Salwa Amreen, Ferraresi Alessandra, Chinthakindi Menaka, Vallino Letizia, Vidoni Chiara, Dhanasekaran Danny N, Isidoro Ciro
Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Via Solaroli 17, 28100 Novara, Italy.
Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Biomedicines. 2021 Feb 18;9(2):207. doi: 10.3390/biomedicines9020207.
and are three tumor suppressor genes located on chromosome 17 and frequently found deleted, silenced, or mutated in many cancers. These genes are involved in autophagy, apoptosis, and drug resistance in ovarian cancer. Haploinsufficiency or loss-of-function of either , or correlates with enhanced predisposition to cancer development and progression, and chemoresistance. Expectedly, the combined altered expression of these three tumor suppressor genes worsens the prognosis of ovarian cancer patients. However, whether such a genotypic pattern indeed affects the chemo-responsiveness to standard chemotherapy thus worsening patients' survival has not been validated in a large cohort of ovarian cancer patients.
We interrogated datasets from the TCGA database to analyze how the expression of these three tumor suppressor genes impacts on the clinical response to platinum-based chemotherapy thus affecting the survival of ovarian cancer patients.
Compared to EOC with homozygous expression of and , tumors expressing low mRNA expression of these two tumor suppressor genes (either because of shallow (monoallelic) co-deletion or of promoter hypermethylation), showed higher sensitivity to platinum-based therapies and were associated with a better prognosis of ovarian cancer-bearing patients. This outcome was independent of status, though it was statistically more significant in the cohort of patients with mutated . Thus, sensitivity to platinum therapy (and probably to other chemotherapeutics) correlates with low expression of a combination of critical tumor suppressor genes. Our study highlights the importance of thoroughly assessing the genetic lesions of the most frequently mutated genes to stratify the patients in view of a personalized therapy. More importantly, the present findings suggest that targeting the function of both and could be a strategy to restore chemosensitivity in refractory tumors.
[基因名称1]、[基因名称2]和[基因名称3]是位于17号染色体上的三个肿瘤抑制基因，在许多癌症中经常发现它们缺失、沉默或发生突变。这些基因参与卵巢癌的自噬、凋亡和耐药性。[基因名称1]、[基因名称2]或[基因名称3]的单倍体不足或功能丧失与癌症发生发展和化疗耐药的易感性增加相关。不出所料，这三个肿瘤抑制基因的联合表达改变会使卵巢癌患者的预后恶化。然而，这种基因型模式是否确实影响对标准化疗的化疗反应从而恶化患者生存，尚未在大量卵巢癌患者队列中得到验证。
我们查询了TCGA数据库中的数据集，以分析这三个肿瘤抑制基因的表达如何影响对铂类化疗的临床反应，从而影响卵巢癌患者的生存。
与[基因名称1]和[基因名称2]纯合表达的上皮性卵巢癌（EOC）相比，表达这两个肿瘤抑制基因低mRNA水平（要么是由于浅度（单等位基因）共缺失，要么是由于启动子高甲基化）的肿瘤对铂类疗法表现出更高的敏感性，并且与卵巢癌患者的较好预后相关。这一结果与[基因名称3]状态无关，尽管在[基因名称3]突变的患者队列中在统计学上更显著。因此，对铂类疗法（可能还有其他化疗药物）的敏感性与关键肿瘤抑制基因组合的低表达相关。我们的研究强调了全面评估最常突变基因的遗传损伤以根据个性化治疗对患者进行分层的重要性。更重要的是，目前的研究结果表明，靶向[基因名称1]和[基因名称2]的功能可能是恢复难治性肿瘤化疗敏感性的一种策略。
