Ph.D. in Pathology, Tianjin Medical University, 2014
M.D. in Clinical Medicine, Hebei Medical University, 2009
2013-2014: Visiting graduate student at the Wang Genomics Lab
Clinical Geneticist, Peking Union Medical College Hospital
integrative genomics on pituitary adenoma, colon cancer and glioblastomas
Epigenetics of pituitary adenomas
Pituitary adenomas (PAs) are neoplasms that may cause a variety of neurological and endocrine effects. Although known causal contributors include heredity, hormonal influence and somatic mutations, the pathophysiologic mechanisms driving tumorigenesis and invasion of sporadic PAs remain unknown. We hypothesized that alterations in DNA methylation are associated with PA invasion and histopathology subtype, and that genome-scale methylation analysis may complement current classification methods for sporadic PAs. Twenty-four surgically-resected sporadic PAs with varying histopathological subtypes were assigned dichotomized Knosp invasion scores and examined using genome-wide DNA methylation profiling and RNA sequencing. PA samples clustered into subgroups according to functional status. Compared with hormonally-active PAs, nonfunctional PAs exhibited global DNA hypermethylation (mean beta-value 0.47 versus 0.42, P?=?0.005); the most significant site of differential DNA methylation was within the promoter region of the potassium voltage-gated channel KCNAB2 (FDR?=?5.11×10-10). Pathway analysis of promoter-associated CpGs showed that nonfunctional PAs are potentially associated with the ion-channel activity signal pathway. DNA hypermethylation tended to be negatively correlated with gene expression. DNA methylation analysis may be used to identify candidate genes involved in PA function and may potentially complement current standard immunostaining classification in sporadic PAs. DNA hypermethylation of KCNAB2 and downstream ion-channel activity signal pathways may contribute to the endocrine-inactive status of nonfunctional PAs.
Candidate gene sequencing on colon cancer
Background: Previous genetic studies on colorectal carcinomas (CRC) have identified multiple somatic mutations in four candidate pathways (TGF-ß, Wnt, P53 and RTK-RAS pathways) on populations of European ancestry. However, it is under-studied whether other populations harbor different sets of hot-spot somatic mutations in these pathways and other oncogenes.
Methods: To evaluate the mutational spectrum of novel somatic mutations, we assessed 41 pairs of tumor-stroma tissues from Chinese patients with CRC, including 29 colon carcinomas and 12 rectal carcinomas. We designed Illumina Custom Amplicon panel to target 43 genes, including genes in the four candidate pathways, as well as several known oncogenes for other cancers. Candidate mutations were validated by Sanger sequencing, and we further used SIFT and Polyphen2 to assess the potentially functional mutations.
Results: we discovered 3 new somatic mutations in gene APC, TCF7L2, and PIK3CA that had never been reported in the COSMIC or NCI-60 databases. Additionally, we confirmed 6 known somatic mutations in gene SMAD4, APC, FBXW7, BRAF and PTEN in Chinese CRC patients. While most were previously reported in CRC, one mutation in PTEN was reported only in malignant endometrium cancer.
Conclusions: Our study confirmed the existence known somatic mutations in the four candidate pathways for CRC in Chinese patients. We also discovered a number of novel somatic mutations in these pathways, which may have implications for the pathogenesis of CRC.
- Ling C, Pease M, Shi L, Punj V, Shiroishi MS, Commins D, Weisenberger DJ, Wang K*, Zada G*. A Pilot Genome-Scale Profiling of DNA Methylation in Sporadic Pituitary Macroadenomas: Association with Tumor Invasion and Histopathological Subtype. PLoS ONE, 9: e96178, 2014
- Pease M, Ling C, Mack WJ, Wang K, Zada G. The role of epigenetic modification in tumorigenesis and progression of pituitary adenomas: a systematic review of the literature. PLoS ONE, 8:e82619, 2013
- Gao F, Ling C, Shi L, Commins D, Zada G, Mack W, Wang K. Inversion-mediated gene fusion involving NAB2-STAT6 in an unusual malignant meningioma. British Journal of Cancer, 109:1051-1055, 2013