Sporadic Prostate Cancer Research Articles

Abstract A031: Methylomic Biomarkers Associated with Prostate Cancer in Black Men

Abstract Introduction: The prostate cancer (PCa) disparity remains the highest cancer disparity in the US, with Black men facing an estimated 78% higher incidence and 230% higher mortality than White men. However, current understanding of risk factors for PCa such as socioeconomic status (SES), diet, and genetics cannot fully explain these disparities. Our objective is to examine DNA methylation (DNAm) markers in a cohort of Black men and assess their associations with PCa status. Methods: We randomly selected 100 Black men for DNAm profiling (50 cases diagnosed with clinically significant (Gleason Grade 3+) prostate cancer and 50 age-matched controls) from two larger cohorts. The cohorts recruited 400 Black men who were newly diagnosed with sporadic PCa as well as 400 controls matched on age and race. All men were 40-79 at recruitment and were enrolled from urology clinics at five Chicago-area medical institutions. All PCa cases underwent a transrectal prostate biopsy for abnormal prostate-specific antigen (PSA) or digital rectal exam and had a histologically confirmed prostate cancer and were not previously diagnosed with PCa. All men in the control group had been recruited from community prostate cancer screening events or were referred to participating urology clinics and had a negative prostate biopsy for a PSA <10ng/ml and were not diagnosed with PCa for 2 years of follow-up. Men with prior PCa diagnosis or conditions known to affect PSA levels were excluded. After enrollment and informed consent, all men provided demographic and lifestyle data via three questionnaires, followed by venipuncture for DNA collection. These specimens were obtained using buffy coat extraction after red blood cell lysis, centrifugation, and pipetting off the overlying plasma and buffy coat for freezing followed by Illumina EPIC arrays for DNAm assays. We examined DNAm markers in gene promoter regions associated with PCa using logistic regression and adjusted for multiple testing using Bonferroni correction. All models controlled for age, BMI, smoking status, first degree family history of PCa, blood cell types, and technical control variables. Results: We found 2,180 CpG sites in gene promoter regions associated with any PCa in this population. The top ten strongest associations identified in our models include loci on genes that have already been associated with prostate cancer progression (MAFG, FAM65B, OSM, PRKAG2), risk (SLC11A1, LAT), and metastasis (S1PR4) as well as immune system functioning (RAP1GAP2). Conclusions: Our initial findings suggest that DNAm markers may be useful predictors of clinically significant PCa status among Black men. Additional research is currently ongoing to expand the sample size of the DNAm profiling and to explore links between these loci and social determinants of health, as well as associations with more advanced (i.e., higher Gleason Grade) PCa. Citation Format: Brian T. Joyce, Yishu Qu, Jun Wang, Kai Zhang, Zequn Sun, Lifang Hou, Adam B. Murphy. Methylomic Biomarkers Associated with Prostate Cancer in Black Men [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A031.

SNPs-Panel Polymorphism Variations in GHRL and GHSR Genes Are Not Associated with Prostate Cancer.

Prostate cancer (PCa) is a major public health problem worldwide. Recent studies have suggested that ghrelin and its receptor could be involved in the susceptibility to several cancers such as PCa, leading to their use as an important predictive way for the clinical progression and prognosis of cancer. However, conflicting results of single nucleotide polymorphisms (SNPs) with ghrelin (GHRL) and its receptor (GHSR) genes were demonstrated in different studies. Thus, the present case-control study was undertaken to investigate the association of GHRL and GHSR polymorphisms with the susceptibility to sporadic PCa. A cohort of 120 PCa patients and 95 healthy subjects were enrolled in this study. Genotyping of six SNPs was performed: three tag SNPs in GHRL (rs696217, rs4684677, rs3491141) and three tag SNPs in the GHSR (rs2922126, rs572169, rs2948694) using TaqMan. The allele and genotype distribution, as well as haplotypes frequencies and linked disequilibrium (LD), were established. Multifactor dimensionality reduction (MDR) analysis was used to study gene-gene interactions between the six SNPs. Our results showed no significant association of the target polymorphisms with PCa (p > 0.05). Nevertheless, SNPs are often just markers that help identify or delimit specific genomic regions that may harbour functional variants rather than the variants causing the disease. Furthermore, we found that one GHSR rs2922126, namely the TT genotype, was significantly more frequent in PCa patients than in controls (p = 0.040). These data suggest that this genotype could be a PCa susceptibility genotype. MDR analyses revealed that the rs2922126 and rs572169 combination was the best model, with 81.08% accuracy (p = 0.0001) for predicting susceptibility to PCa. The results also showed a precision of 98.1% (p < 0.0001) and a PR-AUC of 1.00. Our findings provide new insights into the influence of GHRL and GHSR polymorphisms and significant evidence for gene-gene interactions in PCa susceptibility, and they may guide clinical decision-making to prevent overtreatment and enhance patients' quality of life.

