Young-Age Prostate Cancer
Ethnic differences in prostate cancer incidence and outcome may result from the interaction of epidemiological and genetic factors. The highest reported incidence rate for prostate cancer is among African-American and Jamaican men of African descent. It is well recognised that black men are at a higher risk of being diagnosed with advanced stage prostate cancer at a young age. African-American men present their prostate cancer 2–3 years earlier than white Caucasian men. Powell et al reported more advanced disease and more frequent biochemical recurrence among young African-American compared with Caucasian men. Their recent (2014) analysis of SEER data demonstrated that African-American men at the age of 40–49 years had higher Gleason score and 2.8–3.2 times higher mortality and metastatic disease compared with American men of European descent of the same age group. These observations suggest a higher incidence of aggressive and rapidly growing early-onset prostate cancer in American-African men. The authors of this study speculated that the aggressiveness of prostate cancer in African-American men may be due to increased expression of genes associated with lethal prostate cancer like fatty acid synthase gene and higher expression of inflammatory cytokines, such as interleukin 6 (IL6), IL8 and IL 1B.
Familial clustering of prostate carcinoma is the strongest determinant for prostate cancer risk. About 5%–10% of prostate cancers are hereditary and show a Mendelian pattern of inheritance just like in breast and colon cancer. The familial prostate cancer manifests at a younger age, usually 6–7 years earlier than sporadic disease and the risk of (familial) prostate cancer increases when a family member develops the disease at a younger age. If a father is diagnosed with prostate cancer prior to 60 years of age, the relative risk (RR) for developing prostate cancer increases from 1.5 to 2.5. The RR increases to four times when there are two or more affected first-degree relatives, diagnosed at any age (RR=4.39; 95% CI 2.61 to 7.39).
Genome wide association studies have revealed several single nucleotide polymorphisms in the germline DNA associated with an increased risk of prostate cancer, including a few associated with young-age prostate cancer. However, highly penetrant susceptibility genes causing young-age or early-onset prostate cancer have not yet been identified. Some of the rare genetic predisposition loci with small-to-moderate penetrance contributing to young-age prostate cancer are summarised in Table 1.
Carriers of the BRCA 1 and 2 mutations are at risk for breast carcinomas and several other carcinomas. Although there is controversy about the increased risk of BRCA1 carriers for prostate cancer, all studies consistently reported that BRCA2 carriers have increased risk of more aggressive prostate cancer at younger age. The strongest predictors for the presence of a germline mutation of BRCA2 genes in patients with prostate cancer are a young age at onset and a family history of breast and/or ovarian cancer. Nevertheless, its contribution to young-age prostate cancer is limited. BRCA2 mutation is only found in 2% of prostate cancer cases diagnosed at the age of ≤55 years. On the other hand, in their study of 263 men with a known BRCA mutation, BRCA2 carriers had an estimated 23-fold increased risk of prostate cancer in men aged <55 years. Furthermore, Kote-Jarai et al reported an RR of 1.8-fold to 4.5-fold for BRCA1 carriers and 2.5-fold to 8.6-fold increase for BRCA2 carriers at the age of ≤65 years. Similarly, the Icelandic founder mutation BRCA2 999del5 is a specific mutation associated with prostate cancer at younger age and with poor survival.BRCA1/2 carriers have been shown to present with early-onset and aggressive disease, characterised by higher rates of lymph node involvement, distant metastasis at diagnosis and a higher mortality rate as compared with non-carriers. Histology of patient-derived xenografts from BRCA2 mutation carriers, high-risk breast cancer BRCA negative families and sporadic prostate cancer cases revealed that a substantial proportion of them carried the features of intraductal carcinoma (figure 1) in association with conventional acinar adenocarcinoma. Thus, BRCA2 mutation carriers displayed the histopathological features of intraductal carcinoma in 14/33 cases (42%) as compared with patients with BRCX (16/62, 25.8%) and sporadic prostate cancer cases (3/32, 9%). Moreover, 64% of the BRCA2 carriers with intraductal carcinoma of the prostate had T3–T4 disease and poor outcome even after treatment with curative intent, in line with its more aggressive biology.
(Enlarge Image)
Figure 1.
Histopathology of intraductal carcinoma (arrows) as can be identified in about 42% of BRCA2-associated prostate cancers.
