ESA-SRB-AOTA 2019

Involvement of somatic copy-number gains with the tumorigenesis of Thyrotropin-secreting pituitary adenomas. (#786)

KAZUHIKO HORIGUCHI 1 , KAZUMA SAITO 1 , MASAYUKI YOSHIOKA 1 , TETSUYA TAKAMIZAWA 1 , TAKASHI OKAMURA 1 , EMI ISHIDA 1 , SHUNICHI MATSUMOTO 1 , SATOSHI YOSHINO 1 , YASUYO NAKAJIMA 1 , EIJIRO YAMADA 1 , TSUGUMICHI SAITO 1 , ATSUSHI OZAWA 1 , MASAHIKO TOSAKA 2 , SHOZO YAMADA 3 4 , MASANOBU YAMADA 1 , Kazuhiko Horiguchi 1
  1. Division of Endocrinology and Metabolism, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
  2. Department of Neurosurgery, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
  3. Department of Hypothalamic and Pituitary Surgery, Toranomon Hospital, Minato-KU, Tokyo, Japan
  4. Moriyama neurological center hospital, Edogawa-Ku, Tokyo, Japan

Objectives: We have recently reported an analysis of genetic abnormalities in TSHomas using next-generation sequencer (J Clin Endocrinol Metab. 102:566-575, 2017).  We found six somatic DNA variants as candidate driver mutations, but no variants were so far recurrent.  However, SNP array analysis revealed multiple somatic focal and chromosomal arm-length copy-number abnormalities in 8 cases of TSHomas.  The objective of this study is to investigate the involvement of this copy-number abnormalities with the tumorigenesis of TSHomas. 

Methods: We performed a Single Nucleotide Ploymorphism (SNP) array analysis of tumor DNA extracted from 12 TSHomas and 12 non-functional pituitary adenomas (NFPAs).  SNP array analysis were also performed for DNA extracted from peripheral blood leukocytes of patients with 8 TSHomas.  In addition, cDNA microarray analyses were performed using total RNA isolated form 4 TSHomas and 4 NFPAs.

Results: We observed that 75.0 % (9/12) of TSHoma samples were involved in at least one gain, copy neutral LOH (cnLOH) and loss event.  In these copy-number abnormalities, copy number gain were fairly common compared to copy number loss, and chromosomal arm-length gain was found to be most frequent on chromosomes 4, 5, 7, 9 and 19.  All copy-number changes examined were somatic changes, because no changes were found in blood samples.  In contrast, only few focal copy number abnormalities were found in NFPAs, although only one case had a chromosomal arm-length loss.  In TSHomas having copy number gain, the expression levels of all gene included in copy number gain region were not changed compared to the expression levels of the same genes without copy number gain.  Microarray analysis revealed that the expression levels of the genes involved with chromosome segregation in TSHomas were not differed from those in NFPAs.    

Conclusion: Somatic copy-number gains of chromosomes may be involved in the tumorigenesis of TSHomas.