Aberrant MUC1-TRIM46-KRTCAP2 Chimeric RNAs in High-Grade Serous Ovarian Carcinoma.
High-grade serous ovarian cancer (HGSC) is among the most lethal forms of cancer in women. By analyzing the mRNA-seq reads from The Cancer Genome Atlas (TCGA), we uncovered a novel cancer-enriched chimeric RNA as the result of splicing between MUC1, a highly glycosylated transmembrane mucin, TRIM46, a tripartite motif containing protein, and KRTCAP2, a keratinocyte associated protein. Experimental analyses by RT-PCR (reverse transcription PCR) and Sanger sequencing using an in-house cohort of 59 HGSC patient tumors revealed a total of six MUC1-TRIM46-KRTCAP2 isoforms joined by different annotated splice sites between these genes. These chimeric isoforms are not detected in non-cancerous ovaries, yet are present in three out of every four HGSC patient tumors, a significant frequency given the exceedingly heterogeneous nature of this disease. Transfection of the cDNA of MUC1-TRIM46-KRTCAP2 isoforms in mammalian cells led to the translation of mutant MUC1 fusion proteins that are unglycosylated and cytoplasmically localized as opposed to the cell membrane, a feature resembling the tumor-associated MUC1. Because the parental MUC1 is overexpressed in 90% of HGSC tumors and has been proposed as a clinical biomarker and therapeutic target, the chimeric MUC1-TRIM46-KRTCAP2 isoforms identified in this report could represent significantly better MUC1 variants for the same clinical utilities.
Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA. kalpana.kann@gmail.com.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. kalpana.kann@gmail.com.
Kalpana
K
Kannan
Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Gonakarimi188@gmail.com.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Gonakarimi188@gmail.com.
Gona Karimi
GK
Kordestani
Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA. anikagalagoda@gmail.com.
Anika
A
Galagoda
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. coarfa@bcm.edu.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. coarfa@bcm.edu.
Cristian
C
Coarfa
Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA. yen@bcm.edu.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. yen@bcm.edu.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. yen@bcm.edu.|Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030, USA. yen@bcm.edu.
Laising
L
Yen
MUC1; RNA-seq; TCGA; chimeric RNA; high-grade serous ovarian cancer