Ewing et al identified a rare but recurrent germline mutation c.252G–>A (p.G84E, rs138213197), in the first exon of the homeobox B13 associated with increased risk of non-aggressive prostate cancer at young age and with positive family history. The mutation is primarily seen in West European people; however, different HOXB13 mutations have been detected in prostate cancer cases of African and Asian ancestry. A carrier frequency of G84E mutation among European–American with young-age familial prostate cancer was found to be 3.1%, but its frequency was threefold higher (8.4%) for both the Finnish and Swedish population. Although uncommon, this mutation accounts for an eightfold increased risk of prostate cancer diagnosis at the age of 55 years or less. This mutation was found to be more associated with hereditary prostate cancer (OR: 6.6; 95% CI 3.3 to 12.0).HOXB13 interacts with androgen receptors (ARs) to promote development and differentiation of normal and cancerous prostate. It may act both as a tumour suppressor gene and as an oncogene, but the exact mechanism of HOXB13 in carcinogenesis remains unknown. In a Finnish population, HOXB13 G84E mutation was associated with young age (<55 years), familial prostate cancer and elevated PSA of 20 ng/mL or more at the time of diagnosis. However, it was not associated with other clinical features related to disease aggressiveness, such as higher Gleason score, prostate cancer progression or recurrence. Review of the histomorphological features and molecular subtypes of prostatectomy specimens in 23 patients with prostate cancer with HOXB13 G84E mutation carriers revealed a more frequent occurrence of (Gleason pattern 3) pseudohyperplastic-variant carcinoma (figure 2) and a markedly low prevalence of ERG+ cancers (17% of dominant tumour foci). The majority of the cases had Gleason score 7 prostate cancer (54%), whereas 23% were Gleason score 6 and 14% Gleason score >8. Their findings suggest that this could be a novel molecular pathway for carcinogenesis in HOXB13 carriers with more favourable outcome.
(Enlarge Image)
Figure 2.
An example of pseudohyperplastic variant of prostate cancer, characteristic for HOXB13-associated prostate cancers.
The molecular basis of young-age prostate cancer is not yet understood. The integrative genomic analysis of 11 early-onset prostate cancer cases by Weischenfeldt et al revealed a key role of the androgen–androgen receptor axis as reflected by an increased frequency of the androgen regulated transmembrane serine protease 2 (TMPRSS2) gene fusion with the ERG gene in these cancers. This fusion is a very early event in prostate carcinogenesis and thought to be driven by increased androgen stimulation, The age dependency of ERG expression was further confirmed in this study using a tissue micro array of a large number of prostatectomy samples, including low-risk prostate cancers. In addition, the young-age prostate cancers demonstrated a significantly increased tumour AR level and positive correlation of AR levels with ERG rearrangements. The authors suggested a specific pathogenesis for young-age prostate cancers, distinct from the classical elderly-onset prostate cancers, although their proliferative kinetics as judged from the MIB-1 labelling index were the same as in elderly-onset prostate cancer. In a separate study, Schaefer et al analysed ERG protein overexpression in 1039 radical prostatectomy specimen in a PSA screened population and they similarly found a much higher frequency of ERG+ prostate cancer for the age group of 35–55 years (ie, 64%) as compared with 41% in the age group of 56–67 years. The ERG-positive status was significantly associated with young age at diagnosis, low-serum PSA and lower prostate volume but not with disease progression or biochemical tumour recurrence. Huang et al analysed ERG protein overexpression in a cohort of 121 men diagnosed with localised prostate cancer at <50 years of age and reported similar high frequency (64%) of ERG-positive prostate cancers. In this study, the ERG-positive status was significantly associated with Gleason score and higher biochemical relapse rate but not with presurgical PSA levels, tumour volume, pathological stage, surgical margin or lymphovascular invasion. Steurer et al further confirmed the strong age dependency of TMPRSS2–ERG fusion for Gleason score <7 (4+3) cancers in young patients, while this age dependency was lost for higher Gleason score prostate cancers. In the same patient series, the age-dependent loss of the PTEN suppressor gene was only observed in ERG-positive prostate cancers, while the age-dependent loss of 5q21 and 6q15 was only noted in ERG-negative prostate cancers. The latter findings may be interpreted as evidence for a distinct genomic pathway of young-age TMPRSS2–ERG fusion positive and negative prostate cancers, the former pathway being the more dominant in low-grade young-age prostate cancers.
