Demeure Michael J, Aziz Meraj, Rosenberg Richard, Gurley Steven D, Bussey Kimberly J, Carpten John D
Translational Genomics Research Institute, 445 N. Fifth St, Phoenix, AZ, 85004, USA,
World J Surg. 2014 Jun;38(6):1296-305. doi: 10.1007/s00268-014-2485-3.
Recent advances in the treatment of cancer have focused on targeting genomic aberrations with selective therapeutic agents. In radioiodine resistant aggressive papillary thyroid cancers, there remain few effective therapeutic options. A 62-year-old man who underwent multiple operations for papillary thyroid cancer and whose metastases progressed despite standard treatments provided tumor tissue.
We analyzed tumor and whole blood DNA by whole genome sequencing, achieving 80× or greater coverage over 94 % of the exome and 90 % of the genome. We determined somatic mutations and structural alterations.
We found a total of 57 somatic mutations in 55 genes of the cancer genome. There was notably a lack of mutations in NRAS and BRAF, and no RET/PTC rearrangement. There was a mutation in the TRAPP oncogene and a loss of heterozygosity of the p16, p18, and RB1 tumor suppressor genes. The oncogenic driver for this tumor is a translocation involving the genes for anaplastic lymphoma receptor tyrosine kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4). The EML4-ALK translocation has been reported in approximately 5 % of lung cancers, as well as in pediatric neuroblastoma, and is a therapeutic target for crizotinib.
This is the first report of the whole genomic sequencing of a papillary thyroid cancer in which we identified an EML4-ALK translocation of a TRAPP oncogene mutation. These findings suggest that this tumor has a more distinct oncogenesis than BRAF mutant papillary thyroid cancer. Whole genome sequencing can elucidate an oncogenic context and expose potential therapeutic vulnerabilities in rare cancers.
癌症治疗的最新进展集中在使用选择性治疗药物靶向基因组畸变。在放射性碘难治性侵袭性乳头状甲状腺癌中，有效的治疗选择仍然很少。一名62岁男性因乳头状甲状腺癌接受了多次手术，尽管接受了标准治疗，其转移灶仍有进展，该患者提供了肿瘤组织。
我们通过全基因组测序分析肿瘤和全血DNA，在外显子组的94%和基因组的90%上实现了80倍或更高的覆盖度。我们确定了体细胞突变和结构改变。
我们在癌症基因组的55个基因中总共发现了57个体细胞突变。值得注意的是，NRAS和BRAF基因没有突变，也没有RET/PTC重排。TRAPP致癌基因存在突变，p16、p18和RB1肿瘤抑制基因存在杂合性缺失。该肿瘤的致癌驱动因素是一种涉及间变性淋巴瘤受体酪氨酸激酶（ALK）和棘皮动物微管相关蛋白样4（EML4）基因的易位。EML4-ALK易位在大约5%的肺癌以及儿童神经母细胞瘤中已有报道，是克唑替尼的治疗靶点。
这是关于乳头状甲状腺癌全基因组测序的首次报告，我们在其中鉴定出了TRAPP致癌基因突变的EML4-ALK易位。这些发现表明，与BRAF突变型乳头状甲状腺癌相比，该肿瘤具有更独特的肿瘤发生机制。全基因组测序可以阐明致癌背景，并揭示罕见癌症中潜在的治疗弱点。
