دورية أكاديمية
Oncogenic Mutations in PI3K/AKT/mTOR Pathway Effectors Associate with Worse Prognosis in BRAF V600E -Driven Papillary Thyroid Cancer Patients.
| العنوان: | Oncogenic Mutations in PI3K/AKT/mTOR Pathway Effectors Associate with Worse Prognosis in BRAF V600E -Driven Papillary Thyroid Cancer Patients. |
|---|---|
| المؤلفون: | Pappa T; Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Ahmadi S; Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Marqusee E; Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Johnson HL; Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Nehs MA; Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Cho NL; Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Barletta JA; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Lorch JH; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Doherty GM; Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Lindeman NI; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Alexander EK; Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. ilanda@bwh.harvard.edu ekalexander@bwh.harvard.edu.; Harvard Medical School, Boston, Massachusetts., Landa I; Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. ilanda@bwh.harvard.edu ekalexander@bwh.harvard.edu.; Harvard Medical School, Boston, Massachusetts. |
| المصدر: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Aug 01; Vol. 27 (15), pp. 4256-4264. Date of Electronic Publication: 2021 Jun 04. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Denville, NJ : The Association, c1995- |
| مواضيع طبية MeSH: | Mutation*, Phosphatidylinositol 3-Kinases/*physiology , Proto-Oncogene Proteins B-raf/*genetics , Proto-Oncogene Proteins c-akt/*physiology , TOR Serine-Threonine Kinases/*physiology , Thyroid Cancer, Papillary/*genetics , Thyroid Neoplasms/*genetics, Adult ; Female ; Humans ; Male ; Middle Aged ; Prognosis ; Signal Transduction/physiology |
| مستخلص: | Purpose: The extent to which routine genomic sequencing can identify relevant secondary genomic alterations among BRAF V600E -mutant papillary thyroid carcinoma (PTC) is unknown. Such markers would prove highly valuable for prognostic purposes. Experimental Design: We reviewed clinicopathologic data of 225 patients with BRAF V600E -mutant PTC and integrated them with genomic data derived from targeted next-generation sequencing (NGS) on tumor specimens. We defined patient subgroups based on bona fide secondary oncogenic events (separate from BRAF V600E ) and compared their clinical features and outcomes with those without additional oncogenic alterations. Results: Additional oncogenic alterations were identified in 16% of tumors. Patients in the " BRAF +additional mutations" group were more likely to be at high American Thyroid Association (ATA) risk of recurrence (48.6% vs. 17.6%; P = 0.0009), had larger baseline tumor (2.7 vs. 1.9 cm; P = 0.0005) and more advanced stage at presentation (14.3% vs. 1.1% stage 4; P < 0.0001). Importantly, over a 65-month follow-up, disease-specific mortality (DSM) was increased when additional mutations were identified (13.8% vs. 1.4% in the BRAF -only group; P = 0.005). Separately, we identified a subcluster of patients harboring oncogenic mutations in key effectors of the PI3K/AKT/mTOR pathway, which were independently associated with DSM (OR = 47.9; 95% confidence interval, 3.5-1,246.5; P = 0.0043). Conclusions: Identification of additional PIK3/AKT/mTOR alterations in patients with BRAF V600E -mutant PTC provides important and actionable prognostic risk stratification. These data support genomic profiling of PTC tumors to inform prognosis and clinical strategy. (©2021 American Association for Cancer Research.) |
| References: | Davies L, Morris LGT, Haymart M, Chen AY, Goldenberg D, Morris J, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Disease State Clinical Review: the increasing incidence of thyroid cancer. Endocr Pract. 2015;21:686–96. Fagin JA, Wells SA Jr. Biologic and clinical perspectives on thyroid cancer. N Engl J Med. 2016;375:1054–67. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159:676–90. Xing M, Alzahrani AS, Carson KA, Shong YK, Kim TY, Viola D, et al. Association between BRAF V600E mutation and recurrence of papillary thyroid cancer. J Clin Oncol. 2015;33:42–50. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, 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. Thyroid. 2016;26:1–133. Kunstman JW, Juhlin CC, Goh G, Brown TC, Stenman A, Healy JM, et al. Characterization of the mutational landscape of anaplastic thyroid cancer via whole-exome sequencing. Hum Mol Genet. 2015;24:2318–29. Landa I, Ibrahimpasic T, Boucai L, Sinha R, Knauf JA, Shah RH, et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J Clin Invest. 