A, Lis RT, Ahearn TU, Markt SC, Wilson KM, Rider JR, Fiorentino M, Finn S, Kenfield SA, Loda M, Giovannucci EL, Rosner B, Mucci LA. Dietary lycopene intake and risk of prostate cancer defined by ERG protein expression. Am J Clin Nutr 2016;103:851–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Graff RE, Ahearn TU, Pettersson A, Ebot EM, Gerke T, Penney KL, Wilson KM, Markt SC, Pernar CH, Gonzalez-Feliciano AG, Song M, Lis RT, Schmidt DR, Vander Heiden MG, Fiorentino M, Giovannucci EL, Loda M, Mucci LA. Height, obesity, and the risk of TMPRSS2:ERG-defined prostate cancer. Cancer Epidemiol Biomarkers Prev 2018;27:193–200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Egbers L, Luedeke M, Rinckleb A, Kolb S, Wright JL, Maier C, Neuhouser ML, Stanford JL. Obesity and prostate cancer risk according to tumor TMPRSS2:ERG gene fusion status. Am J Epidemiol 2015;181:706–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Pernar CH, Ebot EM, Pettersson A, Graff RE, Giunchi F, Ahearn TU, Gonzalez-Feliciano AG, Markt SC, Wilson KM, Stopsack KH, Gazeeva E, Lis RT, Parmigiani G, Rimm EB, Finn SP, Giovannucci EL, Fiorentino M, Mucci LA. A Prospective Study of the Association between Physical Activity and Risk of Prostate Cancer Defined by Clinical Features and TMPRSS2:ERG. Eur Urol 2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Wright JL, Chery L, Holt S, Lin DW, Luedeke M, Rinckleb AE, Maier C, Stanford JL. Aspirin and NSAID use in association with molecular subtypes of prostate cancer defined by TMPRSS2:ERG fusion status. Prostate cancer and prostatic diseases 2016;19:53–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Geybels MS, McCloskey KD, Mills IG, Stanford JL. Calcium Channel Blocker Use and Risk of Prostate Cancer by TMPRSS2:ERG Gene Fusion Status. Prostate 2017;77:282–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Cuzick J, Yang ZH, Fisher G, Tikishvili E, Stone S, Lanchbury JS, Camacho N, Merson S, Brewer D, Cooper CS, Clark J, Berney DM, Moller H, Scardino P, Sangale Z. Prognostic value of PTEN loss in men with conservatively managed localised prostate cancer. Br J Cancer 2013;108:2582–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Lotan TL, Heumann A, Rico SD, Hicks J, Lecksell K, Koop C, Sauter G, Schlomm T, Simon R. PTEN loss detection in prostate cancer: comparison of PTEN immunohistochemistry and PTEN FISH in a large retrospective prostatectomy cohort. Oncotarget 2017;8:65566–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Han B, Mehra R, Lonigro RJ, Wang L, Suleman K, Menon A, Palanisamy N, Tomlins SA, Chinnaiyan AM, Shah RB. Fluorescence in situ hybridization study shows association of PTEN deletion with ERG rearrangement during prostate cancer progression. Mod Pathol 2009;22:1083–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Lotan TL, Gurel B, Sutcliffe S, Esopi D, Liu W, Xu J, Hicks JL, Park BH, Humphreys E, Partin AW, Han M, Netto GJ, Isaacs WB, De Marzo AM. PTEN protein loss by immunostaining: analytic validation and prognostic indicator for a high risk surgical cohort of prostate cancer patients. Clin Cancer Res 2011;17:6563–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Yoshimoto M, Cunha IW, Coudry RA, Fonseca FP, Torres CH, Soares FA, Squire JA. FISH analysis of 107 prostate cancers shows that PTEN genomic deletion is associated with poor clinical outcome. Br J Cancer 2007;97:678–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Yoshimoto M, Joshua AM, Cunha IW, Coudry RA, Fonseca FP, Ludkovski O, Zielenska M, Soares FA, Squire JA. Absence of TMPRSS2:ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome. Mod Pathol 2008;21:1451–60. [DOI] [PubMed] [Google Scholar]
