Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains and losses, including ETS gene family fusions, PTEN loss and androgen ...receptor (AR) amplification, which drive prostate cancer development and progression to lethal, metastatic castration-resistant prostate cancer (CRPC). However, less is known about the role of mutations. Here we sequenced the exomes of 50 lethal, heavily pre-treated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment-naive, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPCs (2.00 per megabase) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1 that define a subtype of ETS gene family fusion-negative prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in approximately one-third of CRPCs (commonly through TMPRSS2:ERG fusions), is also deregulated through mutation. Furthermore, we identified recurrent mutations in multiple chromatin- and histone-modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with the AR, which is required for AR-mediated signalling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC), and showed that mutated FOXA1 represses androgen signalling and increases tumour growth. Proteins that physically interact with the AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX (also known as KDM6A) and ASXL1 were found to be mutated in CRPC. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signalling deregulated in prostate cancer, and prioritize candidates for future study.
We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on ...the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.
Summary Papillary renal cell carcinoma (P-RCC) is the second most common type of malignant renal epithelial tumor and can be subclassified into type 1, which demonstrates simple cuboidal low-grade ...epithelium and type 2, which demonstrates pseudostratified high-grade epithelium with abundant eosinophilic cytoplasm. Despite this clinically useful subclassification, P-RCCs exhibit considerable histomorphologic diversity, with many cases having features differing from classically described type 1 and type 2 tumors. To our knowledge, there has been no recent study that has methodically evaluated the histomorphologic features of a series of P-RCCs. To address this, we evaluated a cohort of P-RCCs diagnosed between 1997 and 2004 with long-term clinical follow-up data (n = 56). Histomorphologic features previously described in the spectrum of type 1 and type 2 P-RCCs were recorded for each tumor, including nuclear grade, complete tumor capsule, and cytoplasmic eosinophilia as well as several other features. The current TNM staging (American Joint Committee on Cancer, seventh edition) was assigned to all cases. Histomorphologic features were diverse, demonstrating classic type 1 P-RCC and classic type 2 P-RCC morphology and several tumors with nonclassic features. Four patients in this cohort had distant metastasis. The primary tumor was equally divided between type 1 (2 cases) and type 2 (2 cases) morphology in the cases with metastasis. All P-RCC cases with metastases demonstrated presence of high nuclear grade and high tumor stage in the primary tumor. Cluster analysis using staging parameters and histomorphologic features divided tumors into 2 primary clusters. All primary tumors associated with metastasis were in the same cluster.
This study aimed to understand the differential levels of inflammatory chemokines in association with higher prostate cancer incidence and mortality in African American (AA) men than in Caucasians ...(CA).
The authors used a chemokine assay to simultaneously measure 40 chemokines and cytokines levels in the serum of preoperative prostate cancer patients and healthy controls of AA and CA races. Selected chemokines (CXCL2, CXCL5, and CCL23) serum level was validated in 211 serum samples from prostate cancer patients and healthy controls. Differential expression of CXCL5 and CCL23 was analyzed using immunohistochemistry in a representative cohort of prostate tumor tissues of AA and CA races.
Race-specific comparisons from 211 serum samples showed significantly higher levels of CXCL2 (control: 3104.0 pg/mL vs. cancer: 2451.0 pg/mL) and CXCL5 (control: 5189.0 pg/mL vs. cancer: 5459.0 pg/mL) in AA men than in CAs (CXCL2; control: 1155.0 pg/mL vs. cancer: 889.3 pg/mL, and CXCL5; control: 1183.0 pg/mL vs. cancer: 977.5 pg/mL). CCL23 differed significantly within and between the races with a lower level in AA cancer cases (454.5 vs. 966.6 pg/mL) than healthy controls (740.5 vs. 1263.0 pg/mL). Patient age, prostate-specific antigen, or Gleason scores were not significantly associated with these chemokines. Immunostaining for CXCL5 and CCL23 in a representative cohort of archival prostate tissues displayed significantly higher CXCL5 in prostate tumors than in adjacent benign tissues, whereas CCL23 was nondetectable in most of the analyzed tumor tissues.
Lower levels of CCL23 in AA prostate cancer patient sera and tumor tissues and high CXCL2 and CXCL5 may contribute to aggressive prostate cancer, as often seen in AA men. The disproportionate levels of serum chemokines associated with race warrant further exploration to improve equitability in precision oncology to benefit prostate cancer patients.
