BRAFV600E-Associated Gene Expression Profile: Early Changes in the Transcriptome, Based on a Transgenic Mouse Model of Papillary Thyroid Carcinoma.

Abstract

BACKGROUND:

The molecular mechanisms driving the papillary thyroid carcinoma (PTC) are still poorly understood. The most frequent genetic alteration in PTC is the BRAFV600E mutation--its impact may extend even beyond PTC genomic profile and influence the tumor characteristics and even clinical behavior.

METHODS:

In order to identify BRAF-dependent signature of early carcinogenesis in PTC, a transgenic mouse model with BRAFV600E-induced PTC was developed. Mice thyroid samples were used in microarray analysis and the data were referred to a human thyroid dataset.

RESULTS:

Most of BRAF(+) mice developed malignant lesions. Nevertheless, 16% of BRAF(+) mice displayed only benign hyperplastic lesions or apparently asymptomatic thyroids. After comparison of non-malignant BRAF(+) thyroids to BRAF(-) ones, we selected 862 significantly deregulated genes. When the mouse BRAF-dependent signature was transposed to the human HG-U133A microarray, we identified 532 genes, potentially indicating the BRAF signature (representing early changes, not related to developed malignant tumor). Comparing BRAF(+) PTCs to healthy human thyroids, PTCs without BRAF and RET alterations and RET(+), RAS(+) PTCs, 18 of these 532 genes displayed significantly deregulated expression in all subgroups. All 18 genes, among them 7 novel and previously not reported, were validated as BRAFV600E-specific in the dataset of independent PTC samples, made available by The Cancer Genome Atlas Project.

CONCLUSION:

The study identified 7 BRAF-induced genes that are specific for BRAF V600E-driven PTC and not previously reported as related to BRAF mutation or thyroid carcinoma: MMD, ITPR3, AACS, LAD1, PVRL3, ALDH3B1, and RASA1. The full signature of BRAF-related 532 genes may encompass other BRAF-related important transcripts and require further study.

• Authors: Dagmara Rusinek, Michal Swierniak, Ewa Chmielik, Monika Kowal, Malgorzata Kowalska, Renata Cyplinska, Agnieszka Czarniecka, Wojciech Piglowski, Joanna Korfanty, Mykola Chekan, Jolanta Krajewska, Sylwia Szpak-Ulczok, Michal Jarzab, Wieslawa Widlak, Barbara Jarzab
• Journal: PloS one (PLoS One) Vol. 10 Issue 12 Pg. e0143688 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26625260 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins B-raf

Topics

• Animals
• Carcinoma (genetics, metabolism)
• Carcinoma, Papillary
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice
• Mice, Transgenic
• Microarray Analysis
• Mutation, Missense
• Proto-Oncogene Proteins B-raf (genetics)
• Thyroid Cancer, Papillary
• Thyroid Neoplasms (genetics, metabolism)
• Transcriptome