Analysis of Japanese Patients with Acromegaly-Classification By Clinical Parameter and mRNA Expressions

Presentation Number: SUN 436
Date of Presentation: April 2nd, 2017

Azusa Yamato*1, Takashi Kohno1, Hidekazu Nagano1, Kentaro Horiguchi2, Naoko Inoshita3, Shozo Yamada3, Koutaro Yokote1 and Tomoaki Tanaka4
1Chiba University Graduate School of Medicine, Chiba, Japan, 2Chiba University Medical School, Chiba, Japan, 3Toranomon Hospital, Tokyo, Japan, 4Chiba University Graduate School of Medicine, Chiba-city, Japan


Background: Acromegaly is known for wide range of clinical presentation case by case. In recent years, Cuevas-Ramos et al reported clinical and pathological classification of acromegaly (JCEM 2015; 100). Although some genetic mutation, such as GNAS, AIP or GRP101, are revealed as the cause of sporadic somatotropinoma, genotype-phenotype association is not elucidated sufficiently.

Objective: The aim of this study is to classify Japanese acromegaly patients by clinical, pathological characteristics and genetic mutations.

Design, Setting and Patients: We included 158 acromegaly patients who were underwent TSS at Chiba University Hospital and Toranomon Hospital. Medical records of all the cases were reviewed retrospectively. Analysis of somatic mutations was performed by targeted sequencing for GNAS and AIP. SSTR2, SSTR5, pit1, BAX mRNA expression were measured by Real-time PCR. Immunostaining was assessed for GH and CAM5.2. We performed principal component analysis on the basis of clinical characteristics, endocrinological data and mRNA expression levels. We tried to group 158 patients based on the result of principal component analysis and compare of somatic mutation, pathological characteristics and prognosis among groups.

Results: Patients were grouped into 3 groups. Characteristics of group1 is high responsiveness for octreotide 100µg loading test. Group1 also showed high mRNA expression of SSTR2, pit-1 and BAX, and high SSTR2/5 ratio. SSTR2 and pit-1 was significantly correlate with tumor shrinkage rate after administration of preoperative somatostatin analogue (SSA, p=0.003, R=-0.326). Reflecting this result, effect of SSA is significantly higher in Group1 (p=0.001). Group 2 reveals high IGF-1 SDS, high frequency of men and younger people. Group 3 was characterized by large tumor. Pathologically, densely-granulated adenoma was frequent in Group1 and sparsely was in Group3. Frequency of GNAS mutation is significantly low in Group3 and equal population in Group1 and 2. Two of 4 AIP mutation patients were in Group3.

Conclusion: Three groups of our cohort were closely similar to those of previous report in terms of tumor size, invasiveness, pathological characteristics and SSTR2 mRNA expression. Average age of each group, gender distribution and endocrinological data were different between two studies. It may be one of the cause that factors underlying clustering analysis used in each study are different. Although our study and previous report showed that acromegaly patients could be classified by some clinical, pathological findings and somatic mutation, they also clarified intragroup heterogeneity and wide range of overlap of inter-groups. To understand background of tumor characteristics of GHoma more clearly and make more evident classification, RNA-sequencing analysis will be needed.


Disclosure: TT: Investigator, ONO-Pharma. Nothing to Disclose: AY, TK, HN, KH, NI, SY, KY