We present a series of 18 (8 clinically benign, 8 clinically ambiguous ie, lacking sufficient follow-up to determine behavior, and 2 clinically malignant) large cell calcifying Sertoli cell tumors ...(LCCSCT) of the testis. The median patient age and size were 15.5 years and 1.9 cm for the benign tumors; 19 years and 1.6 cm for the ambiguous tumors; and 28.5 years and 2.3 cm for the malignant tumors. The most common presentation was a mass (n=12/18, 67%). Two patients (11%) had the Carney complex, and 2 had neurofibromatosis type 1. All tumors showed nodular growth with frequent lymphoid aggregates at the periphery. Within the nodules, there were nests and trabeculae of pale to eosinophilic epithelioid tumor cells with frequent cytoplasmic vacuolization interspersed with hypocellular, often myxoid stroma with conspicuous neutrophils. Spindled tumor cells were a minor component (<5%) in the clinically benign, ambiguous, and malignant tumors, except in 1 malignant tumor where they comprised 50% to 60% of the cellularity. Calcifications were noted in all but 2 benign tumors that were otherwise of typical appearance. Six tumors (3 in the clinically benign, 1 in the clinically ambiguous, and 2 in the malignant groups) were considered potentially malignant based on the presence of ≥1 adverse pathologic features previously recognized (see reference 1)-that is, size>4 cm, extratesticular growth, necrosis, significant atypia, vascular invasion, and >3 mitotic figures/10 HPFs. Of these, 3 tumors had ≥2 adverse features. One in a 7-year-old was clinically benign despite 5 "malignant" features; the remaining 2 in 27- and 30-year-olds, were clinically malignant, with both fulfilling previously suggested criteria for pathologically malignant tumors (age above 25 y and ≥2 adverse pathologic features). No clinically benign or ambiguous tumor met those same criteria. Of the adverse features, each of the 2 clinically malignant tumors showed tumor necrosis and lymphovascular invasion. All patients, except 1 with a clinically malignant tumor, were alive at a median follow-up of 33 months. In addition, in our literature review of 97 additional LCCSCTs, we identified 2 clinically malignant tumors in 42- and 45-year-old men that lacked any documented adverse pathologic criterion and 2 clinically malignant cases in patients with either the Carney complex or Peutz-Jeghers syndrome. In summary, our study and literature review support that all LCCSCTs in patients above 25 years old should be considered potentially malignant, and those in this age group with ≥2 adverse pathologic features warrant aggressive clinical management; furthermore, syndrome-associated cases are not uniformly benign. Tumor necrosis and lymphovascular invasion likely should receive greater adverse prognostic weight. LCCSCTs in young children may show benign outcomes despite several adverse pathologic features.
Purpose We assess the accuracy of a biopsy directed treatment algorithm in correctly assigning active surveillance vs treatment in patients with small renal masses by comparing biopsy results with ...final surgical pathology. Materials and Methods From 1999 to 2011, 151 patients with small renal masses 4 cm or smaller underwent biopsy and subsequent surgical excision. Biopsy revealed cell type and grade in 133 patients, allowing the hypothetical assignment of surveillance vs treatment using an algorithm incorporating small renal mass size and histological risk group. We compared the biopsy directed management recommendation with the ideal management as defined by final surgical pathology. Results Biopsy called for surveillance of 36 small renal masses and treatment of 97 small renal masses. Final pathology showed 11 patients initially assigned to surveillance should have been assigned to treatment (8.3% of all patients, 31% of those recommended for surveillance), whereas no patients moved from treatment to surveillance. Agreement between biopsy and final pathology was 92%. Using management based on final pathology as the reference standard, biopsy had a negative predictive value of 0.69 and positive predictive value 1.0 for determining management. Of the 11 misclassified cases, 7 had a biopsy indicating grade 1 clear cell renal cancer which was upgraded to grade 2 (5) or grade 3 (2). After modifying the histological risk group assignment to account for undergrading of clear cell renal cancer, agreement improved to 97%, with a negative predictive value of 0.86 and a positive predictive value of 1.0. Conclusions Our results suggest that compared to final pathology, biopsy of small renal masses accurately informs an algorithm incorporating size and histological risk group that directs the management of small renal masses.
