ECE2016 Guided Posters Thyroid Cancer (10 abstracts)
Genomic alterations of anaplastic thyroid carcinoma detected by targeted massive parallel sequencing of a BRAFV600E mutation-prevalent area
Yun Jae Chung 3 , Min Ji Jeon 1 , Sung Min Chung 2 , Deokhoon Kim 2 , Hyemi Kwon 1 , Won Gu Kim 1 , Young Kee Shong 1 , Dong Eun Song 2 & Won Bae Kim 1
1Depatment of Internal Medicine, Asan Medical Center, Seoul, Republic of Korea; 2Department of Pathology, Asan Medical Center, Seoul, Republic of Korea; 3Department of Internal Medicine, Chung-Ang University Hospital, Seoul, Republic of Korea.
Background: Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid cancer and has no effective therapy. Due to its dismal prognosis, it is vital to understand the genetic alterations of ATC and identify effective molecular targets. We performed targeted next-generation sequencing to investigate the mutational profile of ATC using a massive parallel sequencing approach.
Methods: DNA from formalin-fixed, paraffin-embedded archival samples of 11 ATCs and normal matched pairs were used. We identified 45 genetic alterations by targeted exome sequencing. They were validated by mass spectrometric genotyping and direct Sanger sequencing.
Results: The most commonly mutated gene was BRAF identified in ten samples (91%); all showed the V600E point mutation. A KRAS point mutation was observed in the one sample (9%) without the BRAF V600E mutation. All 11 ATCs harboured BRAF or RAS mutations, reflecting the possibility that differentiated thyroid carcinomas progress to ATCs after the accumulation of mutations. A loss of function mutation of TP53 was observed in eight samples (73%) and a PIK3CA mutation was observed in two samples (18%). We found 29 novel mutated genes that had not previously been associated with ATC. Of these, loss of function mutations of NF2, KMT2D and PKHD1 were repeatedly seen in three samples (27%), two samples (18%) and two samples (18%), respectively. Using direct Sanger sequencing, we also found two samples (18%) with a RASAL1 mutation. KMT2D and RASAL1 mutations were significantly associated with shorter ATC patient survival.
Conclusions: In this comprehensive analysis of ATCs using targeted massive parallel sequencing identified several novel mutations of ATCs, such as loss of function mutations of NF2 or KMT2D. Future studies are needed to confirm the role of these novel mutations as independent drivers for ATC development.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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