Role of genetic testing for inherited prostate cancer risk: Philadelphia prostate cancer consensus conference 2017

Purpose: Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-dri

The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma

We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) based on multidimensional and comprehensive characterization, including mitochondrial DNA (mtDNA) and whole genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared to other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT up-regulation in cancer distinct from previously-observed amplifications and point mutations

Whole-genome analysis of papillary kidney cancer finds significant noncoding alterations

<div><p>To date, studies on papillary renal-cell carcinoma (pRCC) have largely focused on coding alterations in traditional drivers, particularly the tyrosine-kinase, Met. However, for a significant fraction of tumors, researchers have been unable to determine a clear molecular etiology. To address this, we perform the first whole-genome analysis of pRCC. Elaborating on previous results on <i>MET</i>, we find a germline SNP (rs11762213) in this gene predicting prognosis. Surprisingly, we detect no enrichment for small structural variants disrupting <i>MET</i>. Next, we scrutinize noncoding mutations, discovering potentially impactful ones associated with <i>MET</i>. Many of these are in an intron connected to a known, oncogenic alternative-splicing event; moreover, we find methylation dysregulation nearby, leading to a cryptic promoter activation. We also notice an elevation of mutations in the long noncoding RNA <i>NEAT1</i>, and these mutations are associated with increased expression and unfavorable outcome. Finally, to address the origin of pRCC heterogeneity, we carry out whole-genome analyses of mutational processes. First, we investigate genome-wide mutational patterns, finding they are governed mostly by methylation-associated C-to-T transitions. We also observe significantly more mutations in open chromatin and early-replicating regions in tumors with chromatin-modifier alterations. Finally, we reconstruct cancer-evolutionary trees, which have markedly different topologies and suggested evolutionary trajectories for the different subtypes of pRCC.</p></div

Evolutionary trees and genomic alteration landscape of 35 pRCC WGS samples.

<p><b>(A)</b> Two individual evolutions trees. Mutations in cancer-related gene are shown in colors corresponding to where they first appear. <b>(B)</b> Summary table of alterations in 35 pRCC WGS. Index: patient index, see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006685#pgen.1006685.s009" target="_blank">S2 table</a>.</p

Noncoding alterations in <i>ERRFI1</i> and <i>NEAT1</i>.

<p><b>(A)</b> A schematic diagram of noncoding mutations discovered in <i>ERRFI1</i>. <b>(B)</b> A schematic diagram of noncoding mutations discovered in <i>NEAT1</i>. One tumor carries two mutations on <i>NEAT1</i>. <b>(C)</b> Tumors with mutations in <i>NEAT1</i> show higher <i>NEAT1</i> expression. <b>(D)</b> Survival analysis shows mutations in <i>NEAT1</i> are associated with worse prognosis. Log-rank test.</p

Patient clinical profiles of the type II pRCC cohort in rs11762213 survival analysis.

<p>AJCC: American Joint Committee on Cancer; IQR: interquartile range; NA: not available. Percentages may not add up to 100% because of rounding.</p

Mutation spectra and mutation processes in pRCC.

<p><b>(A)</b> The mutation spectrum of all pRCC WGS samples. Mutations are ordered in alphabetical order of the reference trinucleotides (with the mutated nucleotide in the middle, from A[C>A]A to T[T>G]T) from left to right. Lower panel; we used PCA to maximize inter-sample variation. The loadings on the first principle component are dominated by C>T in CpGs. <b>(B)</b> PC1, C>T in CpGs mutation counts and the percentages of such mutations among total mutations are significantly different between two methylation clusters. <b>(C)</b> APOBEC mutation signatures are shown for both pRCC (along with three UC samples, blue outer circles) and ccRCC TCGA cohorts. Red dashed line represents the median APOBEC enrichment. <b>(D)</b> Mutation counts, mutations counts in open chromatin regions and the percentages of mutations in open chromatin regions are significantly higher in tumors with chromatin remodeling gene alterations compared to the ones without.</p

MET Expression in Primary and Metastatic Clear Cell Renal Cell Carcinoma: Implications of Correlative Biomarker Assessment to MET Pathway Inhibitors

Aims. Inhibitors of the MET pathway hold promise in the treatment for metastatic kidney cancer. Assessment of predictive biomarkers may be necessary for appropriate patient selection. Understanding MET expression in metastases and the correlation to the primary site is important, as distant tissue is not always available. Methods and Results. MET immunofluorescence was performed using automated quantitative analysis and a tissue microarray containing matched nephrectomy and distant metastatic sites from 34 patients with clear cell renal cell carcinoma. Correlations between MET expressions in matched primary and metastatic sites and the extent of heterogeneity were calculated. The mean expression of MET was not significantly different between primary tumors when compared to metastases (P=0.1). MET expression weakly correlated between primary and matched metastatic sites (R=0.5) and a number of cases exhibited very high levels of discordance between these tumors. Heterogeneity within nephrectomy specimens compared to the paired metastatic tissues was not significantly different (P=0.39). Conclusions. We found that MET expression is not significantly different in primary tumors than metastatic sites and only weakly correlates between matched sites. Moderate concordance of MET expression and significant expression heterogeneity may be a barrier to the development of predictive biomarkers using MET targeting agents

Neoadjuvant targeted therapy and advanced kidney cancer: observations and implications for a new treatment paradigm.

International audienceOBJECTIVE To evaluate our early experience with neoadjuvant therapy (sunitinib or sorafenib) in advanced renal cell carcinoma (RCC), to explore the effect on both tumour biology and potential for downstaging advanced tumours, as systemic therapy for RCC has historically resulted in little if any primary tumour response, but recent experience with targeted therapy suggests otherwise. PATIENTS AND METHODS The preliminary experience with neoadjuvant therapy for the surgical management of RCC was reviewed at two large referral centres. Several unique patients were identified who had a novel response to systemic therapy that altered the surgical strategy. RESULTS Four patients who had targeted therapy before surgery are described and in whom there were effects on tumour biology not seen previously with chemotherapy and cytokine therapy. The selected patients who had neoadjuvant targeted therapy had shrinkage of a tumour thrombus in the inferior vena cava, nodal involvement, renal fossa recurrence and tumour within a solitary kidney. CONCLUSIONS The introduction of new molecular agents has revolutionized the treatment of patients with metastatic RCC. Responses to targeted therapy within the primary tumour, tumour thrombus, renal fossa recurrence, and lymph node metastases are novel findings not seen during treatment with immunotherapeutic-based strategies. This might be a signal for urological surgeons to re-evaluate the paradigm for the surgical management of advanced RCC. Potential applications are presented to encourage further investigations with targeted therapy in the neoadjuvant setting