Risk Factors
Ethnicity
Ethnic differences in prostate cancer incidence and outcome may result from the interaction of epidemiological and genetic factors. The highest reported incidence rate for prostate cancer is among African-American and Jamaican men of African descent. It is well recognised that black men are at a higher risk of being diagnosed with advanced stage prostate cancer at a young age. African-American men present their prostate cancer 2–3 years earlier than white Caucasian men. Powell et al reported more advanced disease and more frequent biochemical recurrence among young African-American compared with Caucasian men. Their recent (2014) analysis of SEER data demonstrated that African-American men at the age of 40–49 years had higher Gleason score and 2.8–3.2 times higher mortality and metastatic disease compared with American men of European descent of the same age group. These observations suggest a higher incidence of aggressive and rapidly growing early-onset prostate cancer in American-African men. The authors of this study speculated that the aggressiveness of prostate cancer in African-American men may be due to increased expression of genes associated with lethal prostate cancer like fatty acid synthase gene and higher expression of inflammatory cytokines, such as interleukin 6 (IL6), IL8 and IL 1B.
Familial Prostate Cancer
Familial clustering of prostate carcinoma is the strongest determinant for prostate cancer risk. About 5%–10% of prostate cancers are hereditary and show a Mendelian pattern of inheritance just like in breast and colon cancer. The familial prostate cancer manifests at a younger age, usually 6–7 years earlier than sporadic disease and the risk of (familial) prostate cancer increases when a family member develops the disease at a younger age. If a father is diagnosed with prostate cancer prior to 60 years of age, the relative risk (RR) for developing prostate cancer increases from 1.5 to 2.5. The RR increases to four times when there are two or more affected first-degree relatives, diagnosed at any age (RR=4.39; 95% CI 2.61 to 7.39).
Susceptibility Genes
Genome wide association studies have revealed several single nucleotide polymorphisms in the germline DNA associated with an increased risk of prostate cancer, including a few associated with young-age prostate cancer. However, highly penetrant susceptibility genes causing young-age or early-onset prostate cancer have not yet been identified. Some of the rare genetic predisposition loci with small-to-moderate penetrance contributing to young-age prostate cancer are summarised in Table 1.
BRCA Gene Mutations
Carriers of the BRCA 1 and 2 mutations are at risk for breast carcinomas and several other carcinomas. Although there is controversy about the increased risk of BRCA1 carriers for prostate cancer, all studies consistently reported that BRCA2 carriers have increased risk of more aggressive prostate cancer at younger age. The strongest predictors for the presence of a germline mutation of BRCA2 genes in patients with prostate cancer are a young age at onset and a family history of breast and/or ovarian cancer. Nevertheless, its contribution to young-age prostate cancer is limited. BRCA2 mutation is only found in 2% of prostate cancer cases diagnosed at the age of ≤55 years. On the other hand, in their study of 263 men with a known BRCA mutation, BRCA2 carriers had an estimated 23-fold increased risk of prostate cancer in men aged <55 years. Furthermore, Kote-Jarai et al reported an RR of 1.8-fold to 4.5-fold for BRCA1 carriers and 2.5-fold to 8.6-fold increase for BRCA2 carriers at the age of ≤65 years. Similarly, the Icelandic founder mutation BRCA2 999del5 is a specific mutation associated with prostate cancer at younger age and with poor survival.BRCA1/2 carriers have been shown to present with early-onset and aggressive disease, characterised by higher rates of lymph node involvement, distant metastasis at diagnosis and a higher mortality rate as compared with non-carriers. Histology of patient-derived xenografts from BRCA2 mutation carriers, high-risk breast cancer BRCA negative families and sporadic prostate cancer cases revealed that a substantial proportion of them carried the features of intraductal carcinoma (figure 1) in association with conventional acinar adenocarcinoma. Thus, BRCA2 mutation carriers displayed the histopathological features of intraductal carcinoma in 14/33 cases (42%) as compared with patients with BRCX (16/62, 25.8%) and sporadic prostate cancer cases (3/32, 9%). Moreover, 64% of the BRCA2 carriers with intraductal carcinoma of the prostate had T3–T4 disease and poor outcome even after treatment with curative intent, in line with its more aggressive biology.
(Enlarge Image)
Figure 1.
Histopathology of intraductal carcinoma (arrows) as can be identified in about 42% of BRCA2-associated prostate cancers.
