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Renal Cell Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Increasingly molecular biomarkers are likely to play a role in how patients are stratified for prognostic risk and appropriate treatments selected. The identification of loss of multiple tumor suppressor genes from chromosome 3p and other prevalent mutations in ccRCC has had implications both for the design of new treatments but also for providing information about prognosis. Identifying the molecular profile on an individual level is likely to provide greater information as RCC shows marked interpatient and intratumoral heterogeneity. Targeted sequencing of 341 cancer genes in 258 tumor samples from the RECORD-3 Trial identified the multiple common mutations in tumor suppressor genes including VHL (75%), PBRM1 (46%), SETD2 (30%), BAP1 (19%), KDM5C (15%), PTEN (12%).39 BAP1 mutations are seen to be associated with higher tumor grade and shorter overall survival; the prognostic role of PBRM1 is less clear but those with PBRM1 mutations are seen to do well on VEGF TKI, MTOR inhibitors, and checkpoint inhibitors. PBRM1 mutant patients had 12.8-month PFS on everolimus first line versus 5.5 months in wild type (WT) patients in RECORD3. BAP1 mutant patients did better with first-line sunitinib (4.9 months everolimus PFS versus 10.5 months). Those with KDM5C mutations demonstrated 20.6 months PFS on sunitinib first line versus 8.3 months with everolimus.39
Aicardi Syndrome and Klinefelter Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Gene dosage compensation involves genetic equalization through X-inactivation, which randomly silences one of the X-chromosomes in female cell and keeps the other X-chromosome transcriptionally active. In cases of X-chromosome aneuploidy, extra X-chromosome is similarly inactivated. However, two pseudoautosomal regions (PAR1 and PAR2) along with up to 15% of additional genes on the short arm of the X chromosome (Xp) escape inactivation and are expressed from both X-chromosomes. In males with Klinefelter syndrome, extra copies of these escapee genes are transcriptionally active, and their overexpressions modulate the related cellular and developmental pathways. Located at the terminal region of the short arms and consisting of 24 genes (including short-stature homeobox-containing gene on chromosome X or SHOX), PAR1 is required during male meiosis for X–Y chromosome pairing, a process which is known to have a critical function in spermatogenesis. PAR2 is situated at the tips of the long arms and contains four genes (Eif2s3x, Ddx3x, Kdm5c, Kdm6a).
Molecular characterization and diagnostic criteria of renal cell carcinoma with emphasis on liquid biopsies
Published in Expert Review of Molecular Diagnostics, 2020
Alessia Cimadamore, Francesco Massari, Matteo Santoni, Veronica Mollica, Vincenzo Di Nunno, Liang Cheng, Antonio Lopez-Beltran, Marina Scarpelli, Rodolfo Montironi, Holger Moch
The cancer genomic improvements in the understanding of RCC tumor biology have translational values in terms of refining risk-stratification schemes based not only on histotype and morphological-clinical parameters but also on molecular profile. The prognostic value of PBRM1, SETD2, BAP1, KDM5C, TP53, and TERT promoter mutations in ccRCC has previously been commented on [21–25]. Of note, these mutations have been studied also for their link to response to therapy. Genomic results from a randomized phase II clinical trial (RECORD-3) comparing first-line Everolimus (mTOR inhibitor) and Sunitinib (anti-VEGFR) in patients with metastatic RCC showed that, with first-line everolimus, patients with PBRM1 mutations experienced a longer (12.8 months) progression-free survival (PFS), compared to patients with BAP1 mutations (4.9 months). In patients treated with first-line sunitinib, KDM5C mutations were associated with longer PFS (20.6 mo) compared to PBRM1, and BAP1 mutations (11.0 and 8.1 mo, respectively) [42]. Remarkable responses in metastatic RCC patients were also obtained after VEGF-directed agents in patients harboring genetic alterations in KDM5C, PBRM1, and VHL with lower frequency of alterations associated with response to mTOR-directed therapy [43].
Somewhere over the sex differences rainbow of myocardial infarction remodeling: hormones, chromosomes, inflammasome, oh my
Published in Expert Review of Proteomics, 2019
Kristine Y. DeLeon-Pennell, Merry L. Lindsey
In a mouse model of ischemia and reperfusion, four genes were more highly expressed in the myocardium from XX relative to XY mice: Eif2s3x, Kdm5c, Kdm6a, and Usp9x [11]. Eif2s3x serves as a translation initiation factor and regulates the rate of protein translation through interactions with eukaryotic translation initiation factor 2 [56]. In the brain, sex differences in Eif2s3x transcription are not preserved at the protein level [56]; whether this holds true in the heart is unknown. Kdm5c and Kdm6a are two histone demethylases that affect transcription of numerous autosomal genes. Kdm6a is required for proper embryonic development of the heart as deletion leads to severe congenital heart defects [57,58]. Usp9x, a ubiquitin-specific protease, is a novel mTORC1 and −2 binding partner that negatively regulates mTOR activity indicating it may be protective after MI [59,60]. These four genes provide potential mechanistic sex differences in MI remodeling.
Guiding treatment selection with immunotherapy compared to targeted therapy agents in patients with metastatic kidney cancer
Published in Expert Review of Precision Medicine and Drug Development, 2022
Matteo Rosellini, Andrea Marchetti, Elisa Tassinari, Giacomo Nuvola, Alessandro Rizzo, Matteo Santoni, Veronica Mollica, Francesco Massari
The histological features of RCC should also be taken into account by physicians to define a better treatment strategy in these patients. In particular, the sarcomatoid dedifferentiation of the primary tumor identifies a subgroup of RCCs with extremely aggressive course and low likelihood of response to front-line TKIs, as stated before [71]. Conversely, strong survival benefits and improved clinical activity were reported with the administration of immune-based combinations in untreated sarcomatoid RCC patients, mostly with nivolumab/ipilimumab [28,86–88]. Bakouny et al. revealed that these tumors harbor distinct genomic alterations, including a significant enrichment of BAP1 and NF2 somatic alterations, along with CDKN2A/B deletions and EZH2 amplifications with less frequent mutations in KDM5C. Other genetic abnormalities involved amplifications of MYC and CCNE1, as well as RB1 and NF2 deletions [141]. The poor prognosis of sarcomatoid RCCs appeared to be related with the upregulation of MYC-related genes, shedding light on their pathogenetic role as potential molecular drivers [141]. Furthermore, sarcomatoid RCCs were shown to have an immuno-inflamed phenotype characterized by the higher PD-L1 expression over malignant cells, along with an enriched CD8+ T-cells and M1 macrophages intratumoral infiltration or increased levels of Th1 T cells and activated NK cells, thus potentially explaining their responsiveness to ICIs. Another meaningful feature is the overexpression of all the eight ‘hallmark’ immune gene sets (such as IL6-JAK-STAT3 signaling and IFN-γ response) [15,141].