Abstract Objective To understand potential harms associated with delaying resection of small renal masses (SRMs) in patients ultimately treated, and whether these patients have factors associated ...with adverse pathology. Methods Patients with SRMs (≤4 cm) who underwent surgical resection at our institution (2009–2015) were classified as undergoing early resection or initial surveillance with delayed resection (defined by a time from presentation to intervention of at least 6 mo). Demographic and clinical variables were compared among groups. Using multivariable logistic regression, we examined the association between delayed resection and adverse pathology (Fuhrman grade 3−4, papillary type 2, sarcomatoid histology, angiomyolipoma with epithelioid features, or stage≥pT3). For patients who underwent delayed intervention, we used similar methods to examine the association between SRM growth rate and adverse pathology. Results Overall, 401 (81%) and 94 (19%) patients underwent early and delayed resection, respectively. Median time to resection was 84 days (interquartile range: 59−121) and 386 days (interquartile range: 272−702) ( P <0.001). Patients undergoing delayed resection were older (62 vs. 58 y, P = 0.01) and had smaller masses (2.3 vs. 2.7 cm, P <0.001) at initial presentation. Utilization of partial vs. radical nephrectomy was similar regardless of resection timing ( P = 0.5). Delayed resection was not associated with adverse pathology ( P = 0.8); however, male sex was independently associated with adverse pathology (odds ratio: 1.7, 95% CI: 1.1–2.4, P = 0.009). In patients on surveillance, increasing annual SRM growth rate was associated with adverse pathology (odds ratio: 1.2, 95% CI: 1.03–1.3mm/y, P = 0.02). Conclusions Delayed resection was not associated with adverse pathology. Patients on surveillance with increased SRM growth rates had a modest but significant increase in the risk of adverse pathology.
Serum prostate-specific antigen (PSA), used in prostate cancer screening, is nonspecific for cancer and is affected by age and prostate volume. More specific biomarkers could be more accurate for ...early detection of prostate cancer and reduce unnecessary prostate biopsies.
To evaluate the association of age and prostate volume with urinary MyProstateScore (MPS) in a screened, longitudinal cohort without evidence of prostate cancer.
The Olmsted County Study included men aged 40–79 yr who underwent biennial prostate cancer screening. PSA ≥4.0 ng/ml or abnormal rectal examination triggered prostate biopsy, and patients with cancer were excluded. The remaining men submitted urinary specimens for PCA3 and TMPRSS2:ERG testing.
MPS was calculated using the validated, locked model for grade group ≥2 cancer that includes serum PSA, urinary PCA3, and urinary TMPRSS2:ERG. The associations of age and volume with biomarkers were assessed in multivariable regression models. The t statistic was used to quantify the strength of associations independent of the unit of measurement, and R2 values were used to estimate the proportion of biomarker variance explained by each factor.
The study included 314 screened men without evidence of cancer. In multivariable models including age and volume, PCA3 score was significantly associated with age (t = 7.51; p < 0.001), while T2:ERG score was not associated with age or volume. MPS was significantly associated with both age (t = 7.45; p < 0.001) and volume (t = 3.56; p < 0.001), but accounting for age alone explained the variability observed (R2 = 0.29) in a similar way to the model including age and volume (R2 = 0.31). The variability of PCA3, T2:ERG, and MPS was less dependent on age and volume than the variability for PSA (R2 = 0.45).
In a cohort of longitudinally screened men without evidence of cancer, we found that MPS demonstrated less variability with noncancer factors (age, prostate volume) than PSA did. These findings support the biology of these markers as more cancer-specific than PSA and highlight their promise in reducing the morbidity associated with PSA-based screening.
In a group of men with no evidence of prostate cancer, we found that each of three urine-based markers of cancer—PCA3, T2:ERG, and the commercially available MyProstateScore test—showed less variability with noncancer factors (age and prostate volume) than serum PSA (prostate-specific antigen) did. These findings support their proposed use as noninvasive markers of prostate cancer that could improve the accuracy of early detection.
In a longitudinally screened population of men with no evidence of prostate cancer, the urine-based PCA3 score, T2:ERG score, and the composite MyProstateScore each demonstrated less variability with noncancer factors (age, prostate volume) than serum prostate-specific antigen (PSA) did. These findings are consistent with the cancer-specific biology of these markers and reflect their promise in reducing the morbidity associated with PSA-based early detection.
PDF
