Pituitary adenomas are one of the common intracranial tumors with a high incidence, which can result in death of patients either by pressing their pituitary tissue or by excessively secreting pituitary hormones. The exact pathogenesis of pituitary adenomas remains unclear yet, so that there are still many bottlenecks in the clinical diagnosis and treatment.
To overcome the challenges the clinical diagnosis and treatment, the 3-year study on pituitary adenomas has been officially completed by the Bio-X Institute of Shanghai Jiaotong University together with Duke University, Genetron Health (Beijing) Co., Ltd.[A1] and other participants led by the pituitary tumor research team of Huashan Hospital Affiliated to Fudan University.
This study was an unprecedented large-scale next generation sequencing study, covering all subtypes of pituitary adenomas. In it, a comprehensive somatic gene mutation map of pituitary adenomas has been completed for the first time, by which the correlation in gene pathways between the subtypes of pituitary adenomas was analyzed and potential drug pathways for targeting therapy in the future was explored for several pituitary adenomas. Relevant studies were online published in Cell Research, an internationally renowned academic journal, on September 27, 2016 (IF 14.8).
1. Somatic gene mutation map of pituitary adenomas
Fig. A. Somatic mutation and CNV landscape of 125 cases of pituitary adenomas covering all seven subtypes
125 patients with pituitary adenomas (including 20 GH, 20 ACTH, 20 PRL, 20 GT, 10 TSH, and 20 nonfunctioning and 15 multi-hormone mixed subtypes) that underwent surgical treatment at the Neurosurgery Department of Huashan Hospital were included in the study. A total of 412 mutation sites which were distributed in different subtypes were found using whole-exome comparative sequencing of tumor and peripheral blood in all the patients. Based on such mutation sites, a comprehensive somatic mutation map of pituitary adenomas is completed (Fig. A):
① High frequency GNAS (54%) and USP8 (55%) gene mutations have been demonstrated in GH and ACTH pituitary adenomas
② Re-appearance of new NR3C1 and MEN1 mutations were found in pituitary adenomas.
③ Low frequency re-appearance of KIF5A, GRB10, SP100 and other gene mutations were firstly found in pituitary adenomas. Meanwhile, the resolution copy number variation (SCNA) of pituitary adenomas was demonstrated unprecedentedly in this study, revealing largely missed fragments of chromosome (11q13.2, 11p15.5, 1p36.31, 9q34.11, 16p13.3 and 3p21.31) and amplification region (20q13.33, 3p22.3, 1q31.3, 7q21.11 and 16q12.2).
2. Correlation between the subtypes of pituitary adenomas
Fig. B. Enrichment molecular network map of mutation pathway based on 7 subtypes of pituitary adenomas
Fig. C. Correlation between subtypes based on somatic mutations
To investigate the correlation between the subtypes of pituitary adenomas, an enrichment analysis was conducted by the research team. A total of 47 enrichment pathways including Raf / MEK / ERK, PI3K / AKT / mTOR, insulin and cAMP signalings were found. ACTH, GH, PRL, multi-hormone mixed and nonfunctioning sub-types can be connected with each other via several pathways into a molecular network system, while GT and TSH subtypes of pituitary adenomas were formed into another molecular network system via different pathways. These findings suggest some commonalities in the genetic mechanism of the subtypes of pituitary adenomas; the pathogenesis of GT and TSH subtypes, on the whole, is different from that of others (Figs B and C).
3. Potential drug pathways of targeting therapy
Fig. D. Seven potential drug-targeted molecular pathways and target genes and drugs in pituitary adenomas
To initially explore new therapeutic drugs for pituitary adenomas, the team has found seven potential targeted drug pathways: cAMP, cell cycle, PI3K-Akt, immune response, MAPK, endocrine and Rap1, and screened 48 target drugs against specific gene mutations on these seven signal transduction pathways from DrugBank Database (Fig. D), of which 21 drugs were approved by the FDA for marketing, 28 were under phases I-III clinical trials. 28% of the tumor samples collected from 125 patients in this study contained at least one gene mutation in the above-mentioned signal transduction pathways.
3. Analysis on the correlation among invasion, drug resistance and gene mutation of pituitary adenomas
The correlation between significant clinical phenotypes (invasion and resistance) and gene mutations of pituitary adenomas was analyzed by researchers:
① Surprisingly, no significant difference was found in the number of gene mutations between large-volume invasive pituitary adenomas whose biological behavior appeared to be "malignant" and non-invasive pituitary adenomas (including drug target genes and signaling pathways), but the GNAS and USP8 gene mutations were negatively correlated with the invasiveness/size of GH and ACTH subtypes;
② GNAS-mutant GH-secreting pituitary adenomas were generally sensitive to somatostatin analogues.
As a pioneer focusing on the clinical transformation of cancer genomics, Genetron Health always plays an active role at the forefront of clinical research. In the field of science and technology, Genetron Health, relying on high-quality sequencing platform and the ability to interpret big, has successfully found PPM1D mutation that was an important factor contributing to the pathogenesis of brain stem glioma; participated in and completed the largest international study on the molecular pathology of Cushing disease that utilized the most definitive genetic mechanism; participated in and completed the largest study on the exome sequencing of esophageal squamous cell carcinoma to illustrate the histone modification as well as clinical significance of genetic variations of Hippo signal pathway-related genes; participated in and completed the largest-scale important scientific studies on the molecular typing of glioma using IDH and TERT promoter mutation for the Chinese population up to date.
In the clinical field, Genetron Health has successfully developed a number of precise medical products for patients with cancer, and built clinical medical test centers covering a total area of 8,000 sq. m in Beijing, Shanghai and Hangzhou. In the future, Genetron Health will exert its utmost strength to serve cancer patients in China and throughout the world with its professional marketing, product, medical and research team, its sales network covering east, south, west and north China, its powerful cancer genomic techniques and efficient transformation of such technologies to clinical applications.
The genome-wide mutational landscape of pituitary adenomas. Cell Res 2016
Other co-published literatures from Genetron Health：
Exome sequencing identifies somaticgain-of-function PPM1D mutations in brainstem gliomas
Genetic landscape of esophageal squamous cell carcinoma
Recurrent gain-of-function USP8 mutationsin Cushing’s disease
TERT promoter mutations contribute to IDH mutations in predicting differential responses to adjuvant therapies in WHO grade II and III diffuse gliomas
Prevalence of deleterious ATM germline mutations in gastric cancer patients
Recurrent TERT promoter mutations identified in a large-scale study of multiple tumor types are associated with increased TERT expression and telomerase activation