- 23.Giovannucci E, Liu Y, Platz EA, Stampfer MJ, Willett WC. Risk factors for prostate cancer incidence and progression in the Health Professionals Follow-up Study. Int J Cancer 2007;121:1571–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Ahearn TU, Pettersson A, Ebot EM, Gerke T, Graff RE, Morais CL, Hicks JL, Wilson KM, Rider JR, Sesso HD, Fiorentino M, Flavin R, Finn S, Giovannucci EL, Loda M, Stampfer MJ, De Marzo AM, Mucci LA, Lotan TL. A prospective investigation of PTEN loss and ERG expression in lethal prostate cancer. J Natl Cancer Inst 2016;108. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Lunn M, McNeil D. Applying Cox regression to competing risks. Biometrics 1995;51:524–32. [PubMed] [Google Scholar]
- 26.Glynn RJ, Rosner B. Comparison of risk factors for the competing risks of coronary heart disease, stroke, and venous thromboembolism. Am J Epidemiol 2005;162:975–82. [DOI] [PubMed] [Google Scholar]
- 27.Hoffmann TJ, Van Den Eeden SK, Sakoda LC, Jorgenson E, Habel LA, Graff RE, Passarelli MN, Cario CL, Emami NC, Chao CR, Ghai NR, Shan J, Ranatunga DK, Quesenberry CP, Aaronson D, Presti J, Wang Z, Berndt SI, Chanock SJ, McDonnell SK, French AJ, Schaid DJ, Thibodeau SN, Li Q, Freedman ML, Penney KL, Mucci LA, Haiman CA, Henderson BE, Seminara D, Kvale MN, Kwok PY, Schaefer C, Risch N, Witte JS. A large multiethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences. Cancer Discov 2015;5:878–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Yoo S, Pettersson A, Jordahl KM, Lis RT, Lindstrom S, Meisner A, Nuttall EJ, Stack EC, Stampfer MJ, Kraft P, Brown M, Loda M, Giovannucci EL, Kantoff PW, Mucci LA. Androgen receptor CAG repeat polymorphism and risk of TMPRSS2:ERG-positive prostate cancer. Cancer Epidemiol Biomarkers Prev 2014;23:2027–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Farrell J, Young D, Chen Y, Cullen J, Rosner IL, Kagan J, Srivastava S, Mc LD, Sesterhenn IA, Srivastava S, Petrovics G. Predominance of ERG-negative high-grade prostate cancers in African American men. Mol Clin Oncol 2014;2:982–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Magi-Galluzzi C, Tsusuki T, Elson P, Simmerman K, LaFargue C, Esgueva R, Klein E, Rubin MA, Zhou M. TMPRSS2-ERG gene fusion prevalence and class are significantly different in prostate cancer of Caucasian, African-American and Japanese patients. Prostate 2011;71:489–97. [DOI] [PubMed] [Google Scholar]
- 31.Zhou CK, Young D, Yeboah ED, Coburn SB, Tettey Y, Biritwum RB, Adjei AA, Tay E, Niwa S, Truelove A, Welsh J, Mensah JE, Hoover RN, Sesterhenn IA, Hsing AW, Srivastava S, Cook MB. TMPRSS2:ERG gene fusions in prostate cancer of West African men and a meta-analysis of racial differences. Am J Epidemiol 2017;186:1352–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Jacobsen PB, Lamonde LA, Honour M, Kash K, Hudson PB, Pow-Sang J. Relation of family history of prostate cancer to perceived vulnerability and screening behavior. Psychooncology 2004;13:80–5. [DOI] [PubMed] [Google Scholar]
- 33.McDowell ME, Occhipinti S, Chambers SK. The influence of family history on cognitive heuristics, risk perceptions, and prostate cancer screening behavior. Health Psychol 2013;32:1158–69. [DOI] [PubMed] [Google Scholar]
- 34.Bratt O, Garmo H, Adolfsson J, Bill-Axelson A, Holmberg L, Lambe M, Stattin P. Effects of prostate-specific antigen testing on familial prostate cancer risk estimates. J Natl Cancer Inst 2010;102:1336–43. [DOI] [PubMed] [Google Scholar]
- 35.Chen YC, Page JH, Chen R, Giovannucci E. Family history of prostate and breast cancer and the risk of prostate cancer in the PSA era. Prostate 2008;68:1582–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Paquette EL, Sun L, Paquette LR, Connelly R, McLeod DG, Moul JW. Improved prostate cancer-specific survival and other disease parameters: impact of prostate-specific antigen testing. Urology 2002;60:756–9. [DOI] [PubMed] [Google Scholar]