Clinicopathological Features of Primary Small Cell Neuroendocrine Carcinoma of the Bladder

Objective To investigate the clinicopathological features,immunohistochemical features,diagnosis,and relationship with sporadic prostate cancer in primary small cell neuroendocrine carcinoma of the bladder. Methods We retrospectively analyzed the clinical characteristics of 12 patients with primary small cell neuroendocrine carcinoma of the bladder diagnosed at Beijing Chao-Yang Hospital affiliated to Capital Medical University from January 2013 to September 2022.The histological features of primary small cell neuroendocrine carcinoma of the bladder were re-evaluated by two pathologists according to the 2022 revision of the World Health Organization Classification of Tumors of the Urinary System and Male Genital Organs.Electronic medical records were retrieved,and telephone follow-up was conducted from the time of histopathological diagnosis to the death or the end of the last follow-up until January 31,2023. Results The 12 patients include 7 patients in pT3 stage and 1 patient in pT4 stage.Eight patients were complicated with other types of tumors,such as high-grade urothelial carcinoma of the bladder and squamous cell carcinoma.Five patients had sporadic prostate cancer.Immunohistochemical staining showed that 12 (100.0%),10 (83.3%),and 8 (66.7%) patients were tested positive for CD56,Syn,and CgA,respectively.The Ki67 proliferation index ranged from 80% to 90%.Five patients with urothelial carcinoma were tested positive for CK20,GATA3,and CK7.P504S was positive in all the 5 patients with prostate cancer,while P63 and 34βE12 were negative.The follow-up of the 12 patients lasted for 3-60 months.Eight of these patients died during follow-up,with the median survival of 15.5 months.Four patients survived. Conclusions Primary small cell neuroendocrine carcinoma of the bladder is a rare urological tumor with high aggressiveness and poor prognosis.In male patients with bladder prostatectomy,all prostate tissue should be sampled.If prostate cancer is detected,the prostate-specific antigen level should be monitored.

Multiple primary cancers in men with sporadic or familial prostate cancer: Its clinical implications.

To evaluate the risk of concordant cancers in patients with prostate cancer (CaP) and examine whether this risk differed according to family history of CaP. We examined 1,102 patients with CaP , having prospectively acquired pedigrees, and analyzed information regarding multiple primary cancers. The prevalence of concordant cancers was assessed with respect to the family history of CaP . First-degree familial CaP was defined as a positive history of CaP in first-degree relatives (parents, siblings, and offspring). Odds ratios for each concordant cancer in men with first-degree familial CaP were estimated. Clinical characteristics were compared between men with and without concordant cancers. The prevalence of multiple primary cancers in sporadic PCa was 12.0%, similar to that of first-degree familial CaP (13.5%, P = 0.698). Gastrointestinal cancer was the most common concordant cancer (3.6%), followed by colorectal (2.9%), lung (1.5%), urothelial (1.3%), kidney (1.1%), and other cancers. Colorectal cancer was more frequent in first-degree familial CaP than in sporadic disease (6.8 vs. 2.7%, P = 0.045). However, the rates of other concordant cancers were similar between the 2 groups (P range, 0.242-0.963). Compared with sporadic disease, the age-adjusted odds ratio for concordant colorectal cancer in first-degree familial CaP was 2.930 (95% confidence interval, 1.082-7.929). Patients with concordant colorectal cancer had fewer (2.8 vs. 3.9 cores, P = 0.041) and a lower percentage of (23.5 vs. 33.1%, P = 0.030) positive biopsy cores than CaP only patients. A family history of CaP was significantly associated with a risk of concordant colorectal cancer. These findings imply that some CaP shares a genetic pathogenesis with colorectal cancer.

Variants in HOXB13, G132E and F127C, Are Associated With Prostate Cancer Risk in Japanese Men.

