PI3K/AKT信号传导通路基因突变
ATC中还存在多种PI3K/AKT信号传导通路的异常分子改变，例如，PI3K3CA突变（影响PIK3CA激酶中起催化作用的α-亚基）、AKT突变（影响PIP3靶点）和PTEN突变（影响PIP3磷酸酶）[23]。PI3K/AKT通路的基因改变经常与其他参与恶性转化的基因突变共同发生，提示了这些是癌症进展过程中的晚期事件。
图52-2所示的PTC、PDTC和ATC中的体细胞突变率来源于截至目前发表的最大样本量二代测序研究。鉴于ATC中存在大量肿瘤相关巨噬细胞浸润，需要进一步测序仪保证突变检测的可靠性。3种类型甲状腺癌的驱动突变（BRAF、RAS和RET突变）率请见标记。在恶性程度高的甲状腺癌中，可能同时具有两种或两种以上突变，所以总突变率合计超过100%。但主要的驱动突变（BRAF、RAS和RET突变）发生率合计不足100% ，这是因为部分病例的驱动突变尚未探明或因为发生频率过低而未被列出（如NF1突变和PTEN突变）。TERT启动子突变似乎是甲状腺肿瘤微进化的关键环节。PTC中TERT突变并不常见且通常为亚克隆；但在PDTC和ATC中，TERT突变发生率明显升高，且为同一克隆。TP53突变仅在ATC中常见，发生率可高达70%以上。ATC中还存在PI3K-AKTmTOR 信号通路中相关基因的突变，以及编码表观遗传学调控的基因突变。PDTC中上述突变的发生率介于PTC和ATC之间。EIF1AX突变罕见于PTC，但在PDTC和ATC中的出现频率明显增多，且与RAS突变有很强的相关性。
图52-2 甲状腺癌进展过程中的基因改变
（引自Fagin J A， Wells S A Jr.Biologic and clinical perspectives on thyroid cancer.N Engl J Med 2016；375：1054-67.DOI： 10.1056/NEJMra1501993）
参考文献
[1] Weinberg R A.How cancer arises[J].Sci Am,1996,275(3):62-70.
[2] Friend S H, Dryja T P, Weinberg R A.Oncogenes and tumor-suppressing genes[J].N Engl J Med, 1988,318(10):618-622.
[3] Vogelstein B, Kinzler K W.The multistep nature of cancer[J].Trends Genet: TIG, 1993, 9(4): 138-141.
[4] Bishop J M.Cancer: the rise of the genetic paradigm[J].Genes Dev, 1995, 9(11):1309-1315.
[5] Mingzhao Xing.Molecular pathogenesis and mechanisms of thyroid cancer[J].Nat Rev Cancer, 2013, 13(3):184-199.
[6] Cabanillas M E, McFadden D G, Durante C.Thyroid cancer[J].Lancet,2016,388(10061):2783- 2795.
[7] Fagin J A, Wells S A Jr.Biologic and clinical perspectives on thyroid cancer[J].N Engl J Med, 2016, 375:1054-1067.
[8] Huang F W, Hodis E, Xu M J, et al.Highly recur rent TERT promoter mutations in human melanoma[J].Science,2013,339:957-959.
[9] Vinagre J, Almeida A, Pópulo H, et al.Frequency of TERT promoter mutations in human cancers[J].Nat Commun,2013, 4: 2185.(https://www.daowen.com)
[10] Cancer Genome Atlas Research Network.Integrated genomic characterization of papillary thyroid carcinoma[J].Cell,2014,159(3):676-690.
[11] Cohen Y, Xing M, Mambo E, et al.BRAF mutation in papillary thyroid carcinoma[J].Natl Cancer Inst, 2003,95: 625-627.
[12] Xing M, Haugen B R, Schlumberger M.Progress in molecular-based management of differentiated thyroid cancer[J].Lancet, 2013, 381(9871):1058-1069.
[13] Xing M, Alzahrani A S, Carson K A, et al.Association between BRAF V600E muta tion and recurrence of papillary thyroid cancer[J] .Clin Oncol, 2015, 33:42-50.
[14] Xing M, Alzahrani A S, Carson K A, et al.Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer[J].JAMA, 2013,309(14):1493-1501.
[15] Haugen B R, Alexander E K, Bible KC, et al.2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer[J].Thyroid, 2016, 26:1-133.
[16] Xing M, Liu R, Liu X, et al.BRAFV600E and TERT promoter mutations co operatively identify the most aggressive papillary thyroid cancer with highest recurrence [J].Clin Oncol, 2014,32:2718-2726.
[17] Liu R, Bishop J, Zhu G, et al.Mortality risk stratification by combining BRAFV600E and TERT promoter mutations in papillary thyroid cancer: genetic duet of BRAF and TERT promoter mutations in thyroid cancer mortality[J].JAMA Oncol,2016 Sep 1.doi: 10.1001/jamaoncol.2016.3288.[Epub ahead of print] PubMed PMID, 27581851.
[18] Rabes H M, Demidchik E P, Sidorow J D, et al.Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-Chernobyl papillary thyroid carcinomas:biological, phenotypic, and clinical implications[J].Clin Cancer Res, 2000, 6:1093-1103.
[19] Nikiforova M N, Lynch R A, Biddinger P W, et al.RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma[J].J Clin Endocrinol Metab, 2003, 88:2318-2326.
[20] Nikiforov Y E, Seethala R R, Tallini G, et al.Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors[J].JAMA Oncol, 2016,2:1023-1029.
[21] Song Y S, Lim J A, Choi H, et al.Prognostic effects of TERT promoter mutations are enhanced by coexistence with BRAF or RAS mutations and strengthen the risk prediction by the ATA or TNM staging system in differentiated thyroid cancer patients[J].Cancer,2016,122(9): 1370-1379.
[22] Landa I, Ganly I, Chan T A, et al.Frequent somatic TERT promoter mutations in thyroid cancer: higher prevalence in advanced forms of the disease [J].Clin Endocrinol Metab,2013,98(9):E1562-E1566.
[23] Nikiforova M N, Wald A I, Roy S, et al.Targeted nextgeneration sequencing panel (ThyroSeq) for detection of mutations in thyroid cancer[J].Clin Endocrinol Metab,2013,98(11): E1852-E1860.
[24] Murugan A K, Xing M.Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene[J].Cancer Res, 2011, 71(13):4403-4411.