ABSTRACT
BACKGROUND: Clear-cell renal cell carcinomas (ccRCCs) are malignant tumors with high metastatic potential and resistance to treatments occurs almost constantly. Compared to primary tumors, there are still limited genomic data that has been obtained from metastatic samples. METHODS: We aimed to characterize metastatic ccRCC by way of whole-genome analyses of metastatic formalin-fixed samples, using OncoScan® technology. We identified a frequent, unexpected pL1575P NOTCH1 mutation which we set out to characterize for translational purposes. We thus implemented patient-derived xenografts from metastatic samples of human ccRCC to explore its clinical significance. RESULTS: We showed that pL1575P NOTCH1 mutation was an activating mutation, leading to the expression of NOTCH1-intracellular domain-active fragments in both cancer cells and tumor endothelial cells, suggesting a trans-differentiation of cancer cells into tumor micro-vessels. We demonstrated that this mutation could be used as a predictive biomarker of response to CB-103, a specific NOTCH1-intracellular domain inhibitor. One striking result was the considerable anti-angiogenic effect, coherent with the presence of NOTCH1 mutation in tumor micro-vessels. CONCLUSIONS: We identified a frequent, unexpected pL1575P_c4724T_C NOTCH1 mutation as a new biomarker for ccRCC metastases, predictive of response to the CB103 NOTCH1-intracellular domain inhibitor.
ABSTRACT
CONTEXT: Although antiangiogenic treatments and immunotherapies have significantly improved the prognosis of metastatic renal cell carcinoma (RCC), many patients will develop resistance, leading to treatment failure. Genetic tumor heterogeneity is a major cause of this resistance. OBJECTIVE: To perform a meta-analysis of genomic data for clear-cell RCC obtained from primary tumors and metastases to assess the prevalence of gene mutations and copy number alterations (CNAs). EVIDENCE ACQUISITION: Articles were selected from Medline and Embase libraries using the search algorithm ("Kidney Neoplasms"[Mesh] OR "Renal Cell Carcinoma") AND ("Genomics"[Mesh] OR "Mutation") from January 1999 to February 2021. A critical review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. Ninety-three publications were selected for inclusion in this meta-analysis. EVIDENCE SYNTHESIS: Our meta-analysis included a total 14 696 patients, 14 299 primary tumor samples, and 969 metastatic samples. We evaluated the overall and subgroup prevalence of gene mutations and CNAs, including comparisons between primary tumors and metastases. In particular, for metastases we observed that the mutation prevalence was significantly more marked for ten genes compared to primary tumors, with no or little heterogeneity across studies. The VHL mutation prevalence increased significantly from 64% in primary tumors to 75% in metastases (p < 0.001). There was a significant increase in CNA prevalence from primary tumors to metastases for chromosomes 1p36.11, 9p21.3, and 18 in terms of losses, and for chromosomes 1q21.3, 7q36.3, 8q, and 20q11.21 in terms of gains. CDKN2A, also called p16 and involved in cell-cycle progression, is located at the 9p21.3 locus and was lost in 76% of metastatic samples. ASXL1, located on 20p11.21 and amplified in 50% of metastatic RCCs compared to 21% of primary tumors (p < 0.001), is closely linked to BAP1 function. CONCLUSIONS: Our results underline the added value of preferential biopsies on RCC metastases to fully explore the biology of metastatic disease for therapeutic purposes. PATIENT SUMMARY: We reviewed the literature on genetic mutations in primary tumors and metastatic lesions in kidney cancer. Our pooled results for all the relevant studies show a higher level of mutations in metastases than in primary tumors. This highlights the importance of taking biopsies of metastases to analyze genetic mutations and potentially guide selection of the most suitable treatment strategy.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Carcinoma, Renal Cell/pathology , DNA Copy Number Variations , Female , Genomics , Humans , Kidney Neoplasms/pathology , Male , PrognosisABSTRACT
WHAT IS KNOWN AND OBJECTIVE: There is limited data on the specific risks of anaphylaxis induced by beta-lactam drugs. The aim of this study was to compare the risks of reporting beta-lactam-induced anaphylaxis using the national pharmacovigilance database of Vietnam (NPDV). METHODS: The multivariate generalised linear regression model was applied for signal generation and comparison of beta-lactams. RESULTS: Between 2010 and 2016, there were 2,921 reports of anaphylaxis (19.93%) from 14,655 spontaneous reports of beta-lactam use in the NDPV. Anaphylaxis signal generation was also found for the subgroup J01D (cephalosporins and carbapenems) (ROR = 1.27 [1.16-1.39]) and beta-lactamase-sensitive penicillins (ROR = 1.74 [1.27-2.35]). In the third generation cephalosporin subgroup, different risks were identified for the following combinations of beta-lactams: 1) cefotaxime with cefoperazone+sulbactam; 2) cefixime/cefpodoxime/cefdinir with cefoperazone+sulbactam or ceftizoxime/cefoperazone/ceftazidime/ceftriaxone/cefotaxime. For the second generation cephalosporin subgroup, different risks were found for cefotiam compared to cefmetazole, cefaclor, cefamandole and cefuroxime. WHAT IS NEW AND CONCLUSION: These findings identified and highlighted the different anaphylactic risks caused by various beta-lactams in the main subgroups.
