Abstract
Background: The BRAF protein kinase is widely studied as a cancer driver and therapeutic target. However, the regulation of its expression is not completely understood. Results: Taking advantage of the RNA-seq data of more than 4800 patients belonging to 9 different cancer types, we show that BRAF mRNA exists as a pool of 3 isoforms (reference BRAF, BRAF-X1, and BRAF-X2) that differ in the last part of their coding sequences, as well as in the length (BRAF-ref: 76 nt; BRAF-X1 and BRAF-X2: up to 7 kb) and in the sequence of their 3'UTRs. The expression levels of BRAF-ref and BRAF-X1/X2 are inversely correlated, while the most prevalent among the three isoforms varies from cancer type to cancer type. In melanoma cells, the X1 isoform is expressed at the highest level in both therapy-naïve cells and cells with acquired resistance to vemurafenib driven by BRAF gene amplification or expression of the Δ[3-10] splicing variant. In addition to the BRAF-ref protein, the BRAF-X1 protein (the full length as well as the Δ[3-10] variant) is also translated. The expression levels of the BRAF-ref and BRAF-X1 proteins are similar, and together they account for BRAF functional activities. In contrast, the endogenous BRAF-X2 protein is hard to detect because the C-terminal domain is selectively recognized by the ubiquitin-proteasome pathway and targeted for degradation. Conclusions: By shedding light on the repertoire of BRAF mRNA and protein variants, and on the complex regulation of their expression, our work paves the way to a deeper understanding of a crucially important player in human cancer and to a more informed development of new therapeutic strategies.
| Original language | English (US) |
|---|---|
| Article number | 85 |
| Journal | Molecular Cancer |
| Volume | 16 |
| Issue number | 1 |
| DOIs | |
| State | Published - Apr 28 2017 |
Fingerprint
Keywords
- BRAF
- Exon-spanning reads
- Melanoma
- Protein variants
- RNA-sequencing
- Transcript variants
ASJC Scopus subject areas
- Molecular Medicine
- Oncology
- Cancer Research
Cite this
The landscape of BRAF transcript and protein variants in human cancer. / Marranci, Andrea; Jiang, Zhijie; Vitiello, Marianna; Guzzolino, Elena; Comelli, Laura; Sarti, Samanta; Lubrano, Simone; Franchin, Cinzia; Echevarría-Vargas, Ileabett; Tuccoli, Andrea; Mercatanti, Alberto; Evangelista, Monica; Sportoletti, Paolo; Cozza, Giorgio; Luzi, Ettore; Capobianco, Enrico; Villanueva, Jessie; Arrigoni, Giorgio; Signore, Giovanni; Rocchiccioli, Silvia; Pitto, Letizia; Tsinoremas, Nicholas; Poliseno, Laura.
In: Molecular Cancer, Vol. 16, No. 1, 85, 28.04.2017.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The landscape of BRAF transcript and protein variants in human cancer
AU - Marranci, Andrea
AU - Jiang, Zhijie
AU - Vitiello, Marianna
AU - Guzzolino, Elena
AU - Comelli, Laura
AU - Sarti, Samanta
AU - Lubrano, Simone
AU - Franchin, Cinzia
AU - Echevarría-Vargas, Ileabett
AU - Tuccoli, Andrea
AU - Mercatanti, Alberto
AU - Evangelista, Monica
AU - Sportoletti, Paolo
AU - Cozza, Giorgio
AU - Luzi, Ettore
AU - Capobianco, Enrico
AU - Villanueva, Jessie
AU - Arrigoni, Giorgio
AU - Signore, Giovanni
AU - Rocchiccioli, Silvia
AU - Pitto, Letizia
AU - Tsinoremas, Nicholas
AU - Poliseno, Laura
PY - 2017/4/28
Y1 - 2017/4/28
N2 - Background: The BRAF protein kinase is widely studied as a cancer driver and therapeutic target. However, the regulation of its expression is not completely understood. Results: Taking advantage of the RNA-seq data of more than 4800 patients belonging to 9 different cancer types, we show that BRAF mRNA exists as a pool of 3 isoforms (reference BRAF, BRAF-X1, and BRAF-X2) that differ in the last part of their coding sequences, as well as in the length (BRAF-ref: 76 nt; BRAF-X1 and BRAF-X2: up to 7 kb) and in the sequence of their 3'UTRs. The expression levels of BRAF-ref and BRAF-X1/X2 are inversely correlated, while the most prevalent among the three isoforms varies from cancer type to cancer type. In melanoma cells, the X1 isoform is expressed at the highest level in both therapy-naïve cells and cells with acquired resistance to vemurafenib driven by BRAF gene amplification or expression of the Δ[3-10] splicing variant. In addition to the BRAF-ref protein, the BRAF-X1 protein (the full length as well as the Δ[3-10] variant) is also translated. The expression levels of the BRAF-ref and BRAF-X1 proteins are similar, and together they account for BRAF functional activities. In contrast, the endogenous BRAF-X2 protein is hard to detect because the C-terminal domain is selectively recognized by the ubiquitin-proteasome pathway and targeted for degradation. Conclusions: By shedding light on the repertoire of BRAF mRNA and protein variants, and on the complex regulation of their expression, our work paves the way to a deeper understanding of a crucially important player in human cancer and to a more informed development of new therapeutic strategies.
AB - Background: The BRAF protein kinase is widely studied as a cancer driver and therapeutic target. However, the regulation of its expression is not completely understood. Results: Taking advantage of the RNA-seq data of more than 4800 patients belonging to 9 different cancer types, we show that BRAF mRNA exists as a pool of 3 isoforms (reference BRAF, BRAF-X1, and BRAF-X2) that differ in the last part of their coding sequences, as well as in the length (BRAF-ref: 76 nt; BRAF-X1 and BRAF-X2: up to 7 kb) and in the sequence of their 3'UTRs. The expression levels of BRAF-ref and BRAF-X1/X2 are inversely correlated, while the most prevalent among the three isoforms varies from cancer type to cancer type. In melanoma cells, the X1 isoform is expressed at the highest level in both therapy-naïve cells and cells with acquired resistance to vemurafenib driven by BRAF gene amplification or expression of the Δ[3-10] splicing variant. In addition to the BRAF-ref protein, the BRAF-X1 protein (the full length as well as the Δ[3-10] variant) is also translated. The expression levels of the BRAF-ref and BRAF-X1 proteins are similar, and together they account for BRAF functional activities. In contrast, the endogenous BRAF-X2 protein is hard to detect because the C-terminal domain is selectively recognized by the ubiquitin-proteasome pathway and targeted for degradation. Conclusions: By shedding light on the repertoire of BRAF mRNA and protein variants, and on the complex regulation of their expression, our work paves the way to a deeper understanding of a crucially important player in human cancer and to a more informed development of new therapeutic strategies.
KW - BRAF
KW - Exon-spanning reads
KW - Melanoma
KW - Protein variants
KW - RNA-sequencing
KW - Transcript variants
UR - http://www.scopus.com/inward/record.url?scp=85018436573&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018436573&partnerID=8YFLogxK
U2 - 10.1186/s12943-017-0645-4
DO - 10.1186/s12943-017-0645-4
M3 - Article
C2 - 28454577
AN - SCOPUS:85018436573
VL - 16
JO - Molecular Cancer
JF - Molecular Cancer
SN - 1476-4598
IS - 1
M1 - 85
ER -