Dora Dias-Santagata, PhD, FACMG - Assistant Professor of Pathology, Harvard Medical School, Assistant Molecular Pathologist, Massachusetts General Hospital
Center for Integrated Diagnostics - Molecular Pathology Unit - GRJ-2
55 Fruit Street
Boston, MA 02114
Targeted cancer therapies require the rapid and accurate identification of genetic abnormalities predictive of therapeutic response. Our lab developed the first high-throughput clinical genotyping platform designed to detect specific mutations in a broad range of human malignancies and enable prospective patient selection to the most appropriate targeted treatments. To obtain a more complete tumor genetic fingerprint and expand the scope of therapeutic options available to each patient, we improved upon our original platform by the development of next generation sequencing technologies. Our clinical molecular panels identify somatic mutations, genetic rearrangements and copy number alterations in a wide range of solid tumors and hematopoietic malignancies.
Our primary research focus has been to explore the genetic signatures of human malignancies, to improve their diagnosis and clinical management. One key area of interest has been the study of thyroid cancer. Our genetic and clinicopathological characterization of follicular variant of papillary thyroid carcinoma (FVPTC), which can be challenging to diagnose: (1) supported the notion that FVPTC is a heterogeneous group of tumors composed of distinct biological entities;
(2) identified therapeutically relevant alterations in a subset of cases; and (3) revealed a correlation between BRAF mutation and infiltrative tumor behavior, which is an important finding, as it highlighted the prognostic value of molecular diagnostics in FVPTC. Our large-scale genomic analysis of aggressive forms of thyroid Hürthle cell carcinoma (HCC) demonstrated that HCC are driven by two major mechanisms: recurrent mutations in complex I of the mitochondrial electron transport chain and early widespread chromosomal losses that result in a near-haploid genome (widespread LOH), both of which are maintained during metastatic progression. Notably, we found that widespread LOH in primary HCC was the most significant predictor of poor outcome in this cohort, being significantly associated with the development of distant metastases and with decreased recurrence-free survival. The potential clinical relevance of widespread LOH as a prognostic marker in HCC is driving additional collaborations and assay development efforts.
We have also been interested in the molecular characterization of rare tumor types, which led to the identification of clinically relevant genetic alterations in Merkel cell carcinoma, pleomorphic xanthoastrocytoma and salivary duct carcinoma. We have developed research collaborations with the MGH Thoracic Oncology, the Endocrine Unit and the Gastrointestinal Cancer teams, to uncover novel genetic drivers of malignancy, monitor disease progression, and identify mechanism of acquired resistance to therapy.
Dias-Santagata D, Lennerz JK, Sadow PM, Frazier RP, Raju SG, Henry D, Chung T, Kherani J, Rothenberg SM, Wirth LJ. Response to RET-Specific Therapy in RET Fusion-Positive Anaplastic Thyroid Carcinoma. Thyroid 2020. doi: 10.1089/ thy.2019.0477. Epub: 2020 Apr 15.
Gopal RK, Kübler K, Calvo SE, Polak P, Livitz D, Rosebrock D, Sadow PM, Campbell B, Donovan SE, Amin S, Gigliotti BJ, Grabarek Z, Hess JM, Stewart C, Braunstein LZ, Arndt PF, Mordecai S, Shih A, Chavez F, Zhan T, Lubitz C, Kim, Iafrate AJ, Wirth L, Parangi S, Leshchiner I, Daniels GH, Mootha VK, Dias-Santagata D*, Getz G*, McFadden DG*. Widespread chromosomal losses and mitochondrial DNA alterations as genetic drivers in Hürthle cell carcinoma. Cancer Cell 2018 Aug 13;34(2):242-255.e5.
McFadden DG*, Dias-Santagata D*, Sadow PM, Lynch KD, Lubitz C, Donovan SE, Zheng Z, Le L, Iafrate AJ, Daniels GH. Identification of oncogenic mutations and gene fusions in the follicular variant of papillary thyroid carcinoma. J Clin Endocrinol Metab 2014; 99(11):E2457-62.
Nardi V, Sadow PM, Juric D, Zhao D, Cosper AK, Bergethon K, Scialabba VL, Batten JM, Borger DR, Iafrate AJ, Heist RS, Lawrence DP, Flaherty KT, Bendell JC, Deschler D, Li Y, Wirth LJ, Dias- Santagata D. Detection of novel actionable genetic changes in salivary duct carcinoma helps direct patient treatment. Clin Cancer Res 2013; 19(2):480-90.