Chida Kohei, Wu Rongrong, Roy Arya Mariam, Ishikawa Takashi, Hakamada Kenichi, Takabe Kazuaki
Roswell Park Comprehensive Cancer Center.
Ohio State University.
Res Sq. 2024 Nov 20:rs.3.rs-5260856. doi: 10.21203/rs.3.rs-5260856/v1.
Intratumoral genomic heterogeneity (ITGH), the existence of genotypic and phenotypic variation within an individual tumor, is known to be a key mechanism in treatment resistance. Deviating gene Expression Profiling Tumor Heterogeneity 2 (DEPTH2) algorithm was developed to estimate ITGH using solely RNA expression data unlike the others that require both DNA- and RNA-expression data. Total of 6,500 breast cancer patients from multiple independent cohorts were analyzed using DEPTH2. High DEPTH2 score patients were associated with worse overall survival consistently across all subtypes in METABRIC, but not in TCGA and SCAN-B cohort. Higher DEPTH2 score was linked to increased cell proliferation, as evidenced by elevated Nottingham histological grades and Ki67 gene expression, as well as enrichment of the cell proliferation-related gene sets, and immune cell infiltrations. DEPTH2 score was significantly higher in triple negative breast cancer among the subtypes but did not reflect with lymph node and distal metastasis. DEPTH2 scores decreased in two but showed no change in another two cohorts after neoadjuvant chemotherapy (NAC). DEPTH2 score was not associated with pathologic complete response after NAC in any subtypes across 3 cohorts. DEPTH2 score may not capture the entire biological aspects of ITGH in breast cancer patients.
肿瘤内基因组异质性（ITGH），即单个肿瘤内基因型和表型变异的存在，是已知的治疗耐药的关键机制。与其他需要DNA和RNA表达数据的方法不同，偏差基因表达谱肿瘤异质性2（DEPTH2）算法仅使用RNA表达数据来估计ITGH。使用DEPTH2对来自多个独立队列的6500例乳腺癌患者进行了分析。在METABRIC队列中，DEPTH2评分高的患者在所有亚型中均与较差的总生存期相关，但在TCGA和SCAN - B队列中并非如此。较高的DEPTH2评分与细胞增殖增加有关，诺丁汉组织学分级和Ki67基因表达升高以及细胞增殖相关基因集的富集和免疫细胞浸润证明了这一点。在各亚型中，三阴性乳腺癌的DEPTH2评分显著更高，但与淋巴结和远处转移无关。新辅助化疗（NAC）后，两个队列中的DEPTH2评分下降，而另外两个队列中则没有变化。在3个队列的任何亚型中NAC后DEPTH2评分与病理完全缓解均无关。DEPTH2评分可能无法捕捉乳腺癌患者ITGH的全部生物学特征。