HOXB13 Mutations
Ewing et al identified a rare but recurrent germline mutation c.252G–>A (p.G84E, rs138213197), in the first exon of the homeobox B13 associated with increased risk of non-aggressive prostate cancer at young age and with positive family history. The mutation is primarily seen in West European people; however, different HOXB13 mutations have been detected in prostate cancer cases of African and Asian ancestry. A carrier frequency of G84E mutation among European–American with young-age familial prostate cancer was found to be 3.1%, but its frequency was threefold higher (8.4%) for both the Finnish and Swedish population. Although uncommon, this mutation accounts for an eightfold increased risk of prostate cancer diagnosis at the age of 55 years or less. This mutation was found to be more associated with hereditary prostate cancer (OR: 6.6; 95% CI 3.3 to 12.0).HOXB13 interacts with androgen receptors (ARs) to promote development and differentiation of normal and cancerous prostate. It may act both as a tumour suppressor gene and as an oncogene, but the exact mechanism of HOXB13 in carcinogenesis remains unknown. In a Finnish population, HOXB13 G84E mutation was associated with young age (<55 years), familial prostate cancer and elevated PSA of 20 ng/mL or more at the time of diagnosis. However, it was not associated with other clinical features related to disease aggressiveness, such as higher Gleason score, prostate cancer progression or recurrence. Review of the histomorphological features and molecular subtypes of prostatectomy specimens in 23 patients with prostate cancer with HOXB13 G84E mutation carriers revealed a more frequent occurrence of (Gleason pattern 3) pseudohyperplastic-variant carcinoma (figure 2) and a markedly low prevalence of ERG+ cancers (17% of dominant tumour foci). The majority of the cases had Gleason score 7 prostate cancer (54%), whereas 23% were Gleason score 6 and 14% Gleason score >8. Their findings suggest that this could be a novel molecular pathway for carcinogenesis in HOXB13 carriers with more favourable outcome.
(Enlarge Image)
Figure 2.
An example of pseudohyperplastic variant of prostate cancer, characteristic for HOXB13-associated prostate cancers.
Pathway Analysis
The molecular basis of young-age prostate cancer is not yet understood. The integrative genomic analysis of 11 early-onset prostate cancer cases by Weischenfeldt et al revealed a key role of the androgen–androgen receptor axis as reflected by an increased frequency of the androgen regulated transmembrane serine protease 2 (TMPRSS2) gene fusion with the ERG gene in these cancers. This fusion is a very early event in prostate carcinogenesis and thought to be driven by increased androgen stimulation, The age dependency of ERG expression was further confirmed in this study using a tissue micro array of a large number of prostatectomy samples, including low-risk prostate cancers. In addition, the young-age prostate cancers demonstrated a significantly increased tumour AR level and positive correlation of AR levels with ERG rearrangements. The authors suggested a specific pathogenesis for young-age prostate cancers, distinct from the classical elderly-onset prostate cancers, although their proliferative kinetics as judged from the MIB-1 labelling index were the same as in elderly-onset prostate cancer. In a separate study, Schaefer et al analysed ERG protein overexpression in 1039 radical prostatectomy specimen in a PSA screened population and they similarly found a much higher frequency of ERG+ prostate cancer for the age group of 35–55 years (ie, 64%) as compared with 41% in the age group of 56–67 years. The ERG-positive status was significantly associated with young age at diagnosis, low-serum PSA and lower prostate volume but not with disease progression or biochemical tumour recurrence. Huang et al analysed ERG protein overexpression in a cohort of 121 men diagnosed with localised prostate cancer at <50 years of age and reported similar high frequency (64%) of ERG-positive prostate cancers. In this study, the ERG-positive status was significantly associated with Gleason score and higher biochemical relapse rate but not with presurgical PSA levels, tumour volume, pathological stage, surgical margin or lymphovascular invasion. Steurer et al further confirmed the strong age dependency of TMPRSS2–ERG fusion for Gleason score <7 (4+3) cancers in young patients, while this age dependency was lost for higher Gleason score prostate cancers. In the same patient series, the age-dependent loss of the PTEN suppressor gene was only observed in ERG-positive prostate cancers, while the age-dependent loss of 5q21 and 6q15 was only noted in ERG-negative prostate cancers. The latter findings may be interpreted as evidence for a distinct genomic pathway of young-age TMPRSS2–ERG fusion positive and negative prostate cancers, the former pathway being the more dominant in low-grade young-age prostate cancers.