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Genetic and Clinical Characteristics of Japanese Patients with Sporadic Somatotropinoma

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Genetic and Clinical Characteristics of Japanese Patients with Sporadic Somatotropinoma 2016, 63 (11), 953-963 Original Genetic and clinical characteristics of Japanese patients with sporadic somatotropinoma Ryusaku Matsumoto1), Masako Izawa2), Hidenori Fukuoka3), Genzo Iguchi3), Yukiko Odake1), Kenichi Yoshida1), Hironori Bando1), Kentaro Suda1), Hitoshi Nishizawa1), Michiko Takahashi1), Naoko Inoshita4), Shozo Yamada5), Wataru Ogawa1) and Yutaka Takahashi1) 1) Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan 2) Department of Pediatric Endocrinology and Metabolism, Aichi Children’s Health and Medical Center, Obu, Japan 3) Division of Diabetes and Endocrinology, Kobe University Hospital, Kobe, Japan 4) Department of Pathology, Toranomon Hospital, Tokyo, Japan 5) Department of Hypothalamic and Pituitary Surgery, Toranomon Hospital, Tokyo, Japan Abstract. Most of acromegaly is caused by a sporadic somatotropinoma and a couple of novel gene mutations responsible for somatotropinoma have recently been reported. To determine the cause of sporadic somatotropinoma in Japanese patients, we analyzed 61 consecutive Japanese patients with somatotropinoma without apparent family history. Comprehensive genetic analysis revealed that 31 patients harbored guanine nucleotide-binding protein, alpha stimulating (GNAS) mutations (50.8%) and three patients harbored aryl hydrocarbon receptor interacting protein (AIP) mutations (4.9%). No patients had G protein-coupled receptor 101 (GPR101) mutations. The patients in this cohort study were categorized into three groups of AIP, GNAS, and others and compared the clinical characteristics. The AIP group exhibited significantly younger age at diagnosis, larger tumor, and higher nadir GH during oral glucose tolerance test. In all patients with AIP mutation, macro- and invasive tumor was detected and repetitive surgery or postoperative medical therapy was needed. One case showed a refractory response to postoperative somatostatin analogue (SSA) but after the addition of cabergoline as combined therapy, serum IGF-I levels were controlled. The other case showed a modest response to SSA and the switching to cabergoline monotherapy was also effective. These data suggest that although resistance to SSA has been reported in patients with AIP mutations, the response to dopamine agonist (DA) may be retained. In conclusion, the cause of sporadic somatotropinoma in Japanese patients was comparable with the previous reports in Caucasians, patients with AIP mutations showed unique clinical characteristics, and DA may be a therapeutic option for patients with AIP mutations. Key words: Acromegaly, Gigantism, GNAS, AIP, GPR101 SOMATOTROPINOMA causes unregulated growth The underlying mechanism which yields this diver- hormone (GH) hypersecretion, which results in acro- sity has not been fully elucidated. Somatotropinoma megaly or gigantism [1]. Patients with acromegaly or is reportedly caused by unrestrained somatotroph pro- gigantism without adequate treatment show a reduced liferation by cell-cycle dysfunction as well as altered life expectancy and impaired quality of life [2, 3]. intracellular signaling regulating GH synthesis/secre- Interestingly, endocrinological and clinical pheno- tion [4]. Although somatotropinoma tumorigenesis has types of somatotropinoma greatly vary among patients; not been fully understood, genetic analysis of somatic regarding serum GH and IGF-I levels, tumor size, or germline mutations in patients with somatotropi- tumor invasiveness, and response to medical therapy. noma revealed several pathogenetic mutations, which determine unique cellular and clinical characteristics. Submitted Feb. 15, 2016; Accepted Jul. 7, 2016 as EJ16-0075 Therefore clarifying these mutations lead us to not only Released online in J-STAGE as advance publication Aug. 6, 2016 the understanding these tumorigenic processes but also Correspondence to: Yutaka Takahashi, Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University to better management of the disease. Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, One of the most well-documented pathogenesis of Kobe, Hyogo, Japan. E-mail: [email protected] somatotropinoma is activating guanine nucleotide- ©The Japan Endocrine Society 954 Matsumoto et al. binding protein, α stimulating (GNAS) mutations [5]. We recruited 61 consecutive patients with sporadic Approximately 40% of patients with sporadic acro- acromegaly or gigantism without a family history of megaly harbor somatic GNAS mutations, leading to pituitary tumors, who underwent surgical treatment constitutively activated cAMP pathway [6]. In general, at Toranomon Hospital between May 2005 and May somatotropinoma harboring GNAS mutations tended to 2010. All patients provided written informed consent have higher serum GH and IGF-I levels, smaller tumor, for genetic analysis. The diagnosis of somatotropinoma and good response to somatostatin analogues (SSA) was histologically confirmed. Clinical data were ret- and dopamine agonists (DA) [7, 8]. rospectively collected from patients’ medical records. Analysis of familial pituitary adenoma revealed that The diagnosis of acromegaly was based on clinical germline mutations in the aryl hydrocarbon receptor signs, lacking of serum GH suppression to <1.0 ng/mL interacting protein (AIP) gene cause pituitary adenoma, during a 75 g oral glucose tolerance test (OGTT), ele- including somatotropinoma, prolactinoma, ACTHoma, vated serum IGF-I levels corresponding to the normal or non-functioning pituitary adenoma [9]. Occurrence range for age- and sex-matched individuals, and the of germline mutations and loss of the normal allele in presence of pituitary tumor according to the guideline tumors suggest that AIP acts as a tumor suppression [11]. The duration of acromegaly was assessed visu- gene. Typically, patients with AIP mutations have a ally by comparison of photographs and by the onset of young age at disease onset, macro- and invasive tumor, related symptoms as previously described [11]. Serum and poor response to SSA. It is noteworthy that AIP GH and IGF-I levels were measured by an immunoen- mutations are occasionally detected in patients without zymometric assay using the ST AIA-PACK hGH kit family history of pituitary adenoma. (TOSOH Co., Tokyo, Japan) and an immunoradiomet- Recently, Trivellin et al. reported that microduplica- ric assay using “Daiichi” IGF-I IRMA kit (FUJIFILM tions on chromosome Xq26.3 cause somatotropinoma RI Pharma Co., Tokyo, Japan), respectively. Intra- and in children with gigantism, named X-linked acrogigan- inter-assay coefficients of variation (C.V.) for the assay tism (X-LAG) [10]. In addition, they also reported that of GH and IGF-I were as follows: GH (intra-C.V. 1.3% among the duplicated genes on Xq26.3, the expres- and inter-C.V. 3.3%) and IGF-I (intra-C.V. 1.1% and sion of G protein-coupled receptor 101 (GPR101) inter-C.V. 2.2%), respectively. Acute octreotide test was highly upregulated in the pituitary tumors. (SSA test) and bromocriptine test (BRC test) were per- Furthermore, GPR101 sequence analysis revealed a formed as previously described [12]. In brief, follow- missense mutation, c.924G>C (p.Glu308Asp), which ing the subcutaneous injection of 50 μg octreotide or resulted in an enhanced action of GPR101, in 11 of 248 the oral administration of 2.5 mg bromocriptine, serum (4.4%) patients with sporadic acromegaly. GH level was measured every two hours until eight The diagnosis of syndromic pituitary adenoma, such hours after administration. as McCune-Albright syndrome, Carney complex, or multiple endocrine neoplasia type 1 is not generally dif- DNA extraction ficult because the patients exhibit several clinical char- Tumor DNA was extracted using the Gentra acteristic manifestations. However, it is difficult to dif- Puregene Tissue Kit (QIAGEN, Venlo, Netherlands). ferentiate the acromegalic patients clinically caused by Genomic DNA was extracted from peripheral leuko- GNAS, AIP, or GPR101, but it would be useful to clarify cytes using the Gentra Puregene Blood Kit (QIAGEN, these mutations because it may help to make the strat- Venlo, Netherlands). egy for treatment. Here, we investigated the prevalence of pathogenetic somatic mutations of GNAS, AIP, and Genetic analysis GPR101 in Japanese patients with sporadic somatotro- Using tumor DNA, GNAS gene analysis was per- pinoma and analyzed the clinical characteristics. formed with amplifications of regions containing 2 sites of activating somatic mutations in codons 201 Materials and Methods and 227 [5]. AIP gene analysis was performed in patients who revealed negative for GNAS mutations Patients as previously described [9]. We also analyzed dele- This study was approved by the Kobe University tions/duplications in AIP gene in the patients without Hospital and Toranomon Hospital Ethics Committee. AIP mutation with younger age (< 40 years), invasive Genetic analysis of Japanese GHoma 955 tumor, or macroadenoma (> 10 mm). Deletions/dupli- the patients revealed a macroadenoma. The analy- cations analysis was performed using SALSA MLPA sis of GNAS mutation in the tumor revealed 31 het- kit P244 designed to detect deletions/duplications erozygous mutations (50.8%); 22 case of c.601C>T in AIP, MEN1, and CDKN1B genes (MRC-Holland, (p.Arg201Cys), 4 case of c.680A>T (p.Gln227Leu), Amsterdam, Netherlands) according to the manufac- 3 case of c.602G>A (p.Arg201His), 1 case of turer’s instructions. We further analyzed AIP muta- c.601C>A (p.Arg201Ser),
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