Several studies have reported on the relationship between HOXB13 variants and an increased prostate cancer (PC) risk. To our knowledge there are not many studies on HOXB13 mutations in Japanese patients with prostate cancer, and there many issues remain uninvestigated. We herein clarified the association between HOXB13 genetic variants and PC risk in a Japanese population. PC patients were diagnosed at the Gunma University Hospital and affiliated hospitals from 1994 to 2016. Sanger sequencing was performed on the coding regions of the HOXB13 gene in 152 familial PC (FPC) patients. Genotyping was performed on single nucleotide variants (SNVs) found in Sanger sequencing in 230 FPC patients from 152 pedigrees and 197 sporadic PC (SPC) patients and 144 controls. Allelic frequency and clinical data for each variant were studied in cases and controls. G132E and F127C were identified in FPC patients. The frequencies of G132E and F127C were significantly higher compared to the control group (p=0.039). In three families, seven PC patients shared the G132E variant, within second-to-third-degree relatives. It was not possible to clarify to pathogenicity of each SNV alone. We found two significant variants of the HOXB13 gene, G132E, F127C by analyzing and comparing gene samples from PC and non-PC patients. Furthermore, the HOXB13 G132E variant was found significantly increased in the FPC group.

Tumor immune microenvironment of primary prostate cancer with and without germline mutations in homologous recombination repair genes

BackgroundAberrations in homologous recombination repair (HRR) genes are emerging as important biomarkers for personalized treatment in prostate cancer (PCa). HRR deficiency (HRD) could affect the tumor immune microenvironment (TIME), potentially...

Elevated Enhancer-Oncogene Contacts and Higher Oncogene Expression Levels By Recurrent CTCF inactivating Mutations in T Cell Acute Lymphoblastic Leukemia

Introduction. The CCCTC-binding factor (CTCF) regulates the 3D chromatin architecture by facilitating chromosomal loops and forming the boundaries of structural domains. In addition, CTCF is an important transcription factor and regulator of antigen receptor and T cell receptor recombination events. CTCF inactivating events have been found in various human cancers. Loss-of-heterozygosity (LOH) or inactivating missense mutations in specific zinc- fingers have been identified in many human cancers including sporadic breast cancer, prostate cancer, Wilms-tumors and acute lymphoblastic leukemia (ALL). Heterozygous deletions or point mutations have been identified in over half of the patients with breast cancer or uterine endometrial cancers, deregulating global gene expression by altering methylated genomic states and poor survival. Here, we investigated the functional significance and molecular-cytogenetic associations of CTCF aberrations in T-cell acute lymphoblastic leukemia patients.Methods. Biopsies from a cohort of 181 pediatric T-ALL patients who enrolled on DCOG or COALL protocols and/or their derivative patient-derived xenograft models were screened for alterations in global DNA copy number, methylation status, topologically associating domain organization and CTCF and cohesion binding patterns and changes in local TLX3 and BCL11B promoter enhancer loops using array-comparative genomic hybridization, single molecule Molecular Inversion Probe sequencing, targeted locus amplification, gene expression and DNA methylation microarrays, Hi-C sequencing, Chromatin Immunoprecipitation and/or real-time quantitative PCR. Ctcf f/fl mice 1 were crossed on a the Lck-cre transgenic background 2 to study the impact of Ctcf loss during early T-cell development.Results. We here describe that inactivation of CTCF can drive subtle and local genomic effects that elevate oncogene expression levels from driver chromosomal rearrangements. We find that for T cell acute lymphoblastic leukemia (T-ALL), heterozygous CTCF deletions or inactivating mutations are present in nearly 50 percent of t(5;14)(q35;q32.2) rearranged patients that positions the TLX3 oncogene in the vicinity of the BCL11B enhancer. Functional CTCF loss results in diminished expression of the αβ-lineage commitment factor BCL11B from the non-rearranged allele and γδ-lineage development. Unexpectedly, it also drives higher levels of the TLX3 oncogene from the translocated allele. We demonstrate that heterozygous CTCF aberrations specifically occur in TLX3-rearranged patients with distal breakpoints that preserve CTCF bindings sites in the translocation breakpoint areas in between the BCL11B enhancer and the TLX3 oncogene. We show that these intervening CTCF sites insulate TLX3 from the enhancer by forming competitive loops with TLX3. Upon loss of CTCF, or the deletion of the intervening CTCF sites, these competitive loops are weakened and loops with the BCL11B enhancer are stimulated, boosting TLX3 oncogene expression levels and leukemia burden in these T-ALL patients.Conclusions. CTCF aberrations are especially associated with t(5;14)(q35;q32.2) rearranged T-ALL patients who maintain TLX3-proximal CTCF sites reflects a necessity to neutralize these sites in order to topologically enable the distal BCL11B enhancer to interact with the TLX3 oncogene and to boost its expression. Collectively, this provides direct demonstration of a mechanism in which loss of CTCF result in removal of enhancer insulation that facilitates elevated levels of an oncogene in leukemia.References.1. Heath H, Ribeiro de Almeida C, Sleutels F, et al. CTCF regulates cell cycle progression of alphabeta T cells in the thymus. EMBO J. 2008;27(21):2839-2850.2. Lee PP, Fitzpatrick DR, Beard C, et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity. 2001;15(5):763-774. DisclosuresSplinter: Cergentis BV: Current Employment. Van Eyndhoven: Agilent Technologies Netherland: Current Employment. Van Min: Cergentis BV: Current Employment. Mullighan: Pfizer: Research Funding; Illumina: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Amgen: Current equity holder in publicly-traded company.

