Dataset Information

A genomic mutation spectrum of collecting duct carcinoma in the Chinese population.

ABSTRACT:

Background

Renal collecting duct carcinoma (CDC) is a rare and lethal subtype of renal cell carcinoma (RCC). The genomic profile of the Chinese population with CDC remains unclear. In addition, clinical treatments are contradictory. In this study, we aimed to identify the genomic mutation spectrum of CDC in the Chinese population.

Methods

Whole-exome sequencing was performed using the Illumina Novaseq™ 6000 platform. MuTect2 detects single-nucleotide variants (SNVs) and small scale insertions/deletions (INDELs). The identified mutations were annotated with ANNOVAR and validated by Sanger sequencing. Control-FREEC was used to detect copy number variation (CNV), and GISTIC was applied to detect frequently mutated altered regions. These data were compared with associated The Cancer Genome Atlas cohorts.

Results

Ten normal-matched CDC patients were included. The mean tumour mutation burden was 1.37 Mut/Mb. Six new recurrent somatic mutated genes were identified, including RBM14, MTUS1, GAK, DST, RNF213 and XIRP2 (20% and 2 of 10, respectively), and validated by Sanger sequencing. In terms of common mutated genes, SETD2 was altered in both CDC and other RCC subtypes but not in bladder urothelial carcinoma (BLCA); CDKN2A was a driver gene in both CDC (SNV: 10%, 1 of 10) and BLCA but not in other RCC subtypes. Next, 29 amplifications and 6 deletions of recurrent focal somatic CNVs were identified by GISTIC2.0, which displayed differences from kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP) and BLCA cohorts. Of note, CDKN2A (CNV alteration: 30%, 3 of 10) and CDKN2A-AS1 were the only overlapping genes of these four cohorts. Importantly, the CDKN2A mutation in our cohort differed from previous studies in urinary carcinomas. Moreover, CDKN2A-altered cases had significantly worse overall survival than wild-type cases in both KIRC and KIRP cohorts. In addition, the most frequently altered genomic pathway of our CDC cohort was the CDKN2A-mediated p53/RB1 pathway.

Conclusions

Our study offers the first genomic spectrum of the Chinese population with CDC, which differs from that of the Western population. The altered CDKN2A-mediated p53/RB1 pathway might provide new insight into potential therapeutic targets for CDC patients.

SUBMITTER: Zhang H

PROVIDER: S-EPMC8722201 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:ObjectiveTo investigate the exact age-adjusted incidence (AAI), clinical characteristics, and survival data of collecting duct carcinoma of the kidney (CDCK) recorded in the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute.MethodsPatients with CDCK confirmed by microscopic examination from 2004 to 2018 were selected from the SEER database. AAI rates were calculated using SEER*Stat software (version 8.3.9). The Kaplan-Meier method was used to evaluate cancer-specific survival (CSS) rates according to tumor size, tumor stage, and treatment methods, and differences among these variables were assessed by the log-rank test. Cox regression analysis was employed to identify variables independently related to CSS.ResultsA total of 286 patients with CDCK were identified from the database. The majority of the patients were white (69.2%), male (67.5%), and married (60.5%), and the median age was 59 years. Most patients with CDCK (74.4%) presented with stages III or IV disease. The diameter of most (59.4%) tumors was less than 7 cm, and the tumors were more commonly found on the left than on the right (55.2% vs. 44.8%). The incidence of CDCK decreased over time. The median CSS time was 17 months. In terms of the treatment modalities used, 83.9% of the patients underwent surgery; 32.9% underwent chemotherapy, and 13.6% underwent radiotherapy. The CSS rates at 1, 2, and 5 years were 57.3%, 43.2%, and 30.7%, respectively. In patients with stage IV CDCK treated with surgery alone, chemotherapy alone, and surgery plus chemotherapy, the median survival time was 5 months, 9 months, and 14 months, respectively (P =0.024). Multivariate Cox regression analysis showed surgery, chemotherapy, stage, regional lymph node metastasis, and distant metastasis were independent prognostic factors for patients with CDCK.ConclusionsCDCK is an uncommon malignant renal carcinoma, and its incidence is decreasing based on the analysis of current data. CDCK is a high stage, regional lymph-nodes positive, and metastatic disease. Compared with surgery alone or chemotherapy alone, patients with stage IV could gain survival benefit from surgery combined with chemotherapy.

Project description:Renal medullary carcinomas (RMCs) and collecting duct carcinomas (CDCs) are rare subsets of lethal high-stage, high-grade distal nephron-related adenocarcinomas with a predilection for the renal medullary region. Recent findings have established an emerging group of fumarate hydratase (FH)-deficient tumors related to hereditary leiomyomatosis and renal cell carcinoma (HLRCC-RCCs) syndrome within this morphologic spectrum. Recently developed, reliable ancillary testing has enabled consistent separation between these tumor types. Here, we present the clinicopathologic features and differences in the morphologic patterns between RMC, CDC, and FH-deficient RCC in consequence of these recent developments. This study included a total of 100 cases classified using contemporary criteria and ancillary tests. Thirty-three RMCs (SMARCB1/INI1-deficient, hemoglobinopathy), 38 CDCs (SMARCB1/INI1-retained), and 29 RCCs defined by the FH-deficient phenotype (FH/2SC or FH/2SC with FH mutation, regardless of HLRCC syndromic stigmata/history) were selected. The spectrum of morphologic patterns was critically evaluated, and the differences between the morphologic patterns present in the 3 groups were analyzed statistically. Twenty-five percent of cases initially diagnosed as CDC were reclassified as FH-deficient RCC on the basis of our contemporary diagnostic approach. Among the different overlapping morphologic patterns, sieve-like/cribriform and reticular/yolk sac tumor-like patterns favored RMCs, whereas intracystic papillary and tubulocystic patterns favored FH-deficient RCC. The tubulopapillary pattern favored both CDCs and FH-deficient RCCs, and the multinodular infiltrating papillary pattern favored CDCs. Infiltrating glandular and solid sheets/cords/nested patterns were not statistically different among the 3 groups. Viral inclusion-like macronucleoli, considered as a hallmark of HLRCC-RCCs, were observed significantly more frequently in FH-deficient RCCs. Despite the overlapping morphology found among these clinically aggressive infiltrating high-grade adenocarcinomas of the kidney, reproducible differences in morphology emerged between these categories after rigorous characterization. Finally, we recommend that definitive diagnosis of CDC should only be made if RMC and FH-deficient RCC are excluded.