Tuft cell-like carcinomas: novel cancer subsets present in multiple organs sharing a unique gene expression signature

• Published in: British journal of cancer Vol. 127; no. 10; pp. 1876 - 1885
• Main Authors: Yamada, Yosuke, Bohnenberger, Hanibal, Kriegsmann, Mark, Kriegsmann, Katharina, Sinn, Peter, Goto, Norihiro, Nakanishi, Yuki, Seno, Hiroshi, Chigusa, Yoshitsugu, Fujimoto, Masakazu, Minamiguchi, Sachiko, Haga, Hironori, Simon, Ronald, Sauter, Guido, Ströbel, Philipp, Marx, Alexander
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.11.2022; Nature Publishing Group
• Subjects: 631/67/395; 692/4028/67/395; Apoptosis; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Carcinoma; Cell differentiation; Chemoreception; Drug Resistance; Epidemiology; Epithelial cells; Gene expression; Genomes; Immunohistochemistry; Innate immunity; Molecular Medicine; Oncology; Poly(ADP-ribose) polymerase; Sox9 protein; Transient receptor potential proteins; Tumors
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-022-01957-6

Background Tuft cells are chemosensory epithelial cells playing a role in innate immunity. Recent studies revealed cancers with a tuft cell-like gene expression signature in the thorax. We wondered whether this signature might also occur in extrathoracic cancers. Methods We examined mRNA expression of tuft cell markers ( POU2F3 , GFI1B , TRPM5 , SOX9 , CHAT , and AVIL ) in 19 different types of cancers in multiple extrathoracic organs with The Cancer Genome Atlas (TCGA) ( N  = 6322). Four different extrathoracic cancers in our local archives ( N  = 909) were analysed by immunohistochemistry. Results Twenty-two (0.35%) extrathoracic tumours with co-expression of POU2F3 and other tuft cell markers were identified in various TCGA datasets. Twelve of the 22 “tuft cell-like tumours” shared poor differentiation and a gene expression pattern, including KIT , anti-apoptotic BCL2 , and ionocyte-associated genes. In our archival cases, eleven (1.21%) tumours co-expressing POU2F3, KIT, and BCL2 on immunohistochemistry, i.e., were presumable tuft cell-like cancers. In three among five TCGA cohorts, the tuft cell-like cancer subsets expressed SLFN11 , a promising biomarker of PARP inhibitor susceptibility. Conclusions Tuft cell-like carcinomas form distinct subsets in cancers of many organs. It appears warranted to investigate their shared gene expression signature as a predictive biomarker for novel therapeutic strategies.