The landscape and therapeutic relevance of cancer-associated transcript fusions

Abstract

Transcript fusions as a result of chromosomal rearrangements have been a focus of attention in cancer as they provide attractive therapeutic targets. To identify novel fusion transcripts with the potential to be exploited therapeutically, we analyzed RNA sequencing, DNA copy number and gene mutation data from 4,366 primary tumor samples. To avoid false positives, we implemented stringent quality criteria that included filtering of fusions detected in RNAseq data from 364 normal tissue samples. Our analysis identified 7,887 high confidence fusion transcripts across 13 tumor types. Our fusion prediction was validated by evidence of a genomic rearrangement for 78 of 79 fusions in 48 glioma samples where whole genome sequencing data was available. Cancers with higher levels of genomic instability showed a corresponding increase in fusion transcript frequency, whereas tumor samples harboring fusions contained statistically significantly fewer driver gene mutations, suggesting an important role for tumorigenesis. We identified at least one in-frame protein kinase fusion in 324 of 4,366 samples (7.4%). Potentially druggable kinase fusions involving ALK, ROS, RET, NTRK, and FGFR gene families were detected in bladder carcinoma (3.3%), glioblastoma (4.4%), head and neck cancer (1.0%), low grade glioma (1.5%), lung adenocarcinoma (1.6%), lung squamous cell carcinoma (2.3%), and thyroid carcinoma (8.7%), suggesting a potential for application of kinase inhibitors across tumor types. In-frame fusion transcripts involving histone methyltransferase or histone demethylase genes were detected in 111 samples (2.5%) and may additionally be considered as therapeutic targets. In summary, we described the landscape of transcript fusions detected across a large number of tumor samples and revealed fusion events with clinical relevance that have not been previously recognized. Our results support the concept of basket clinical trials where patients are matched with experimental therapies based on their genomic profile rather than the tissue where the tumor originated.

Identification of novel cyclin gene fusion transcripts in endometrioid ovarian carcinomas

“…The genes NINJ2 , PAK1, PCMTD1, SNTB1 , and ZNF512 were also found fused with different partners in HGSC (Figure 4). 5 Taking all these results together, we see that all the mentioned genes were recurrently rearranged in ovarian cancer, admittedly at very low frequencies. Furthermore, 21 of the genes we found involved in fusions were previously reported in 35 different fusion transcripts in studies of breast cancer and 14 fusion transcripts were identified in lung cancer5, 31, 32 (Table 3), hinting that they may be generally relevant in carcinogenesis of different types.…”

“…The uniqueness of these fusion transcripts was checked against the Mitelman Database for Chromosome Aberrations and Gene Fusions in Cancer (https://cgap.nci.nih.gov/Chromosomes/Mitelman). Only the fusion transcripts KDMA5‐NINJ2 and NSD1‐ZNF346 were previously identified, by Yoshihara et al 5. in HGSC.…”

“…Though the fusions ESSRA‐C11orf20 ,16 CDKN2D‐WDFY2 14 and BCAM‐AKT2 17 were initially described as recurrent in HGSC at rates of 15%, 20% and 7%, respectively, the findings have not been validated by other groups or in different series 18. More than 700 samples were screened in other studies and fusion transcripts were found at frequencies ranging from 0.5% ( KAT6B‐ADK ) to 2.7% ( CRHR1‐KANSL1 ) 4, 5, 6, 7. It is worthy of note in the context that most studies focused on HGSC, whereas the other four types of ovarian carcinoma were less often investigated; only 63 endometrioid carcinomas, 36 clear cell carcinomas, and six mucinous carcinomas had been analyzed for fusion genes prior to this study 7, 16.…”

“…Although >700 samples have been analyzed so far, only a few recurrent transcripts were found, and always with a low rate of recurrence (0.5–5%). Two studies used the genomic data produced by the Cancer Genome Atlas project4, 5 to find that three fusion transcripts were recurrent in HGSC carcinomas: CCDC6‐ANK3 (found in 4 samples or 1% of the tumors), and COL14A1‐DEPTOR and KAT6B‐ADK (each found in 2 samples or 0.5%). Patch et al 6.…”

RNA‐sequencing identifies novel GREB1‐NCOA2 fusion gene in a uterine sarcoma with the chromosomal translocation t(2;8)(p25;q13)

“…It is a critical mediator of both estrogen‐stimulated proliferation of breast cancer cells and androgen‐stimulated proliferation of prostate cancer cells 13, 14. According to the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer (http://cgap.nci.nih.gov/Chromosomes/Mitelman), GREB1 was previously found involved in various types of neoplasia and with different partners: a GREB1‐E2F6 fusion was seen in T‐cell acute lymphoblastic leukemia15 and a GREB1‐PDE1A in adenocarcinoma of the prostate 16. Although its exact function in the cascade of hormone action remains unclear, GREB1 may regulate proliferation in hormone responsive ovarian and endometrial cancer cells and thus be a candidate for further consideration as a potential therapeutic target 17…”