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

Misako Nagasaka; Danielle Brazel; Yasmine Baca; Joanne Xiu; Mohammed Najeeb Al-Hallak; Chul Kim; Jorge Nieva; Jeffrey J Swensen; David Spetzler; Wolfgang Michael Korn; Mark A Socinski; Luis E Raez; Balazs Halmos; Sai-Hong Ignatius Ou

doi:10.1016/j.tranon.2023.101744

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

Transl Oncol. 2023 Oct:36:101744. doi: 10.1016/j.tranon.2023.101744. Epub 2023 Jul 27.

Authors

Affiliations

¹ University of California Irvine School of Medicine, Orange, CA, USA; Chao Family Comprehensive Cancer Center, Orange, CA, USA; Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan. Electronic address: nagasakm@hs.uci.edu.
² University of California Irvine School of Medicine, Orange, CA, USA.
³ Caris Life Sciences, Phoenix, AZ, USA.
⁴ Karmanos Cancer Institute, Detroit, MI, USA.
⁵ Georgetown Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, USA.
⁶ USC Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
⁷ University of California San Francisco, San Francisco, CA, USA.
⁸ Advent Health Cancer Institute, Orlando, FL, USA.
⁹ Memorial Healthcare System, Pembroke Pines, FL, USA.
¹⁰ Montefiore Health System, New York, NY, USA.
¹¹ University of California Irvine School of Medicine, Orange, CA, USA; Chao Family Comprehensive Cancer Center, Orange, CA, USA.

Abstract

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.

Keywords: Next-generation sequencing; Pan-tumor survey; Pralsetinib; RET fusion; RNA sequencing; Selective RET inhibitors; Selpercatinib.