Abstract: LB MON 58

Whole-Exome Sequencing and Copy Number Variation Array Analysis of Thyrotropin Secreting Pituitary Adenomas (TSHomas)

Presenter: Santosh Sapkota


Abstract


Santosh Sapkota*1, Kazuhiko Horiguchi1, Shunichi Matsumoto1, Satoshi Yoshino1, Yasuyo Nakajima1, Takuya Tomaru1, Sumiyasu Ishii1, Atsushi Ozawa1, Nobuyuki Shibusawa1, Tetsurou Satoh1, Masahiko Tosaka1, Syozo Yamada2 and Masanobu Yamada1

1Gunma University, Graduate School of Medicine, Japan, 2Toranomon
Hospital, Tokyo, Japan

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Santosh Sapkota*1, Kazuhiko Horiguchi1, Shunichi Matsumoto1, Satoshi Yoshino1, Yasuyo Nakajima1, Takuya Tomaru1, Sumiyasu Ishii1, Atsushi Ozawa1, Nobuyuki Shibusawa1, Tetsurou Satoh1, Masahiko Tosaka1, Syozo Yamada2 and Masanobu Yamada1

1Gunma University, Graduate School of Medicine, Japan, 2Toranomon
Hospital, Tokyo, Japan

Abstract: TSHomas are a rare pituitary tumors presenting with various endocrinal abnormalities and mass effect, and an increasing number of these cases have been reported in the last decade. While somatic gene mutations and copy-number abnormalities in related pituitary adenomas have been described using array based and Next generation sequencing technology, such a systemic evaluation of genetic abnormalities have not been performed in TSHomas and the genetic abnormalities in these tumors remain largely unknown.

To study the somatic genetic abnormalities in TSHomas, we performed a Single Nucleotide Ploymorphism (SNP) array analysis on eight TSHomas and Whole-Exome Sequencing was performed on four TSHomas along with the corresponding blood samples. Sanger sequencing was used to confirm the identified somatic variants, and an additional validation set of eight TSHomas was also evaluated to identify the recurrence. We confirmed six somatic DNA variants (1.5 variant per tumor) as candidate driver mutations involving genes ZSCAN23, ASTN2, R3HDM2, CWH43, SMOX and SYTL3. No mutations were recurrent. Two of these mutations occurred in genes with an established role in malignant tumorigenesis (SMOX, SYTL3), and four had an unknown role (ZSACN23, ASTN2, R3HDM2, CWH43). Similarly, SNP array analysis revealed multiple focal and chromosomal arm-length copy-number abnormalities as well as regions of copy-number neutral Loss-of-Heterozygosity (cnLOH). We observed that 87.5 % (7/8), 62.5 % (5/8) and 37.5 % (3/8) of samples were involved in at least one gain, cnLOH and loss event respectively. Interestingly, recurrent copy-number gains were observed in four of the six gene loci identified in Whole-Exome Sequencing [CWH43 (50%), ASTN2 (37.5%), R3HDM2 and SMOX (25%)]. Additionally, assessment of the copy-number status of three pituitary oncogenic gene loci (GNAS, USP8, GPR101) and eighteen Tumor suppressor gene (TSG) loci previously reported to be linked to pituitary tumorigenesis revealed recurrent copy-number gain at GNAS, USP8 (37.5%, each) gene loci and recurrent cnLOH at CDKN2C (25%) TSG loci.

In conclusions, this study presented several candidate somatic mutations as well as changes in copy number in TSHomas, and the observed low mutation frequency highlighted the benign nature of these tumors. The results, however showed no recurrence of the identified mutations, and further studies on larger cohort of TSHomas using additional epigenetic and transcriptomic approaches may reveal genetic lesions responsible for tumorigenesis.

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