The homologous recombination deficiency (HRD) score integrates three DNA-based measures of genomic instability, and has been understudied in prostate cancer. Given the recent FDA approval of two PARP ...inhibitors for prostate cancer, HRD score analysis could help to refine treatment selection. We assessed HRD score (defined as the sum of loss-of-heterozygosity, telomeric allelic imbalance, and large-scale state transitions) in three cohorts of primary prostate cancer, including a Johns Hopkins University (JHU) cohort with germline mutations in BRCA2, ATM, or CHEK2 (n = 64), the TCGA cohort (n = 391), and the PROGENE cohort (n = 102). In the JHU cohort, tumors with germline BRCA2 mutations had higher HRD scores (median = 27) than those with germline ATM or CHEK2 mutations (median = 16.5 p = 0.029 and 9 p < 0.001, respectively). For TCGA tumors without underlying HR pathway mutations, the median HRD score was 11, significantly lower than ovarian carcinoma lacking BRCA1/2 mutations (median = 28). In the absence of HR gene mutations, the median HRD score was unexpectedly higher among prostate cancers with TP53 mutations versus those without (17 vs. 11; p = 0.015); this finding was confirmed in the PROGENE cohort (24 vs. 16; p = 0.001). Finally, among eight BRCA2-altered patients who received olaparib, progression-free survival trended longer in those with HRD scores above versus below the median (14.9 vs. 9.9 months). We conclude that HRD scores are low in primary prostate cancer and higher in cases with germline BRCA2 or somatic TP53 mutations. Germline BRCA2-altered cases have significantly higher HRD scores than germline ATM-altered or CHEK2-altered cases, consistent with the lower efficacy of PARP inhibitors among the latter.
Black men die more often of prostate cancer yet, interestingly, may derive greater survival benefits from immune-based treatment with sipuleucel-T. Since no signatures of immune-responsiveness exist ...for prostate cancer, we explored race-based immune-profiles to identify vulnerabilities. Here we show in multiple independent cohorts comprised of over 1,300 patient samples annotated with either self-identified race or genetic ancestry, prostate tumors from Black men or men of African ancestry have increases in plasma cell infiltrate and augmented markers of NK cell activity and IgG expression. These findings are associated with improved recurrence-free survival following surgery and nominate plasma cells as drivers of prostate cancer immune-responsiveness.
The mechanistic target of rapamycin complex 1 (mTORC1) integrates inputs from growth factors and nutrients, but how mTORC1 autoregulates its activity remains unclear. The MiT/TFE transcription ...factors are phosphorylated and inactivated by mTORC1 following lysosomal recruitment by RagC/D GTPases in response to amino acid stimulation. We find that starvation-induced lysosomal localization of the RagC/D GAP complex, FLCN:FNIP2, is markedly impaired in a mTORC1-sensitive manner in renal cells with TSC2 loss, resulting in unexpected TFEB hypophosphorylation and activation upon feeding. TFEB phosphorylation in TSC2-null renal cells is partially restored by destabilization of the lysosomal folliculin complex (LFC) induced by FLCN mutants and is fully rescued by forced lysosomal localization of the FLCN:FNIP2 dimer. Our data indicate that a negative feedback loop constrains amino acid-induced, FLCN:FNIP2-mediated RagC activity in renal cells with constitutive mTORC1 signaling, and the resulting MiT/TFE hyperactivation may drive oncogenesis with loss of the TSC2 tumor suppressor.
Noninvasive approaches for early detection of bladder cancer are actively being investigated. We recently developed a urine- based molecular assay for the detection and surveillance of bladder ...neoplasms (UroSEEK). UroSEEK is designed to detect alterations in 11 genes that include most common genetic alterations in bladder cancer. In this study, we analyzed 527 cases, including 373 noninvasive and 154 invasive urothelial carcinomas of bladder from transurethral resections or cystectomies performed at four institutions (1991-2016). Two different mutational analysis assays of a representative tumor area were performed: first, a singleplex PCR assay for evaluation of the TERT promoter region (TERTSeqS) and second, a multiplex PCR assay using primers designed to amplify regions of interest of 10 (FGFR3, PIK3CA, TP53, HRAS, KRAS, ERBB2, CDKN2A, MET, MLL, and VHL) genes (UroSeqS). Overall, 92% of all bladder tumors were positive for at least one genetic alteration in the UroSEEK panel. We found TERT promoter mutations in 77% of low-grade noninvasive papillary carcinomas, with a relatively lower incidence of 65% in high-grade noninvasive papillary carcinomas and carcinomas in situ; p = 0.017. Seventy-two percent of pT1 and 63% of muscle-invasive bladder tumors harbored TERT promoter mutations with g.1295228C>T alteration being the most common in all groups. FGFR3 and PIK3CA mutations were more frequent in low-grade noninvasive papillary carcinomas compared with high-grade noninvasive papillary carcinomas and carcinomas in situ (p < 0.0001), while the opposite was true for TP53 (p < 0.0001). Significantly higher rates of TP53 and CDKN2A mutation rates (p = 0.005 and 0.035, respectively) were encountered in muscle-invasive bladder tumors compared with those of pT1 stage. The overwhelming majority of all investigated tumors showed at least one mutation among UroSEEK assay genes, confirming the comprehensive coverage of the panel and supporting its potential utility as a noninvasive urine-based assay.
