- 三家机构经 NGS 检出 44 例（约 4.3%）携带 RAS/RAF/MAPK 通路改变的前列腺腺癌（转移样本 20 例、原发样本 24 例）。
- 改变以 BRAF（21 例）、HRAS（10）、KRAS（5）及 MAPK 相关基因（9）为主；多数为 Grade Group 5（23/35，66%）；69% 见侵袭性组织学特征；84% 出现初诊或后续转移。
- 可见激活型 BRAF 融合；相当一部分病例无其他经典驱动基因共突变，提示该通路可能独立驱动部分肿瘤发生。
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摘要
RAS/RAF/MAPK 通路改变在前列腺腺癌（PCa）中少见，但与转移及进展相关。既往研究提示，这类改变在罕见且侵袭性的组织学亚型中更为常见。我们回顾了三家机构中携带上述通路改变的 PCa 的临床与形态学特征。纳入经二代测序（NGS）检出 RAS/RAF/MAPK 通路改变的 PCa，汇总临床、形态与分子特征，并在癌症基因组图谱（TCGA）中检索同类改变病例以作对照。三家机构经 NGS 共检出 44 例（4.3%）携带 RAS/RAF/MAPK 改变的 PCa（转移样本 20 例、原发样本 24 例）。原发样本包括前列腺穿刺活检、根治性前列腺切除及经尿道前列腺切除标本。改变见于 BRAF（21 例）、HRAS（10）、KRAS（5）及 MAPK 基因（9）。多数病例为 Grade Group 5（23/35，66%）。69% 的病例（24/35）具有侵袭性组织学特征。84% 的病例（37/44）出现初诊转移或后续转移。回顾 TCGA 数据集显示 RAS/RAF/MAPK 改变病例比例相近，其中一部分亦呈侵袭性组织学模式。我们的数据进一步表明，PCa 中 RAS/RAF/MAPK 通路突变并不常见，但本队列多数病例表现为高 Gleason 分级、转移及去势抵抗，且一部分具有侵袭性组织学特征。研究还发现激活型 BRAF 融合。由于相当数量病例并未同时出现其他驱动基因改变，RAS/RAF/MAPK 改变可能在一部分 PCa 中驱动肿瘤发生。
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Abstract
RAS/RAF/MAPK pathway alterations are rare in prostatic adenocarcinoma (PCa) but are implicated in metastasis and progression. Previous studies suggest that these alterations are more common in rare and aggressive histologic PCa subtypes. We reviewed the clinical and morphologic features of PCa with these alterations at our 3 institutions. PCa cases with RAS/RAF/MAPK pathway alterations identified by next generation sequencing (NGS) were selected for our cohort. Clinical, morphologic, and molecular features were compiled. Additionally, PCa cases with these alterations were identified in the Cancer Genome Atlas (TCGA) for comparison. From our 3 institutions, 44 cases of PCa (4.3%) with RAS/RAF/MAPK alteration(s) were identified by NGS (20 metastatic and 24 primary samples). Primary samples included prostate biopsies, radical prostatectomies, and transurethral resections of the prostate. Alterations were found in BRAF (21 cases), HRAS (10), KRAS (5), and MAPK genes (9). Most cases were grade group 5 (23/35, 66%). Aggressive histologic features were seen in 69% of cases (24/35). De-novo or subsequent metastatic disease developed in 84% of cases (37/44). Review of the TCGA dataset showed a similar proportion of RAS/RAF/MAPK-altered cases, and a subset had aggressive histologic patterns. Our data reinforces that mutations in the RAS/RAF/MAPK pathway in PCa are uncommon, but a majority of our cases showed high Gleason grade, metastases, and castration resistance, with a subset showing aggressive histologic features. Activating BRAF fusions were identified. As a significant number of cases did not show co-occurring alterations in driver genes, RAS/RAF/MAPK alterations may be driving tumorigenesis in a subset of PCa cases.