透明细胞肾细胞癌中肿瘤大小不同的突变差异

Differences in mutations across tumour sizes in clear-cell renal cell carcinoma

BJU INTERNATIONAL

影响因子:4.4

分区:医学2区 / 泌尿学与肾脏学2区

发表日期:2025 Feb

作者: Steven M Monda, Benjamin W Carney, Allison M May, Shuchi Gulati, Simpa S Salami, Thenappan Chandrasekar, Evan T Keller, Nicolai A Huebner, Ganesh S Palapattu, Marc A Dall'Era

DOI: 10.1111/bju.16527

摘要

本研究旨在评估透明细胞肾细胞癌（ccRCC）中关键突变在不同肿瘤大小中的分布情况，并次要分析较小ccRCC中具有侵袭性突变的预后影响。通过对1039例接受肾切除治疗的ccRCC样本，结合Tracking Cancer Evolution（TRACERx）、癌症基因组图谱（TCGA）和肾脏癌症基因组（CAGEKID）项目的数据，分析了VHL、PBRM1、SETD2、BAP1及CDKN2A丧失的突变分布。采用逻辑回归模型分析每种突变与肿瘤大小的关系。在次要分析中，评估≤7cm的ccRCC亚组中，关键侵袭性突变（SETD2、BAP1和CDKN2A丧失）与转移、侵袭性疾病和总生存的关系，同时控制肿瘤大小。还利用局限性肿瘤（≤7cm）亚组评估术后复发的相关性。逻辑回归显示，肿瘤每增加1cm，与SETD2、BAP1和CDKN2A丧失的发生风险增加相关，赔率比分别为1.09、1.10和1.19（P<0.001），而PBRM1与肿瘤大小无显著相关（OR 1.02; P=0.23）。VHL在每增加1cm时呈轻度负相关（OR 0.95; P=0.01）。在≤7cm的肿瘤中，SETD2和CDKN2A丧失与转移性疾病显著相关（OR分别为3.86和3.84，P<0.05），且控制肿瘤大小后，CDKN2A丧失与总生存较差相关（HR 2.19，P=0.03）。在局限性肿瘤≤7cm中，SETD2突变与无复发生存率降低相关（HR 2.00，P=0.03）。大型和小型ccRCC在基因组上存在差异。侵袭性突变（SETD2、BAP1和CDKN2A丧失）在小型ccRCC中较少见，但在较大肿瘤中更为常见。即使在≤7cm的肿瘤中，SETD2突变和CDKN2A丧失仍与侵袭性疾病、转移、较差的生存率和术后复发独立相关，控制肿瘤大小后仍具有预后意义。

Abstract

To assess the distribution of key mutations across tumour sizes in clear-cell renal cell carcinoma (ccRCC), and secondarily to examine the prognostic impact of aggressive mutations in smaller ccRCCs.The distribution of mutations (VHL, PBRM1, SETD2, BAP1 and CDKN2A loss) across tumour sizes was assessed in 1039 ccRCCs treated with nephrectomy in cohorts obtained from the Tracking Cancer Evolution (TRACERx), The Cancer Genome Atlas (TCGA) and the Cancer Genomics of the Kidney (CAGEKID) projects. Logistic regression was used to model the presence of each mutation against size. In our secondary analysis, we assessed a subset of ccRCCs ≤7 cm for associations of key aggressive mutations (SETD2, BAP1, and CDKN2A loss) with metastasis, invasive disease and overall survival, while controlling for size. A subset of localised tumours ≤7 cm was also used to assess associations with recurrence after nephrectomy.On logistic regression, each 1-cm increase in tumour size was associated with aggressive mutations, SETD2, BAP1, and CDKN2A loss, at odds ratios (ORs) of 1.09, 1.10 and 1.19 (P < 0.001), whereas no significant association was observed between tumour size and PBRM1 (OR 1.02; P = 0.23). VHL was mildly negatively associated with a 1-cm increase in size (OR 0.95; P = 0.01). Among tumours ≤7 cm, SETD2 and CDKN2A loss were associated with metastatic disease at ORs of 3.86 and 3.84 (P < 0.05) while controlling for tumour size. CDKN2A loss was associated with worse overall survival, with a hazard ratio (HR) of 2.19 (P = 0.03). Among localised tumours ≤7 cm, SETD2 was associated with worse recurrence-free survival (HR 2.00; P = 0.03).Large and small ccRCCs are genomically different. Aggressive mutations, namely, SETD2, BAP1, and CDKN2A loss, are rarely observed in small ccRCCs and are observed more frequently in larger tumours. However, when present in tumours ≤7 cm, SETD2 mutations and CDKN2A loss were still independently associated with invasive disease, metastasis, worse survival, and recurrence after resection, after controlling for size.