Bioinformatics & Computational Biology, Genentech Inc., South San Francisco, California, United States of America.
Oncology Biomarker Development, Genentech Inc., South San Francisco, California, United States of America.
PLoS One. 2021 Dec 31;16(12):e0262198. doi: 10.1371/journal.pone.0262198. eCollection 2021.
Colorectal cancer (CRC) is a leading cause of cancer-related deaths, with a 5% 5-year survival rate for metastatic disease, yet with limited therapeutic advancements due to insufficient understanding of and inability to accurately capture high-risk CRC patients who are most likely to recur. We aimed to improve high-risk classification by identifying biological pathways associated with outcome in adjuvant stage II/III CRC.
We included 1062 patients with stage III or high-risk stage II colon carcinoma from the prospective three-arm randomized phase 3 AVANT trial, and performed expression profiling to identify a prognostic signature. Data from validation cohort GSE39582, The Cancer Genome Atlas, and cell lines were used to further validate the prognostic biology. Our retrospective analysis of the adjuvant AVANT trial uncovered a prognostic signature capturing three biological functions-stromal, proliferative and immune-that outperformed the Consensus Molecular Subtypes (CMS) and recurrence prediction signatures like Oncotype Dx in an independent cohort. Importantly, within the immune component, high granzyme B (GZMB) expression had a significant prognostic impact while other individual T-effector genes were less or not prognostic. In addition, we found GZMB to be endogenously expressed in CMS2 tumor cells and to be prognostic in a T cell independent fashion. A limitation of our study is that these results, although robust and derived from a large dataset, still need to be clinically validated in a prospective study.
This work furthers our understanding of the underlying biology that propagates stage II/III CRC disease progression and provides scientific rationale for future high-risk stratification and targeted treatment evaluation in biomarker defined subpopulations of resectable high-risk CRC. Our results also shed light on an alternative GZMB source with context-specific implications on the disease's unique biology.
结直肠癌（CRC）是癌症相关死亡的主要原因，转移性疾病的 5 年生存率为 5%，但由于对高危 CRC 患者的了解不足且无法准确捕捉，导致治疗进展有限，这些患者最有可能复发。我们旨在通过鉴定与辅助治疗 II/III 期 CRC 结果相关的生物途径来改善高危分类。
我们纳入了前瞻性三臂随机 III 期 AVANT 试验中 1062 名 III 期或高危 II 期结肠癌患者，并进行表达谱分析以鉴定预后标志。使用验证队列 GSE39582、癌症基因组图谱和细胞系的数据进一步验证了预后生物学。我们对辅助 AVANT 试验的回顾性分析揭示了一个预后标志，该标志捕获了三种生物学功能-基质、增殖和免疫-在独立队列中优于共识分子亚型（CMS）和复发预测标志如 OncotypeDx。重要的是，在免疫成分中，高颗粒酶 B（GZMB）表达具有显著的预后影响，而其他单个 T 效应基因则预后较差或无预后。此外，我们发现 CMS2 肿瘤细胞内源性表达 GZMB 且以 T 细胞独立方式具有预后意义。本研究的一个局限性是，这些结果虽然稳健且来自大型数据集，但仍需要在前瞻性研究中进行临床验证。
这项工作进一步了解了推动 II/III 期 CRC 疾病进展的潜在生物学，并为在可切除高危 CRC 的生物标志物定义亚群中进行未来高危分层和靶向治疗评估提供了科学依据。我们的结果还揭示了 GZMB 的替代来源，这对疾病独特生物学具有特定背景的意义。
