PO.BCS01.09 · 生物信息与计算
种系全外显子组测序提示同源重组修复通路基因是无镰状血红蛋白病的SMARCB1缺陷型肾髓质表型的风险因素
Germline whole exome sequencing implicates homologous recombination repair pathway genes as risk factors in SMARCB1 deficient renal medullary phenotypes without sickle hemoglobinopathies
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
肾髓质癌（RMC）是一种高度侵袭性的SMARCB1缺陷型肾癌，典型地发生于患有镰状血红蛋白病（最常见为镰状细胞特质，由种系HBB变异所致）的非洲裔年轻个体。极为罕见的无镰状血红蛋白病的SMARCB1缺陷型病例被归类为具有髓质表型的未分类肾细胞癌（RCCU-MP）。除确认镰状血红蛋白病外，种系检测在RMC或RCCU-MP中尚无确立的作用，RCCU-MP的种系风险因素仍未明确。我们对11例RCCU-MP患者开展了整合的种系全外显子组测序（WES）和bulk RNA测序（RNA-Seq），并将其与23例与镰状血红蛋白病相关的经典RMC患者（镰状细胞特质，n=22；镰状细胞-C病，n=1）以及透明细胞RCC（ccRCC；n=11）和嫌色细胞RCC（chRCC；n=11）的疾病对照队列进行比较。RCCU-MP在11例中有2例（约18%）携带同源重组修复（HRR）通路基因的致病性种系功能丧失蛋白截断变异（PTV）：ATM（W2960*，影响PIKKc_ATM结构域）和RAD50（E696*，影响Rad50_zn_hook结构域）。在RMC、ccRCC或chRCC中未发现种系致病性HRR通路PTV。此外，除RMC队列中定义镰状血红蛋白病的预期HBB变异外，在任何特定队列中均未检测到与其他血红蛋白病相关的额外种系改变——包括α地中海贫血和α/β血红蛋白病（KLF1、ATRX、HBG1、HBS1L、MYB、HBD、HBA1、HBA2、HBG2、HBZ和BCL11A）。RNA-Seq细胞去卷积技术，如ssGSEA肿瘤微环境（TME）重建和Kassandra细胞去卷积，显示在RMC和RCCU-MP病例中微环境均高度富集B细胞、CD4和CD8 T细胞，且内皮细胞存在较少。据我们所知，这些数据代表了迄今为止涵盖RMC和RCCU-MP的最大规模种系分析，并提名HRR通路破坏为专门针对RCCU-MP的潜在种系易感信号。明确RCCU-MP中与HRR相关的种系风险，可细化患者遗传咨询的选择，并为镰状血红蛋白病之外的SMARCB1缺陷型髓质肾癌的机制和治疗研究奠定基础。使用了ChatGPT-5.1来改善可读性和语言，使用该工具后，对内容进行了审阅并按需编辑。
查看英文原文 English abstract
Renal medullary carcinoma (RMC) is a highly aggressive, SMARCB1-deficient kidney cancer classically arising in young individuals of African descent with sickle hemoglobinopathies, most commonly sickle cell trait, due to germline HBB variants. Very rare SMARCB1-deficient cases without sickle hemoglobinopathies are classified as renal cell carcinoma, unclassified with medullary phenotype (RCCU-MP). Apart from confirming sickle hemoglobinopathies, there is no established role for germline testing in RMC or RCCU-MP, and germline risk factors for RCCU-MP remain undefined. We performed an integrated germline whole-exome sequencing (WES) and bulk RNA sequencing (RNA-Seq) on 11 patients with RCCU-MP and compared them with 23 patients with canonical RMC associated with sickle hemoglobinopathies (sickle cell trait, n=22; sickle cell-C disease, n=1) and with disease-control cohorts of clear cell RCC (ccRCC; n=11) and chromophobe RCC (chRCC; n=11). RCCU-MP harbored pathogenic germline loss-of-function protein-truncating variants (PTVs) in homologous recombination repair (HRR) pathway genes in 2 of 11 cases (~18%): ATM (W2960*, affecting the PIKKc_ATM domain) and RAD50 (E696*, affecting the Rad50_zn_hook domain). No germline pathogenic HRR pathway PTVs were found in RMC, ccRCC, or chRCC. Furthermore, aside from the expected HBB variants defining sickle hemoglobinopathies in the RMC cohort, no additional germline alterations associated with other hemoglobinopathies - including alpha-thalassemia and alpha/beta-hemoglobinopathies ( KLF1, ATRX, HBG1, HBS1L, MYB, HBD, HBA1, HBA2, HBG2, HBZ and BCL11A ) - were detected in any specific cohort. RNA-Seq cellular deconvolution techniques such as ssGSEA tumor micro-environment (TME) reconstruction and Kassandra cellular deconvolution showed microenvironment with high enrichment for B cells, CD4 and CD8 T cells, and low presence of endothelial cells in both RMC and RCCU-MP cases. These data represent, to our knowledge, the largest germline analysis to date spanning both RMC and RCCU-MP and nominate HRR pathway disruption as a potential germline susceptibility signal specifically for RCCU-MP. Defining HRR-linked germline risk in RCCU-MP refines patient selection for genetic counseling and lays the groundwork for mechanistic and therapeutic studies in SMARCB1-deficient medullary kidney cancers beyond sickle hemoglobinopathies. The ChatGPT-5.1 was used to improve readability and language, and after using this tool, the content was reviewed and edited as needed.
利益披露 Disclosure
P. K. Chauhan, None..
P. Kontoyiannis, None..
E. V. Eschenbach, None..
J. P. Cheng, None..
S. S. Thomas, None..
L. Perelli, None..
C. J. Logothetis, None..
D. Melikhova, None..
L. Bedniagin, None..
M. Hensley, None..
N. M. Tannir, None..
P. Msaouel, None.