Mutational Footprint of Platinum Chemotherapy in a Secondary Thyroid Cancer.

Although papillary thyroid carcinoma (PTC) is the most frequent endocrine tumor with a generally excellent prognosis, a patient developed a clinically aggressive PTC eleven years after receiving platinum chemotherapy for ovarian endometrioid adenocarcinoma. Germline and somatic analyses of multi-temporal and multi-regional molecular profiles indicated that ovarian and thyroid tumors did not share common genetic alterations. PTC tumors had driver events associated with aggressive PTC behavior, an RBPMS-NTRK3 fusion and a TERT promoter mutation. Spatial and temporal genomic heterogeneity analysis indicated a close link between anatomical locations and molecular patterns of PTC. Mutational signature analyses demonstrated a molecular footprint of platinum exposure, and that aggressive molecular drivers of PTC were linked to prior platinum-associated mutagenesis. This case provides a direct association between platinum chemotherapy exposure and secondary solid tumor evolution, in specific aggressive thyroid carcinoma, and suggests that uniform clinical assessments for secondary PTC after platinum chemotherapy may warrant further evaluation. ### Competing Interest Statement E.M.V. has received research support (to institution) from Novartis and Bristol Myers Squibb. E.M.V. serves as a consultant or on scientific advisory boards of Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Monte Rosa Therapeutics, Manifold Bio, and Janssen. E.M.V. has equity in Tango Therapeutics, Genome Medical, Genomic Life, Syapse, Enara Bio, Manifold Bio, Monte Rosa, and Microsoft. E.M.V. has filed institutional patents on chromatin mutations and immunotherapy response and has intermittent legal consulting on patents for Foaley & Hoag. E.M.V. and B.R. also have institutional patents filed on methods for clinical interpretation. J.C. is an employee of PathAI and has been a consultant to Tango Therapeutics. D.S. is an employee of Vor Biopharma. M.X.H. is an employee of Genentech/Roche and has been a consultant to Amplify Medicines, Ikena Oncology, and Janssen. J.H.L. received the research support from Novartis, BMS, Takeda, and Bauer and has been a consultant for Novartis Bauer.