Familial prostate cancer and genetic predisposition

Twenty percent of all prostate cancer patients have apositive family history (at least 1first-degree relative with prostate cancer) and apart of these patients have agenetic predisposition. Aliterature search and analysis of studies investigating incidence, diagnosis, and clinical course of familial compared to sporadic prostate cancer as well as genetic predisposition was performed using PubMed and Embase. Risk of prostate cancer depends on number, degree of relationship, and age of onset of affected men in the family. The incidence of familial prostate cancer is higher and the age of diagnosis lower compared to sporadic cases. The clinical course of the disease is comparable, but in individuals with agermline mutation, more intensive therapy is needed due to amore aggressive disease. Crucial for risk assessment is adetailed family history, including creation of apedigree with cancer family history if necessary. In high-risk families, genetic counselling and annual prostate-specific antigen (PSA) screening beginning at the age of 40 should be performed. Verification of agermline mutation requires more intensive therapy due to more aggressive disease.

Prohibitin gene regulation in cancer and its possible therapeutic potential

Prohibitin (PHB), an evolutionary conserved gene, is mapped at the chromosomal location 17q21–q22 and is present with two isoforms, namely, PHB1 and PHB2. Both of these isoforms have their individual roles in tumor suppression and cell proliferation. The presence of these isoforms is not restricted to single cellular organelle but can be located in the nucleus, mitochondria, and cytosol. Importantly, loss of heterozygosity in the prohibitin gene has been noted in a significant number of different cancer types. Along with this, there are other mutations that contribute to tumorigenesis and cancer cell proliferation. Sporadic breast cancer, lung cancer, and prostate cancer are a few examples in which regulation of PHB plays a major role. PHB has shown to be both up-regulated and down-regulated depending on the type of cancer or disease. PHB acts as the biomarker for several types of cancers and is also seen as a potential therapeutic target. Along with cancer, PHB has also been seen to play an important role in other diseases such as neurological diseases, cardiac diseases, and renal diseases. The link between PHB and a plethora of diseases opens a new window in which PHB can be actually targeted in treatment as well as disease management. Here, we review the regulation of PHB in different types of cancers along with its significant interaction in other disorders.

Involvement of the MEN1 Gene in Hormone-Related Cancers: Clues from Molecular Studies, Mouse Models, and Patient Investigations

MEN1 mutation predisposes patients to multiple endocrine neoplasia type 1 (MEN1), a genetic syndrome associated with the predominant co-occurrence of endocrine tumors. Intriguingly, recent evidence has suggested that MEN1 could also be involved in the development of breast and prostate cancers, two major hormone-related cancers. The first clues as to its possible role arose from the identification of the physical and functional interactions between the menin protein, encoded by MEN1, and estrogen receptor α and androgen receptor. In parallel, our team observed that aged heterozygous Men1 mutant mice developed cancerous lesions in mammary glands of female and in the prostate of male mutant mice at low frequencies, in addition to endocrine tumors. Finally, observations made both in MEN1 patients and in sporadic breast and prostate cancers further confirmed the role played by menin in these two cancers. In this review, we present the currently available data concerning the complex and multifaceted involvement of MEN1 in these two types of hormone-dependent cancers.

Loss of DNA mismatch repair proteins in prostate cancer.

