PLoS ONE (Jan 2015)

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

  • 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

DOI
https://doi.org/10.1371/journal.pone.0143688
Journal volume & issue
Vol. 10, no. 12
p. e0143688

Abstract

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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.