Understanding the Impact of Belzutifan on Treatment Strategies for Patients with VHL

Belzutifan was recently approved for the management of Von Hippel–Lindau disease (VHL). Given the morbidity of recurrent treatment, systemic therapy to reduce or eliminate the need for surgery has been long-awaited. Herein, we sought to gain insight about future utilization by surveying VHL  experts in the United States. A survey developed by members of the VHL Alliance (VHLA) Clinical Advisory Council was distributed to kidney cancer providers at VHLA and National Comprehensive Cancer Network (NCCN) centers. Surveys were administered on a secure web-based platform. A total of 60 respondents from 29 institutions participated. Urologists (50%) and medical oncologists (43%) represented the majority of participants. The majority (98%) of respondents anticipated that belzutifan’s approval would signifi-cantly change the current treatment landscape. Most reported that therapy should be continuous (76%). There was a difference in willingness to prescribe belzutifan by specialty (38% of urologists vs 91% of medical oncologists (P = 0.02). In individuals with renal tumors <3 cm, 36% would still recommend surveillance, while 36% would initiate belzutifan to prevent growth. In those with multifocal renal lesions and growth of a solitary tumor on belzutifan, 50% would proceed with only treatment of that site. In conclusion, VHL kidney cancer specialists anticipate a paradigm shift with the approval of belzutifan. Provider roles may change with movement away from surgical management. Opinions on treatment indications, such as when to initiate therapy and how to best salvage, vary widely and collaborative efforts among experts may assist in the development of clinical guidelines

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