2016;126:1052–66. Pozdeyev N, Gay L, Sokol ES, Hartmaier RJ, Deaver KE, Davis SN, et al. Genetic analysis of 779 advanced differentiated and anaplastic thyroid cancers. Clin Cancer Res. 2018;24:3059–68. Ibrahimpasic T, Xu B, Landa I, Dogan S, Middha S, Seshan V, et al. Genomic alterations in fatal forms of non-anaplastic thyroid cancer: identification of MED12 and RBM10 as novel thyroid cancer genes associated with tumor virulence. Clin Cancer Res. 2017;23:5970–80. Martinez-Jimenez F, Muinos F, Sentis I, Deu-Pons J, Reyes-Salazar I, Arnedo-Pac C, et al. A compendium of mutational cancer driver genes. Nat Rev Cancer. 2020;20:555–72. Melo M, da Rocha AG, Vinagre J, Batista R, Peixoto J, Tavares C, et al. TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. J Clin Endocrinol Metab. 2014;99:E754–65. Xing M, Liu R, Liu X, Murugan AK, Zhu G, Zeiger MA, et al. BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. J Clin Oncol. 2014;32:2718–26. Garcia EP, Minkovsky A, Jia Y, Ducar MD, Shivdasani P, Gong X, et al. Validation of OncoPanel: a targeted next-generation sequencing assay for the detection of somatic variants in cancer. Arch Pathol Lab Med. 2017;141:751–8. Wagle N, Berger MF, Davis MJ, Blumenstiel B, Defelice M, Pochanard P, et al. High-throughput detection of actionable genomic alterations in clinical tumor samples by targeted, massively parallel sequencing. Cancer Discov. 2012;2:82–93. Chakravarty D, Gao J, Phillips SM, Kundra R, Zhang H, Wang J, et al. OncoKB: a precision oncology knowledge base. JCO Precis Oncol. 2017;2017:PO.17.00011. Charles RP, Silva J, Iezza G, Phillips WA, McMahon M. Activating BRAF and PIK3CA mutations cooperate to promote anaplastic thyroid carcinogenesis. Mol Cancer Res. 2014;12:979–86. Tuttle RM, Haugen B, Perrier ND. Updated American Joint Committee on Cancer/tumor-node-metastasis staging system for differentiated and anaplastic thyroid cancer (eighth edition): what changed and why?. Thyroid. 2017;27:751–6. Wong KS, Dong F, Telatar M, Lorch JH, Alexander EK, Marqusee E, et al. Papillary thyroid carcinoma with high-grade features versus poorly differentiated thyroid carcinoma: an analysis of clinicopathologic and molecular features and outcome. Thyroid. 2021. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1. Xing M, Alzahrani AS, Carson KA, Viola D, Elisei R, Bendlova B, et al. Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA. 2013;309:1493–501. Perera D, Ghossein R, Camacho N, Senbabaoglu Y, Seshan V, Li J, et al. Genomic and transcriptomic characterization of papillary microcarcinomas with lateral neck lymph node metastases. J Clin Endocrinol Metab. 2019;104:4889–99. Garrido-Castro AC, Spurr LF, Hughes ME, Li YY, Cherniack AD, Kumari P, et al. Genomic characterization of de novo metastatic breast cancer. Clin Cancer Res. 2021;27:1105–18. Garcia-Rostan G, Costa AM, Pereira-Castro I, Salvatore G, Hernandez R, Hermsem MJ, et al. Mutation of the PIK3CA gene in anaplastic thyroid cancer. Cancer Res. 2005;65:10199–207. Ricarte-Filho JC, Ryder M, Chitale DA, Rivera M, Heguy A, Ladanyi M, et al. Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer Res. 2009;69:4885–93. Liu Z, Hou P, Ji M, Guan H, Studeman K, Jensen K, et al. Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers. J Clin Endocrinol Metab. 2008;93:3106–16. Lai WA, Liu CY, Lin SY, Chen CC, Hang JF. Characterization of driver mutations in anaplastic thyroid carcinoma identifies RAS and PIK3CA mutations as negative survival predictors. Cancers. 2020;12:1973. Qin Y, Wang JR, Wang Y, Iyer P, Cote GJ, Busaidy NL, et al. Clinical utility of circulating cell-free DNA mutations in anaplastic thyroid carcinoma. Thyroid. 2021. Wong K, Di Cristofano F, Ranieri M, De Martino D, Di Cristofano A. PI3K/mTOR inhibition potentiates and extends palbociclib activity in anaplastic thyroid cancer. Endocr Relat Cancer. 2019;26:425–36. Liu R, Liu D, Trink E, Bojdani E, Ning G, Xing M. The Akt-specific inhibitor MK2206 selectively inhibits thyroid cancer cells harboring mutations that can activate the PI3K/Akt pathway. J Clin Endocrinol Metab. 2011;96:E577–85. Miller KA, Yeager N, Baker K, Liao XH, Refetoff S, Di Cristofano A. Oncogenic Kras requires simultaneous PI3K signaling to induce ERK activation and transform thyroid epithelial cells in vivo. Cancer Res. 2009;69:3689–94. Wagle N, Grabiner BC, Van Allen EM, Amin-Mansour A, Taylor-Weiner A, Rosenberg M, et al. Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med. 2014;371:1426–33. Tolcher AW, Peng W, Calvo E. Rational approaches for combination therapy strategies targeting the MAP kinase pathway in solid tumors. Mol Cancer Ther. 2018;17:3–16. |
| المشرفين على المادة: | EC 2.7.1.1 (MTOR protein, human) EC 2.7.11.1 (BRAF protein, human) EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) EC 2.7.11.1 (TOR Serine-Threonine Kinases) |
| تواريخ الأحداث: | Date Created: 20210605 Date Completed: 20220401 Latest Revision: 20220401 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1158/1078-0432.CCR-21-0874 |
| PMID: | 34088725 |
| قاعدة البيانات: | MEDLINE |
كن أول من يترك تعليقا!