Recent studies have suggested an increased risk of prostate cancer in men with Lynch syndrome driven by germline mutations in mismatch repair (MMR) genes. However, the incidence and clinical implication of MMR deficiency in sporadic prostate cancers remain poorly understood. We immunohistochemically stained for MLH1, MSH2, MSH6, and PMS2 in a set of tissue microarray consisting of 220 radical prostatectomy specimens and evaluated the relationship between loss of their expression and available clinicopathological features. MLH1, MSH2, MSH6, and PMS2 were lost in 2 (0.9%), 6 (2.7%), 37 (16.8%), and 27 (12.3%) prostate cancers, respectively. Loss of at least 1 MMR protein was identified in 50 (22.7%) cases. There were no statistically significant associations between MMR deficiency and patient age, family history of prostate cancer, Gleason score, or pT/pN stage. Nonetheless, the levels of preoperative prostate-specific antigen (PSA) were significantly (P = .015) higher in patients with MMR deficiency (mean ± SD: 9.12 ± 9.01 ng/mL) than in those without abnormal MMR (5.76 ± 3.17 ng/mL). There were 15 (6.8%) cases showing loss of at least 2 MMR proteins, which was not significantly associated with PSA level or tumor grade/stage. Additionally, 5 and 2 cases showed losses of at least 3 MMR proteins and all 4 proteins, respectively. Kaplan–Meier analysis revealed no significant associations between loss of MLH1 (P = .373), MSH2 (P = .348), MSH6 (P = .946), or PMS2 (P = .681), or at least 1 (P = .477), 2 (P = .486), or 3 (P = .352) MMR proteins and biochemical recurrence. Further analyses of the data on programmed death-ligand 1 (PD-L1) expression previously stained in the same set of tissue microarray demonstrated associations between loss of ≥2 MMR proteins and a higher rate of PD-L1 expression in cancer cells (17.2% vs 5.2%; P = .033) as well as between cases showing both loss of ≥1 MMR protein(s) and PD-L1 expression in tumor-infiltrating immune cells vs a higher risk of biochemical recurrence (P = .045). MMR protein loss was seen in a subset of prostate cancers. Interestingly, it was associated with significantly higher levels of PSA. Moreover, immunohistochemical detection of MMR proteins together with other proteins, such as PD-L1, might be helpful in predicting tumor recurrence following radical prostatectomy.

The tumor immune microenvironment of germline BRCA1/2 and sporadic prostate cancer.

152 Background: Prostate cancer (PC) is considered an immunologically ‘cold’ tumor and therefore patients are generally not considered good candidates for immunotherapy. Tumors arising in germline (g) BRCA1/2 mutation carriers are associated with higher genomic instability and levels of immune infiltration in breast and ovarian cancer. We investigated how germline mutations in DNA repair genes affect the tumor immune microenvironment (TME) of PC. Methods: Archival primary tumor samples from 26 patients with g BRCA2 mutations, 5 with g BRCA1, 5 with mutations in other DNA repair genes ( ATM, CHEK2, FANCI, PALB2 or BRCA2+ MSH2), and 26 sporadic patients were analyzed. OPAL multiplex immunohistochemistry was used to detect 7 markers (CD3, CD4, CD8, FOXP3, PDL1, AMACR, DAPI) to identify immune subsets and provide the X,Y coordinates of single cells. We developed novel computational distance-based methods to characterize the spatial distribution of cells. Gene expression was evaluated with the Nanostring panel of 770 immune genes. Results: g BRCA1/2 carriers showed lower levels of T cells (9.73% of the tumor stroma) compared to sporadic tumors (14.8%). In in both cothors the T cell population was dominated by CD4+ cells (69.5%), with CD8+ cells representing only 25.6%. Sporadic PCs displayed aggregation of T cells into large clusters in the stroma dominated by CD4+ cells and few CD8+ cells, while 77% of high-grade g BRCA2 patients were enriched in high levels of free, non-aggregated CD8+ T-cells in the tumor area. HLA-A expression was 2.37 times higher in g BRCA2 patients ( p = 3.4x10−8), who also showed higher expression of genes associated with a present but suppressed immune system ( p = 1.4x10−4). gBRCA2 patients with larger T-cell aggregates had an overall poorer prognosis compared to patients without (time to metastasis 55.1 vs. 85.3 months, survival time 67.3 vs. 85.0 months). Conclusions: g BRCA2 carriers displayed higher levels of HLA-A, more free CD8+ T cells infiltrating tumor regions and higher inflammatory signatures, suggesting an immune system that could potentially be harnessed. The degree of clustering of T cells (free vs. aggregated) within the TME may provide valuable prognostic information that warrants further validation.

