Integrated Genomics Laboratory, ACTREC, Tata Memorial Centre, Navi Mumbai 410210, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400094, India.
Integrated Genomics Laboratory, ACTREC, Tata Memorial Centre, Navi Mumbai 410210, India.
Oral Oncol. 2017 Oct;73:56-64. doi: 10.1016/j.oraloncology.2017.08.003. Epub 2017 Aug 12.
Nodal metastases status among early stage tongue squamous cell cancer patients plays a decisive role in the choice of treatment, wherein about 70% patients can be spared from surgery with an accurate prediction of negative pathological lymph node status. This underscores an unmet need for prognostic biomarkers to stratify the patients who are likely to develop metastases.
We performed high throughput sequencing of fifty four samples derived from HPV negative early stage tongue cancer patients habitual of chewing betel nuts, areca nuts, lime or tobacco using whole exome (n=47) and transcriptome (n=17) sequencing that were analyzed using in-house computational tools. Additionally, gene expression meta-analyses were carried out for 253 tongue cancer samples. The candidate genes were validated using qPCR and immuno-histochemical analysis in an extended set of 50 early primary tongue cancer samples.
Somatic analysis revealed a classical tobacco mutational signature C:G>A:T transversion in 53% patients that were mutated in TP53, NOTCH1, CDKN2A, HRAS, USP6, PIK3CA, CASP8, FAT1, APC, and JAK1. Similarly, significant gains at genomic locus 11q13.3 (CCND1, FGF19, ORAOV1, FADD), 5p15.33 (SHANK2, MMP16, TERT), and 8q24.3 (BOP1); and, losses at 5q22.2 (APC), 6q25.3 (GTF2H2) and 5q13.2 (SMN1) were observed in these samples. Furthermore, an integrated gene-expression analysis of 253 tongue tumors suggested an upregulation of metastases-related pathways and over-expression of MMP10 in 48% tumors that may be crucial to predict nodal metastases in early tongue cancer patients. In overall, we present the first descriptive portrait of somatic alterations underlying the genome of tobacco/nut chewing HPV-negative early tongue cancer, and identify MMP10 asa potential prognostic biomarker to stratify those likely to develop metastases.
早期舌鳞状细胞癌患者的淋巴结转移状态对治疗方案的选择起着决定性作用，其中约 70%的患者可以通过准确预测阴性病理淋巴结状态来避免手术。这凸显了对预后生物标志物的需求，以对可能发生转移的患者进行分层。
我们对 54 例习惯咀嚼槟榔、槟榔、石灰或烟草的 HPV 阴性早期舌癌患者进行高通量测序，使用全外显子（n=47）和转录组（n=17）测序，然后使用内部计算工具进行分析。此外，对 253 例舌癌样本进行了基因表达荟萃分析。在 50 例早期原发性舌癌样本中，使用 qPCR 和免疫组织化学分析验证候选基因。
体细胞分析显示，53%的患者存在经典的烟草突变特征 C：G>A:T 颠换，这些患者的 TP53、NOTCH1、CDKN2A、HRAS、USP6、PIK3CA、CASP8、FAT1、APC 和 JAK1 发生突变。同样，在基因组 11q13.3 （CCND1、FGF19、ORAOV1、FADD）、5p15.33 （SHANK2、MMP16、TERT）和 8q24.3 （BOP1）存在显著的增益；在这些样本中还观察到 5q22.2 （APC）、6q25.3 （GTF2H2）和 5q13.2 （SMN1）的缺失。此外，对 253 例舌肿瘤的综合基因表达分析表明，48%的肿瘤中与转移相关的途径上调，MMP10 表达过度，这可能对预测早期舌癌患者的淋巴结转移至关重要。总之，我们首次描述了烟草/咀嚼槟榔 HPV 阴性早期舌癌基因组中潜在的体细胞改变，并确定 MMP10 是一种潜在的预后生物标志物，可对可能发生转移的患者进行分层。