- 37.Carroll P, Coley C, McLeod D, Schellhammer P, Sweat G, Wasson J, Zietman A, Thompson I. Prostate-specific antigen best practice policy--part I: early detection and diagnosis of prostate cancer. Urology 2001;57:217–24. [DOI] [PubMed] [Google Scholar]
- 38.Clegg LX, Li FP, Hankey BF, Chu K, Edwards BK. Cancer survival among US whites and minorities: a SEER (Surveillance, Epidemiology, and End Results) Program population-based study. Arch Intern Med 2002;162:1985–93. [DOI] [PubMed] [Google Scholar]
- 39.Tosoian JJ, Almutairi F, Morais CL, Glavaris S, Hicks J, Sundi D, Humphreys E, Han M, De Marzo AM, Ross AE, Tomlins SA, Schaeffer EM, Trock BJ, Lotan TL. Prevalence and prognostic significance of PTEN loss in African-American and European-American men undergoing radical prostatectomy. Eur Urol 2017;71:697–700. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Parsons R Human cancer, PTEN and the PI-3 kinase pathway. Semin Cell Dev Biol 2004;15:171–6. [DOI] [PubMed] [Google Scholar]
- 41.Whang YE, Wu X, Suzuki H, Reiter RE, Tran C, Vessella RL, Said JW, Isaacs WB, Sawyers CL. Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci U S A 1998;95:5246–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Zhou XP, Gimm O, Hampel H, Niemann T, Walker MJ, Eng C. Epigenetic PTEN silencing in malignant melanomas without PTEN mutation. Am J Pathol 2000;157:1123–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Nip H, Dar AA, Saini S, Colden M, Varahram S, Chowdhary H, Yamamura S, Mitsui Y, Tanaka Y, Kato T, Hashimoto Y, Shiina M, Kulkarni P, Dasgupta P, Imai-Sumida M, Tabatabai ZL, Greene K, Deng G, Dahiya R, Majid S. Oncogenic microRNA-4534 regulates PTEN pathway in prostate cancer. Oncotarget 2016;7:68371–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Poliseno L, Salmena L, Riccardi L, Fornari A, Song MS, Hobbs RM, Sportoletti P, Varmeh S, Egia A, Fedele G, Rameh L, Loda M, Pandolfi PP. Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation. Sci Signal 2010;3:ra29. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Singh G, Chan AM. Post-translational modifications of PTEN and their potential therapeutic implications. Curr Cancer Drug Targets 2011;11:536–47. [DOI] [PubMed] [Google Scholar]
- 46.Gumuskaya B, Gurel B, Fedor H, Tan HL, Weier CA, Hicks JL, Haffner MC, Lotan TL, De Marzo AM. Assessing the order of critical alterations in prostate cancer development and progression by IHC: further evidence that PTEN loss occurs subsequent to ERG gene fusion. Prostate cancer and prostatic diseases 2013;16:209–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Bismar TA, Yoshimoto M, Duan Q, Liu S, Sircar K, Squire JA. Interactions and relationships of PTEN, ERG, SPINK1 and AR in castration-resistant prostate cancer. Histopathology 2012;60:645–52. [DOI] [PubMed] [Google Scholar]
- 48.Liu W DNA alterations in the tumor genome and their associations with clinical outcome in prostate cancer. Asian J Androl 2016;18:533–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Nam RK, Sugar L, Yang W, Srivastava S, Klotz LH, Yang LY, Stanimirovic A, Encioiu E, Neill M, Loblaw DA, Trachtenberg J, Narod SA, Seth A. Expression of the TMPRSS2:ERG fusion gene predicts cancer recurrence after surgery for localised prostate cancer. Br J Cancer 2007;97:1690–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Reid AH, Attard G, Ambroisine L, Fisher G, Kovacs G, Brewer D, Clark J, Flohr P, Edwards S, Berney DM, Foster CS, Fletcher A, Gerald WL, Moller H, Reuter VE, Scardino PT, Cuzick J, de Bono JS, Cooper CS. Molecular characterisation of ERG, ETV1 and PTEN gene loci identifies patients at low and high risk of death from prostate cancer. Br J Cancer 2010;102:678–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Data Availability Statement
The data that support the findings of this study are available on request. The data are not publicly available due to privacy or ethical restrictions.