Cancer Genetics and Therapeutic Opportunities in Urologic Practice

Abstract

This article aims to summarize the current literature on genetic alterations related to tumors of the genitourinary tract. Novel associations have recently been reported between specific DNA alterations and genitourinary malignancies. The most common cause of chromosome 3p loss in clear cell renal cell carcinoma is a chromothripsis event, which concurrently generates a chromosome 5q gain. Specific patterns of clear cell renal cell carcinoma metastatic evolution have been uncovered. The first therapy targeting a specific molecular alteration has now been approved for urothelial carcinoma. Germline mutations in DNA damage repair genes and the transcription factor HOXB13 are associated with prostate cancer and may be targeted therapeutically. The genetic associations noted across different genitourinary cancers can inform potential screening approaches and guide novel targeted treatment strategies.

Association of differential expression of immunoregulatory molecules and presence of targetable mutations may inform rational design of clinical trials

“…Taken together, these data suggest that pembrolizumab or nivolumab may be a good combination with BRAF V600E inhibitors such as vemurafenib [20][21][22][23][24][25][26] or dabrafenib, 27 based on the significant associations found between BRAF V600E mutations and PD-L1 expression (Figure 1A). 28,29 The strategy of combining dabrafenib, trametinib, and pembrolizumab was shown to have a longer progression-free survival, duration of response, and overall survival compared with dabrafenib, trametinib, and placebo in patients with previously untreated BRAF V600E/K-mutated metastatic melanoma.…”

“…The combination of targeted drugs and immunotherapies has had some of the most success in patients with renal cell carcinoma and hepatocellular carcinoma (HCC) to date. 23 , 24 , 25 Specifically, in patients with metastatic renal cell carcinoma, the combination of anti-PD-1 (pembrolizumab) with targeted therapies to vascular endothelial growth factor (VEGF; axitinib, lenvatinib, and cabozantinib) has shown superiority in patient outcomes compared with targeted therapy (sunitinib) alone. 26 , 27 , 28 Similarly, in patients with HCC, the combination of anti-PD-L1 (atezolizumab) and targeted therapy to VEGF (bevacizumab) had higher survival compared with targeted therapy (sorafenib) alone.…”

Mapping the tumor microenvironment in clear cell renal carcinoma by single-cell transcriptome analysis

“…For instance, the gain or deletion of copy numbers in chromosomes can affect the biological behavior and metabolism of tumor cells. Loss of chromosome 3p results in upregulation of hypoxia signaling, downregulation of glycolysis and oxidative phosphorylation (OXPHOS), and changes in the cell cycle, and is associated with fatty acid metabolism and the TCA cycle ( Adashek et al, 2020 ; Jonasch et al, 2021 ). Gain of chromosome 5q results in the upregulation of mTORC1 and MYC signals ( Li et al, 2013 ; Benstead-Hume et al, 2019 ).…”

The probable role of retroelements in the development of Wilms’ tumor in chromosomal syndromes

“…Та же закономерность наблюдается при спорадических ОВ, обусловленных соматическими изменениями: инсерциями, делециями или транслокациями, причинами которых являются РЭ [13,14]. Характерный для рака почки хромотрипсис [22,23] также часто является следствием патологической активности РЭ [24]. Этим можно объяснить наблюдаемую в ЗНО мочеполовой системы гиперэкспрессию L1, обусловленную гипометилированием CpG динуклеотидов их промоторов [25,26].…”