The prognostic significance of the Gleason grading system has been well established. However, individual Gleason patterns comprise heterogeneous morphologies which might add additional prognostic ...information. Recent evidence suggests that Gleason pattern 4 with cribriform growth pattern is associated with an adverse prognosis. To determine the association between cribriform pattern on biopsies and pathological findings on subsequent prostatectomies, we evaluated the presence of cribriform architecture in a prospective cohort of 367 men from 2014 to 2018 treated at a single institution. Cribriform architecture was present in 63.5% of all biopsies and was correlated with the overall extent of Gleason pattern 4. In addition, cribriform morphology on biopsy showed a statistically significant association with higher Gleason grade and increased pathological stage and nodal metastasis. In a subset analysis of cases with Grade Group 2 (Gleason score 3 + 4, n = 208), these associations did not reach statistical significance, but the presence of cribriform growth in this subgroup showed a trend toward increased upgrading to Grade Group 5 (Gleason score 9/10) (1 0.5% vs. 5 2.4%, P = 0.06). This large prospective study comparing biopsy and prostatectomy finding of cribriform architecture demonstrates that cribriform pattern 4 is associated with adverse prognostic features and highlights the relevance for recognizing specific morphologies with distinct biological and clinical features.
The grading and prognosis of prostatic adenocarcinoma with Paneth cell–like differentiation (PanEC) is controversial with limited available data. We identified 80 cases, not previously published, of ...PanEC first identified on biopsy (n = 69), transurethral resection of the prostate (n = 1), and radical prostatectomy (RP) (n = 10). Of 69 biopsies, 22 did not have a grade assigned. In the remaining 47 biopsies, the Grade Groups (GGs) of the associated usual prostatic adenocarcinoma were GG1–2 (n = 34) and GG3–5 (n = 13). Of 10 RPs, the GGs were as follows: GG1–2 (n = 8), GG4 (n = 1), and no grade due to treatment effect (n = 1); pathological stages were pT2 (n = 8) and pT3a (n = 2), all with negative lymph nodes. We analyzed 19 cases with available follow-up only associated with GG1–2 conventional cancer; 9 underwent RP, and GGs at RP were as follows: GG1–2 (n = 7), no grade due to treatment effect (n = 1), and missing data (n = 1); pathologic stages were pT2 (n = 6) and pT3a (n = 3); there were no positive regional lymph nodes; 3 were managed with active surveillance, without follow-up progression; 5 patients underwent radiation therapy with or without hormone therapy; none showed follow-up progression; 2 (10.5%) patients were recommended to undergo radiotherapy, with no further follow-up. Of the cases with available follow-up, 9 were not associated with conventional adenocarcinoma; the majority of these cases were treated with radiation therapy or active surveillance without evidence of progression. In summary, although a minority of PanECs are associated with conventional higher grade adenocarcinoma and have progression after treatment, the majority have favorable findings, justifying the consideration of them as more indolent tumors despite cases in which PanEC resembles Gleason pattern 5 adenocarcinoma.
Patients diagnosed with high risk localized prostate cancer have variable outcomes following surgery. Trials of intense neoadjuvant androgen deprivation therapy (NADT) have shown lower rates of ...recurrence among patients with minimal residual disease after treatment. The molecular features that distinguish exceptional responders from poor responders are not known.
To identify genomic and histologic features associated with treatment resistance at baseline.
Targeted biopsies were obtained from 37 men with intermediate- to high-risk prostate cancer before receiving 6 mo of ADT plus enzalutamide. Biopsy tissues were used for whole-exome sequencing and immunohistochemistry (IHC).
We assessed the relationship of molecular features with final pathologic response using a cutpoint of 0.05 cm3 for residual cancer burden to compare exceptional responders to incomplete and nonresponders. We assessed intratumoral heterogeneity at the tissue and genomic level, and compared the volume of residual disease to the Shannon diversity index for each tumor. We generated multivariate models of resistance based on three molecular features and one histologic feature, with and without multiparametric magnetic resonance imaging estimates of baseline tumor volume.
