非西班牙裔白人和西班牙裔患者的透明细胞肾细胞癌分子变异。
Clear cell renal cell carcinoma molecular variations in non-Hispanic White and Hispanic patients.
机构信息
Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
Department of Epidemiology and Biostatistics, University of Arizona, Tucson, Arizona, USA.
出版信息
Cancer Med. 2023 Jun;12(11):12792-12801. doi: 10.1002/cam4.5929. Epub 2023 Apr 20.
BACKGROUND
The United States is becoming increasingly diverse, but few molecular studies have assessed the progression of clear cell renal cell carcinoma (ccRCC) in diverse patient populations. This study examined ccRCC molecular variations in non-Hispanic White (NHW) and Hispanic patients and their effect on the association of gene expression with high-grade (Grade 3 or 4) ccRCC and overall mortality.
METHODS
A total of 156 patients were included in VHL sequencing and/or TempO-Seq analysis. DESeq2 was used to identify the genes associated with high-grade ccRCC. Logistic regression analysis was performed to assess whether race and ethnicity was associated with high/moderate impact VHL somatic mutations and the ccA/ccB subtype. Cox regression analysis was performed to assess association of molecular subtype and gene expression with overall mortality.
RESULTS
NHWs had moderate or high impact mutations in the VHL gene at a higher frequency than Hispanics (40.2% vs. 27.4%), while Hispanics had a higher frequency of the ccA subtype than NHWs (61.9% vs. 45.8%). ccA was more common in patients with BMI≥35 (65.2%) than in those with BMI < 25 (45.0%). There were 11 differentially expressed genes between high- and low-grade tumors. The Haptoglobin (HP) gene was most significantly overexpressed in high- compared to low-grade ccRCC in all samples (p-adj = 1.7 × 10 ). When stratified by subtype, the 11 genes were significantly differentially expressed in the ccB subtype, but none of them were significant after adjusting for multiple testing in ccA. Finally, patients with the ccB subtype had a significantly increased risk of overall mortality (HR 4.87; p = 0.01) compared to patients with ccA, and patients with high HP expression and ccB, had a significantly increased risk of mortality compared to those with low HP expression and ccA (HR 6.45, p = 0.04).
CONCLUSION
This study reports ccRCC molecular variations in Hispanic patients who were previously underrepresented.
背景
美国的人种构成越来越多样化，但很少有分子研究评估不同人群中透明细胞肾细胞癌（ccRCC）的进展情况。本研究检测了非西班牙裔白人（NHW）和西班牙裔患者的 ccRCC 分子变化及其对基因表达与高级别（3 或 4 级）ccRCC 和总死亡率关联的影响。
方法
共纳入 156 例患者进行 VHL 测序和/或 TempO-Seq 分析。使用 DESeq2 鉴定与高级别 ccRCC 相关的基因。采用 logistic 回归分析评估种族和民族是否与高/中度影响 VHL 种系突变和 ccA/ccB 亚型相关。采用 Cox 回归分析评估分子亚型和基因表达与总死亡率的关联。
结果
NHW 患者 VHL 基因中中度或高度影响的突变频率高于西班牙裔（40.2% vs. 27.4%），而西班牙裔患者 ccA 亚型的频率高于 NHW（61.9% vs. 45.8%）。ccA 在 BMI≥35 的患者中更为常见（65.2%），而 BMI<25 的患者中则更为少见（45.0%）。高、低级别肿瘤之间有 11 个差异表达基因。在所有样本中，与低级别 ccRCC 相比，高级别肿瘤中 Haptoglobin（HP）基因的表达显著上调（p-adj=1.7×10）。按亚型分层时，ccB 亚型中这 11 个基因的表达存在显著差异，但在 ccA 中经多重检验校正后无基因显著。最后，与 ccA 患者相比，ccB 亚型患者的总死亡率显著增加（HR 4.87；p=0.01），而与低 HP 表达和 ccA 患者相比，高 HP 表达和 ccB 患者的死亡率显著增加（HR 6.45，p=0.04）。
结论
本研究报告了西班牙裔患者的 ccRCC 分子变化情况，此前对这些患者的研究较少。
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