Pan-tumor survey of RET fusions as detected by next-generation RNA sequencing identified RET fusion positive colorectal carcinoma as a unique molecular subset.

Background: RET fusions are driver alterations in cancer and are most commonly found in non-small cell lung cancer and well-differentiated thyroid cancer. However, RET fusion have been reported in other solid tumors.
Material and Methods: A retrospective analysis of RET+ solid malignancies identified by targeted RNA sequencing and whole transcriptome sequencing of clinical tumor samples performed at Caris Life Science (Phoenix, AZ).
Results: As of March 22, 2022, a total of 378 RET+ solid malignancies were identified in 15 different tumor types and carcinoma of unknown primary (CUP) that underwent next-generation RNA sequencing. RET+ NSCLC and RET+ thyroid cancer constituted 66.9% and 11.1% of the RET+ solid malignancies, respectively. RET+ colorectal adenocarcinoma and RET+ breast adenocarcinoma constituted 10.1% and 2.6%, respectively. The estimated frequency of RET fusions within specific tumor types were NSCLC 0.7%, thyroid cancer 3.1%, colorectal cancer 0.2% and breast cancer 0.1%. KIF5B (46.8%) was the most common fusion partner followed by CCDC6 (28.3%) and NCOA4 (13.8%) in RET+ solid tumors. KIF5B-RET was the dominant fusion variant in RET+ NSCLC, NCOA4-RET was the dominant variant in RET+ colorectal carcinoma, and CCDC6-RET was the dominant variant in thyroid cancer. The most common single gene alterations in RET+ tumors were TP53 (34.8%), RASA1 (14.3%) and ARIAD1A (11.6%). RET+ CRC had a high median TMB of 20.0 and were commonly MSI-H.
Conclusions: RET fusions were identified in multiple tumor types. With a higher median TMB and commonly MSI-H, RET fusion positive CRC may be a unique molecular subset of CRC.
Competing Interests: Declaration of Competing Interest There was no funding allocated for this research and there are no direct conflicts of interest. Potential COI from all authors are listed below. MN is on the advisory board for AstraZeneca, Daiichi Sankyo, Takeda, Novartis, EMD Serono, Janssen, Pfizer, Eli Lilly and Company, Bayer and Genentech; consultant for Caris Life Sciences (virtual tumor board); speaker for Blueprint Medicines, Janssen, Mirati and Takeda; and reports travel support from AnHeart Therapeutics.  DB has no disclosures. YB, JX, JJS and DS are employees and shareholders of Caris Life Sciences. MNA discloses the following: Speaker Bureau: IPSEN, AstraZeneca, Guardant Health. External advisory board: CTI-Facts (CRO company). CK served as a consultant for Novartis, Janssen, Astrazeneca, Sanofi, PierianDx, Diffuse pharmaceuticals, Mirati, Jazz Pharmaceuticals, and Arcus Biosciences, and received research funding (to institution) from AstraZeneca, Bristol-Myers Squibb, Novartis, Genentech, Janssen, Regeneron, Debiopharm, Karyopharm, and Blueprint Medicines. JN discloses the following: Consulting: Aadi Biosciences, Astra Zeneca, Bristol Myers Squibb, Fujirebio, G1 Therapeutics, Genentech, Mindmed, Naveris, Takeda, Western Oncolytics., Research Support: Genentech, Merck, Intellectual Property: Cansera and Ownership Interests: Cansera, Epic Sciences, Indee Bio, Quantgene. WMK has stock ownership of Caris Life Sciences. MS has received honoraria from AstraZeneca, Bayer, Roche, Celgene, BMS, Genentech, Novartis and Lilly. MS is a consultant for Genentech and Novartis and has received research support from AstraZeneca, Roche and Takeda. LER has received research support from BMS, Astra-Zeneca, Roche, Pfizer, Merck, Velos, Guardant Health, Natera, Genentech, Bio Alta. BH has grants or contracts from Boehringer Ingelheim, Astra Zeneca, Merck, BMS, Advaxis, Amgen, AbbVie, Daiichi, Pfizer, GSK, Beigene, Janssen, has received consulting fees from Veracyte and has been on monitoring or advisory boards for Astra Zeneca, Boehringer Ingelheim, Apollomics, Janssen, Takeda, Merck, BMS, Genentech, Pfizer, Eli-Lilly, TPT, Arcus and Merus. SHIO has stock ownership and was on the scientific advisory board of Turning Point Therapeutics Inc (until Feb 28, 2019), is a member of the SAB of Elevation Oncology, and has received speaker honorarium from Merck, Roche/Genentech, Astra Zeneca, Takeda/ARIAD and Pfizer; has received advisory fees from Roche/Genentech, Astra Zeneca, Takeda/ARIAD, Pfizer, Foundation Medicine Inc, Spectrum, Daiichi Sankyo, Jassen/JNJ, and X-Covery.
(Copyright © 2023. Published by Elsevier Inc.)