TY - JOUR
T1 - Proteogenomic landscape and clinical characterization of GH-producing pituitary adenomas/somatotroph pituitary neuroendocrine tumors
AU - Yamato, Azusa
AU - Nagano, Hidekazu
AU - Gao, Yue
AU - Matsuda, Tatsuma
AU - Hashimoto, Naoko
AU - Nakayama, Akitoshi
AU - Yamagata, Kazuyuki
AU - Yokoyama, Masataka
AU - Gong, Yingbo
AU - Shi, Xiaoyan
AU - Zhahara, Siti Nurul
AU - Kono, Takashi
AU - Taki, Yuki
AU - Furuki, Naoto
AU - Nishimura, Motoi
AU - Horiguchi, Kentaro
AU - Iwadate, Yasuo
AU - Fukuyo, Masaki
AU - Rahmutulla, Bahityar
AU - Kaneda, Atsushi
AU - Hasegawa, Yoshinori
AU - Kawashima, Yusuke
AU - Ohara, Osamu
AU - Ishikawa, Tetsuo
AU - Kawakami, Eiryo
AU - Nakamura, Yasuhiro
AU - Inoshita, Naoko
AU - Yamada, Shozo
AU - Fukuhara, Noriaki
AU - Nishioka, Hiroshi
AU - Tanaka, Tomoaki
N1 - Funding Information:
This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology (Japan) [Grants-in-Aid: for Scientific Research (S) 26221305, JP19H05650, (B) #21H02974, #19H03708, #22300325; (C) #21K07145, #21K08524, #20K08397, #20K07561, #19K07635, 19K08972, #18K07439, #18K08464; Challenging Research (Exploratory) #21K19398, #20K21837; Early-Career Scientists #20K17527]. T. Tanaka was supported by Japan Society for the Promotion of Science KAKENHI grant JP19H03708. This work was partly supported by The Uehara Memorial Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, The Naito Foundation, Mitsui Life Social Welfare Foundation, Princes Takamatsu Cancer Research Fund, Takeda Science Foundation, Senshin Medical Research Foundation, Kose Cosmetology Research Foundation, Japan Diabetes Foundation, Yamaguchi Endocrine Research Foundation, The Cell Science Research Foundation, The Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care, the Yasuda Memorial Medical Foundation, MSD Life Science Foundation, The Hamaguchi Foundation for the Advancement of Biochemistry, The Novartis Foundation (Japan) for Promotion of Science and the Medical Institute of Bioregulation Kyushu University Cooperative Research Project Program.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - The clinical characteristics of growth hormone (GH)-producing pituitary adenomas/somatotroph pituitary neuroendocrine tumors (GHomas/somatotroph PitNETs) vary across patients. In this study, we aimed to integrate the genetic alterations, protein expression profiles, transcriptomes, and clinical characteristics of GHomas/somatotroph PitNETs to identify molecules associated with acromegaly characteristics. Targeted capture sequencing and copy number analysis of 36 genes and nontargeted proteomics analysis were performed on fresh-frozen samples from 121 sporadic GHomas/somatotroph PitNETs. Targeted capture sequencing revealed GNAS as the only driver gene, as previously reported. Classification by consensus clustering using both RNA sequencing and proteomics revealed many similarities between the proteome and the transcriptome. Gene ontology analysis was performed for differentially expressed proteins between wild-type and mutant GNAS samples identified by nontargeted proteomics and involved in G protein–coupled receptor (GPCR) pathways. The results suggested that GNAS mutations impact endocrinological features in acromegaly through GPCR pathway induction. ATP2A2 and ARID5B correlated with the GH change rate in the octreotide loading test, and WWC3, SERINC1, and ZFAND3 correlated with the tumor volume change rate after somatostatin analog treatment. These results identified a biological connection between GNAS mutations and the clinical and biochemical characteristics of acromegaly, revealing molecules associated with acromegaly that may affect medical treatment efficacy.
AB - The clinical characteristics of growth hormone (GH)-producing pituitary adenomas/somatotroph pituitary neuroendocrine tumors (GHomas/somatotroph PitNETs) vary across patients. In this study, we aimed to integrate the genetic alterations, protein expression profiles, transcriptomes, and clinical characteristics of GHomas/somatotroph PitNETs to identify molecules associated with acromegaly characteristics. Targeted capture sequencing and copy number analysis of 36 genes and nontargeted proteomics analysis were performed on fresh-frozen samples from 121 sporadic GHomas/somatotroph PitNETs. Targeted capture sequencing revealed GNAS as the only driver gene, as previously reported. Classification by consensus clustering using both RNA sequencing and proteomics revealed many similarities between the proteome and the transcriptome. Gene ontology analysis was performed for differentially expressed proteins between wild-type and mutant GNAS samples identified by nontargeted proteomics and involved in G protein–coupled receptor (GPCR) pathways. The results suggested that GNAS mutations impact endocrinological features in acromegaly through GPCR pathway induction. ATP2A2 and ARID5B correlated with the GH change rate in the octreotide loading test, and WWC3, SERINC1, and ZFAND3 correlated with the tumor volume change rate after somatostatin analog treatment. These results identified a biological connection between GNAS mutations and the clinical and biochemical characteristics of acromegaly, revealing molecules associated with acromegaly that may affect medical treatment efficacy.
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U2 - 10.1038/s42003-022-04272-1
DO - 10.1038/s42003-022-04272-1
M3 - Article
C2 - 36435867
AN - SCOPUS:85142619979
SN - 2399-3642
VL - 5
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 1304
ER -