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. 2022 Jul;11(13):2541-2549.
doi: 10.1002/cam4.4561. Epub 2022 May 4.

NTRK fusion positive colorectal cancer is a unique subset of CRC with high TMB and microsatellite instability

Hui Wang  1 , Zhi-Wei Li  2 , Qiuxiang Ou  3 , Xue Wu  3 , Misako Nagasaka  4 , Yang Shao  3   5 , Sai-Hong Ignatius Ou  6 , Yu Yang  7
Affiliations

NTRK fusion positive colorectal cancer is a unique subset of CRC with high TMB and microsatellite instability

Hui Wang et al. Cancer Med. 2022 Jul.

Abstract

TRK fusions are rare but targetable mutations which occur across a wide variety of cancer types. We report the prevalence of approximately 0.7% for NTRK-positive colorectal cancer (CRC) by genetically profiling 2519 colonic and rectal tumors. The aberrations of APC and TP53 frequently co-occurred with NTRK gene fusions, whereas RAS/BRAF oncogenic alterations and NTRK fusions were almost always mutually exclusive. NTRK-driven colorectal cancer patients demonstrated increased TMB (median = 53 mut/MB, 95% CI: 36.8-68.0 mut/MB), high microsatellite instability, and an enrichment for POLE/POLD1 mutations when compared to molecularly unstratified colorectal cancer population. These data shed light on possible future approach of multimodality treatment regimen including TRK-targeted therapy and immune checkpoint inhibitor therapy in NTRK-positive CRCs.

Keywords: POLE/POLD1; NTRK; colorectal cancer; gene fusions; microsatellite instability; tumor mutation burden.

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Conflict of interest statement

QO and XW are the employees of Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China. MN received honorarium from Astra Zeneca and Tempus. YS is an employee and shareholder of Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China. SHIO has received speaking/advisory honorarium from Pfizer, Merck, Roche/Genentech, Takeda/ARIAD, and AstraZeneca. SHIO is a stock owner and former member of the scientific advisory board of Turning Point Therapeutics, Inc. The remaining authors have no conflict of interest to declare.

Figures

FIGURE 1
FIGURE 1
NTRK fusions in colorectal cancer. (A). Colon tumor site. (B). Venn diagram of the relationships between NTRK+ colorectal cancer (CRC), high tumor mutational burden (TMB), and positive microsatellite instability status (MSI). (C). The comparison of TMB between NTRK+ CRC, molecularly unstratified CRC, NTRK+ non‐CRC, and CRC that carried other kinase fusions
FIGURE 2
FIGURE 2
Genomic features observed in NTRK+ colorectal cancers. (A) Co‐mutation plot illustrating alterations with the occurrence of at least one third of the NTRK+ cohort. Each column represents a NTRK‐fusion positive patient. Alteration types are color‐coded shown on the right panel. Patient's clinicopathological features and tumor mutation burden were shown on top of the co‐mutation plot. (B) The lollipop plot mapping identified mutations of POLD1 or POLE to protein sequences
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