Family history in primary hormone therapy for prostate cancer: Analysis from a community-based multi-institutional Japan-wide database.

To determine the association between hormone therapy and outcomes in a cohort of prostate cancer patients with a family history of prostate cancer. Data of patients with prostate cancer who had received hormone therapy were extracted from a nationwide community-based database established by the Japan Study Group for Prostate Cancer. Family history of prostate cancer was available for 13346 of these patients, who thus comprised the study cohort. Prognostic variables, including progression-free survival, cancer-specific survival and overall survival, were compared between men with familial and men with sporadic prostate cancer. A positive family history was identified in 220 patients (1.6%). Patients with a positive family history were younger than those without; however, other clinicopathological characteristics and prognoses were comparable. In subgroup analysis, family history was identified as a possible favorable prognostic factor for overall survival among patients with a prostate-specific antigen level at diagnosis <100ng/mL and those with low or intermediate Japan Cancer of the Prostate Risk Assessment. Our findings show that familial prostate cancer has an early-onset feature or is diagnosed earlier than sporadic prostate cancer. However, the prognosis of individuals with familial prostate cancer undergoing hormone therapy is comparable to those with sporadic prostate cancer.

Clinical and pathologic characteristics of familial prostate cancer in Asian population.

We investigated prevalence of familial and hereditary prostate cancer (PCa) in Asian population, and compared clinical characteristics between familial and sporadic disease. Pedigrees of 1102 patients who were treated for PCa were prospectively acquired. Clinical and pathologic characteristics and biochemical recurrence (BCR)-free survival were compared between familial PCa and sporadic PCa in patients who underwent radical prostatectomy (RP; n = 751). The prevalence of familial, first-degree familial, and hereditary PCa was found to be 8.4%, 6.7%, and 0.9%, respectively; similar result was obtained in patients who underwent RP (8.4%, 6.4%, and 0.9%). Patients with familial PCa were significantly younger than those with sporadic PCa (63.3 vs 65.6 years; P = .015). However, preoperative variables (prostate-specific antigen, clinical stage, biopsy Gleason score [GS], and percentage of positive biopsy cores) and postoperative variables (surgical GS, upgrading rate, pathologic stage, and percentage of tumor volume) did not correlate with family history (P range: .114-.982). Kaplan-Meier analysis of 5-year BCR-free survival revealed no significant difference between sporadic (82.7%), familial (89.4%; P = .594), and first-degree familial (87.1%; P = .774) PCa. Analysis of p53, Bcl-2, Ki67, and other immunohistochemistry biomarkers revealed that only increasing p53 expression and first-degree familial PCa approached significance (P = .059). The prevalence of familial PCa was somewhat lower in the Asian population than in other ethnic groups. Clinical and pathologic variables and selected histologic biomarker abnormalities were not significantly different in patients with and without a family history of PCa. BCR-free survival following RP was also unaffected by family history.

Family history in primary hormone therapy for prostate cancer from a community-based multi-institutional Japan-wide database.

e16549 Background: Although a positive family history is known to increase the risk of morbidity of prostate cancer, little is known about the prognoses with hormone therapy of individuals with familial prostate cancer. Thus, in this study we aimed to determine the associations between hormone therapy and outcomes of a cohort of men with familial prostate cancer from a large community-based multi-institutional Japan-wide registry. Methods: Data of patients with prostate cancer who had received hormone therapy were extracted from a nationwide community-based database established by the Japan Study Group for Prostate Cancer. Family history of prostate cancer was available for 15,873 of these patients, who thus comprised the study cohort. Prognostic variables, including progression-free survival, cancer-specific survival, and overall survival, were compared between men with familial and men with sporadic prostate cancer. Results: A positive family history was identified in 247 patients (1.6%). Patients with a positive family history were younger than those without; however, other clinicopathological characteristics and prognoses were comparable. In subgroup analysis, family history was identified as a significant favorable prognostic factor for progression-free survival among patients treated by castration, as was overall survival among patients with PSA level at diagnosis less than 100 ng/mL and those with low or intermediate J-CAPRA risk. Conclusions: Our findings indicate that familial prostate cancer has an early-onset feature or is diagnosed earlier than sporadic prostate cancer. However, with hormone therapy the prognoses of individuals with familial prostate cancer are comparable to those of individuals with sporadic prostate cancer.