Loss of chromosome 10q (containing PTEN) and alterations to TP53 were predictive of poor response, as were the expression of nuclear ERG on IHC and the presence of intraductal carcinoma of the prostate. Patients with incompletely and nonresponding tumors harbored greater tumor diversity as estimated via phylogenetic tree reconstruction from DNA sequencing and analysis of IHC staining. Our four-factor binary model (area under the receiver operating characteristic curve AUC 0.89) to predict poor response correlated with greater diversity in our cohort and a validation cohort of 57 Gleason score 8–10 prostate cancers from The Cancer Genome Atlas. When baseline tumor volume was added to the model, it distinguished poor response to NADT with an AUC of 0.98. Prospective use of this model requires further retrospective validation with biopsies from additional trials.
A subset of prostate cancers exhibit greater histologic and genomic diversity at the time of diagnosis, and these localized tumors have greater fitness to resist therapy.
Some prostate cancer tumors do not respond well to a hormonal treatment called androgen deprivation therapy (ADT). We used tumor volume and four other parameters to develop a model to identify tumors that will not respond well to ADT. Treatments other than ADT should be considered for these patients.
A subset of patients present with high-risk localized prostate cancer that exhibits greater histologic and genomic diversity. These patients are less likely to respond to intense neoadjuvant androgen deprivation therapy.
Pathogenic mutations in homologous recombination (HR) DNA repair genes may be associated with increased tumor mutational burden and numbers of tumor-infiltrating lymphocytes (TIL). Though ...HR-deficient prostate tumors have been anecdotally associated with improved responses to immunotherapy, it is unclear whether HR mutations or HR deficiency (HRD) scores predict for increased T-cell densities in this cancer. We evaluated 17 primary prostate tumors from patients with pathogenic germline
BRCA2
mutations (g
BRCA2
) and 21 primary prostate tumors from patients with pathogenic germline
ATM
(g
ATM
) mutations, which were compared to 19 control tumors lacking HR gene mutations, as well as the TCGA prostate cancer cohort. HRD score was estimated by targeted sequencing (g
BRCA2
and g
ATM
) or by SNP microarray (TCGA). Tumor-associated T-cell densities were assessed using validated automated digital image analysis of CD8 and FOXP3 immunostaining (g
BRCA2
or g
ATM
) or by methylCIBERSORT (TCGA). CD8 + and FOXP3 + T-cell densities were significantly correlated with each other in g
BRCA2
and g
ATM
cases. There was no significant difference between CD8 + or FOXP3 + TIL densities in g
BRCA2
or g
ATM
cases compared to controls. In the TCGA cohort, HRD score was associated with predicted CD8 + and FOXP3 + TILs. Associations were also seen for HRD score and TIL density among the germline-mutated cases. In contrast to mismatch repair-deficient primary prostate tumors, cancers from germline
BRCA2
or
ATM
mutation carriers do not appear to be associated with elevated TIL density. However, measures of genomic scarring, such as HRD score, may be associated with increased tumor-infiltrating T-cells.
Intraductal (IDC) and cribriform (CRIB) histologies in prostate cancer have been associated with germline BRCA2 (gBRCA2) mutations in small retrospective series, leading to the recommendation of ...genetic testing for patients with IDC in the primary tumour.
To examine the association of gBRCA2 mutations and other tumour molecular features with IDC and/or cribriform (CRIB) histologies, we conducted a case–control study in which primary prostate tumours from 58 gBRCA2 carriers were matched (1:2) by Gleason Grade Group and specimen type to 116 non-carriers. Presence/absence of IDC and CRIB morphologies was established by two expert uropathologists blinded to gBRCA2 status. Fluorescent in-situ hybridization (FISH) and next-generation sequencing (NGS) were used to detect BRCA2 alterations, PTEN deletions and TMPRSS2-ERG fusions. Chi-squared tests were used to compare the frequency of IDC and CRIB in gBRCA2 carriers and controls and to assess associations with other variables. Logistic regression models were constructed to identify independent factors associated with both histology patterns.
No significant differences between gBRCA2 carriers and non-carriers were observed in the prevalence of IDC (36% gBRCA2 versus 50% non-carriers, p = 0.085) or CRIB (53% gBRCA2 versus 43% non-carriers p = 0.197) patterns. However, IDC histology was independently associated with bi-allelic BRCA2 alterations (OR 4.3, 95%CI 1.1–16.2) and PTEN homozygous loss (OR 5.2, 95%CI 2.1–13.1). CRIB morphology was also independently associated with bi-allelic BRCA2 alterations (OR 5.6, 95%CI 1.7–19.3).
While we found no association between gBRCA2 mutations and IDC or CRIB histologies, bi-allelic BRCA2 loss in primary prostate tumours was significantly associated with both variant morphologies, independently of other clinical-pathologic factors.
•Presence of gBRCA2 mutations was not associated with IDC and CRIB patterns.•Results do not support germline BRCA2 testing only based on presence of IDC and/or CRIB.•IDC and CRIB patterns were associated with bi-allelic BRCA2 alterations in our study.
PDF