Abstract B100: High-risk pathologic and genomic features of BRCA2-mutant prostate cancer

Abstract Germline BRCA mutations are associated with an increased risk of developing aggressive prostate cancer with poor clinical outcomes. However, the mechanisms by which BRCA mutations contribute to clinical aggressiveness are not completely understood. Previously, we showed that BRCA2-mutant prostate cancers often have intraductal carcinoma of the prostate (IDC-P), a distinct growth pattern of prostate cancer that is associated with adverse clinical features. Despite this, IDC-P is not routinely reported in pathology and its functional significance remains poorly understood. Thus, we investigated the clinical relevance of IDC-P as well as the underlying molecular features of localised BRCA2-mutant prostate cancers with and without IDC-P. To define the prevalence of IDC-P across cohorts of sporadic and familial prostate cancer, we conducted a systematic review in accordance with PRISMA guidelines. This analysis of over 7,000 patient specimens revealed that the prevalence of IDC-P rises from 2.1% in low-risk cohorts to 56% in cohorts with metastatic/recurrent disease. Since these data showed that IDC-P is a prominent feature of high-risk prostate cancer, we next studied the biologic features of IDC-P using patient-derived xenografts (PDXs). PDXs were established from three patients with germline BRCA mutations and compared to PDXs from four high-risk sporadic cases. IDC-P was successfully grown within the PDXs, maintaining its characteristic morphologic features for up to 800 days. Using classical castration-hormone regeneration experiments, we showed that IDC-P contains a subset of “castrate-tolerant” cells that persist after androgen deprivation and subsequently regenerate the tumor. Notably, we found that PDXs derived from BRCA-mutant tumors have the same response to androgen deprivation as sporadic cases. To further investigate the aggressiveness of BRCA2-mutant tumors, we profiled the genomes and methylomes of localized prostate cancers from 14 germline BRCA2-mutation carriers and compared them to 200 sporadic prostate cancers. BRCA2-mutant prostate cancers had elevated genomic instability and global hypomethylation compared to sporadic tumors. In addition, some genomic features of BRCA2-mutant tumors more closely resembled metastatic than localized disease. Importantly, negative prognostic factors were enriched in BRCA2-mutant prostate cancers harboring IDC-P. Sequencing of macrodissected IDC-P and invasive carcinoma revealed that these two pathologies arise from a common tumor clone and diverge later in tumor evolution. In summary, this work demonstrates that IDC-P pathology and genomic instability are two high-risk features of localized BRCA2-mutant prostate cancers. Given the high prevalence of IDC-P in high-risk patient cohorts, including BRCA2-mutation carriers, IDC-P warrants greater recognition and reporting as this may improve patient risk stratification. Citation Format: Laura H. Porter, Mitchell G. Lawrence, Carmel Pezaro, Heather Thorne, Dragan Ilic, Melissa Papargiris, Michael Fraser, Julie Livingstone, Declan G. Murphy, Mark Frydenberg, Damien Bolton, Daniel Moon, David Clouston, Theo van der Kwast, Paul C. Boutros, Robert G. Bristow, Renea A. Taylor, Gail P. Risbridger. High-risk pathologic and genomic features of BRCA2-mutant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B100.

Landscape of CDKN1B Mutations in Luminal Breast Cancer and Other Hormone-Driven Human Tumors.

The CDKN1B gene encodes for the p27Kip1 protein, firstly characterized as a cyclin dependent kinase (CDK)-inhibitor. Germline CDKN1B pathogenic variants have been described in hereditary tumors, such as multiple endocrine neoplasia (MEN)-like syndromes and familial prostate cancer. Despite its central role in tumor progression, for a long time it has been proposed that CDKN1B was very rarely somatically mutated in human cancer and that its expression levels were almost exclusively regulated at post-transcriptional level. Yet, the advent of massive parallel sequencing has partially subverted this general understanding demonstrating that, at least in some types of cancer, CDKN1B is mutated in a significant percentage of analyzed samples. Recent works have demonstrated that CDKN1B can be genetically inactivated and this occurs particularly in sporadic luminal breast cancer, prostate cancer and small intestine neuroendocrine tumors. However, a clear picture of the extent and significance of CDKN1B mutations in human malignances is still lacking. To fill this gap, we interrogated the COSMIC, ICGC, cBioPortal, and TRANSFAC data portals and current literature in PubMed, and reviewed the mutational spectrum of CDKN1B in human cancers, interpreting the possible impact of these mutations on p27Kip1 protein function and tumor onset and progression.

Association between Krüppel like factor 6 intervening sequence 1-27 G > A and cancer susceptibility: A meta-analysis.

It has been reported that Krüppel like factor 6 intervening sequence (KLF6 IVS) 1-27 G > A might be associated with cancer susceptibility. Here, we conducted a meta-analysis to summarize and clarify this association. A systematic search of studies on the association between KLF6 IVS 1-27 G > A, and cancer susceptibility was conducted in databases. Odds ratios and 95% confidence intervals were used to pool the effect size. Seven articles were included in our meta-analysis. Overall and in prostate cancer, population-based subgroup overall and Caucasian subgroup overall, no evidence was found for the association between KLF6 IVS 1-27 G > A polymorphism and cancer susceptibility in any genetic model and the results showed stability in sensitivity analyses. KLF6 IVS 1-27 G > A may not be associated with cancer susceptibility, especially the susceptibility of unselected prostate cancer. However, there was insufficient data to fully confirm the association between KLF6 IVS 1-27 G > A and familial prostate cancer, sporadic prostate cancer, gastric cancer, and cancers from different ethnicity, and the results should be interpreted with caution.

Clinical characteristics and prognosis influencing factors analysis of bladder resection of the prostate in sporadic prostate cancer

Objective To investigate clinical characteristics and prognosis influencing factors of the bladder resection of the prostate in sporadic prostate cancer. Methods A total of 165 patients with sporadic prostate cancer who underwent bladder resection of the prostate from September 2008 to September 2013 in our hospital were selected as the research object. The influence of prognosis of bladder resection of the prostate in sporadic prostate carcinoma were analyzed by methods of single factor analysis and multifactor analysis with sporadic prostate cancer clinical characteristics. Results The IPCa confined to the prostate in, pT1 was 65.45%(108/165), pT2 was 31.52%(52/165), and the pT3 was 3.03%(5/165), Gleason score less than 6 points was 36.97%(61/165), six points was 33.33%(55/165), seven points was 25.45%(42/165), and 4.24%(7/165) more than 7 points was found. All 4 cases of prostatic positive margin, lymph node metastasis of all the patients was negative. Single factor analysis and multiple factor analysis showed that the factors affecting the prognosis of patients were age, anxiety and disease stage. Conclusions In bladder resection of the prostate, clinical characteristics of sporadic prostate cancer are lymph node metastasis negative IPCa confined to the prostate in and more pT1. Gleason scores are mainly concentrated in less than seven points, there is the potential of prostatic positive margin. Age, disease stage and anxiety are risk factors of sporadic prostate cancer prognosis for bladder resection of the prostate. Key words: Prostatic Neoplasms; Cystectomy; Prostatectomy; Prognosis

Men with family history of prostate cancer have a higher risk of disease recurrence after radical prostatectomy.

We aimed to determine if family history (FH) of prostate cancer (PC) influenced cancer control after radical prostatectomy (RP). Patients were evaluated in a prospectively-collected PC family database: The focus was on hereditary prostate cancer (HPC) defined by Johns Hopkins criteria and sporadic prostate cancer (SPC), rigorously defined by absence of prostate cancer in≥2 brothers aged≥60years. Additionally, patients with first-degree (FPC) and non-first-degree PC (non-FPC) were assessed. Endpoints were biochemical recurrence-free survival (BRFS) and prostate cancer-specific survival (CSS). Finally, clinico-pathological characteristics were compared and multiple proportional hazards regression was used to identify prognostic factors. In total 11,654 patients were included (807 HPC, 2251 FPC, 8072 non-FPC and 524 SPC). Familial imposition (HPC/FPC) was associated with a younger age at diagnosis. Thus, HPC patients were diagnosed 2.9years earlier than SPC patients with more locally advanced tumors (≥pT3). With a median follow up of 6.2years (range 0-31.5) BRFS was significantly different when stratified by FH. In pairwise analyses BRFS differed significantly for HPC compared to SPC (HR=1.27). Consecutively FH was identified as prognostic factor for BRFS (p=0.021) together with age, PSA, pathologic characteristics and adjuvant androgen deprivation. Analyses of CSS did not show a difference. Patients with FH of PC are likely to be diagnosed earlier and present a higher proportion of locally advanced disease. In addition, men with FH are at higher risk of biochemical recurrence after surgery but reveal similar outcomes regarding prostate cancer-specific survival.