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Currently, about 70% of PPGLs can be explained by germline or somatic mutations in several broadly expressed susceptibility genes including <jats:italic>RET<\/jats:italic>, <jats:italic>VHL,<\/jats:italic> and <jats:italic>SDHB<\/jats:italic>, while for the remaining, mainly sporadic cases, the pathogenesis is still unclear. Even for known susceptible genes, how mutations in these mostly ubiquitous genes result in tissue-specific pathogenesis remains unanswered, and why <jats:italic>RET<\/jats:italic>-mutated tumors almost always occur in the adrenal while <jats:italic>SDHB<\/jats:italic>-mutated tumors mostly occur extra-adrenal remains a mystery. By analyzing 22 sporadic PPGLs using SNP 6.0 genotyping arrays combined with expression profiling of 4 normal and 4 tumor tissues, we identified <jats:italic>GIPC2<\/jats:italic>, a gene located at 1p31.1 with preferential expression in adrenal and inducible by adrenal glucocorticoid, as a novel putative tumor suppressor gene for PPGLs. Copy number deletion and <jats:italic>GIPC2<\/jats:italic> promoter hypermethylation but not <jats:italic>GIPC2<\/jats:italic> mutation, accompanied with reduced <jats:italic>GIPC2<\/jats:italic> expression, were observed in 39 of 55 PPGLs in our cohort. Examination of a published expression database consisting of 188 PPGLs found little <jats:italic>GIPC2<\/jats:italic> expression in Cluster 1A (SDHx-associated) and Cluster 2A (NF1\/RET-associated) tumors, but less pronounced reduction of <jats:italic>GIPC2<\/jats:italic> expression in Cluster 1B (VHL-associated) and Cluster 2B\/2C tumors. GIPC2 induced <jats:italic>p27<\/jats:italic>, suppressed MAPK\/ERK and <jats:italic>HIF-1\u0251<\/jats:italic> pathways as well as cancer cell proliferation. Overexpressing GIPC2 in PC12 cells inhibited tumor growth in nude mice. We found GIPC2 interacted with the nucleoprotein NONO and both proteins regulated <jats:italic>p27<\/jats:italic> transcription through the same GGCC box on <jats:italic>p27<\/jats:italic> promoter. Significantly, low expression of both <jats:italic>GIPC2<\/jats:italic> and <jats:italic>p27<\/jats:italic> was associated with shorter disease-free survival time of PPGLs patients in the TCGA database. We found that PPGL-causing mutations in <jats:italic>RET<\/jats:italic> and in <jats:italic>SDHB<\/jats:italic> could lead to primary rat adrenal chromaffin cell proliferation, ERK activation, and <jats:italic>p27<\/jats:italic> downregulation, all requiring downregulating GIPC2. Notably, the RET-mutant effect required the presence of dexamethasone while the SDHB-mutant effect required its absence, providing a plausible explanation for the tumor location preference. In contrast, the PPGL-predisposing VHL mutations had no effect on proliferation and GIPC2 expression but caused p53 downregulation and reduced apoptosis in chromaffin cells compared with wild-type VHL. Thus, our study raises the importance of cortical hormone in PPGL development, and GIPC2 as a novel tumor suppressor provides a unified molecular mechanism for the tumorigenesis of both sporadic and hereditary tumors of Clusters 1A and 2A concerning SDHB and RET, but not tumors of Cluster 1B concerning VHL and other clusters.<\/jats:p>","DOI":"10.1038\/s41419-021-03731-7","type":"journal-article","created":{"date-parts":[[2021,5,4]],"date-time":"2021-05-04T12:04:09Z","timestamp":1620129849000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["GIPC2 is an endocrine-specific tumor suppressor gene for both sporadic and hereditary tumors of RET- and SDHB-, but not VHL-associated clusters of pheochromocytoma\/paraganglioma"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3094-2827","authenticated-orcid":false,"given":"Yeqing","family":"Dong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6114-7730","authenticated-orcid":false,"given":"Yongsheng","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengyan","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5983-7759","authenticated-orcid":false,"given":"Zhengguang","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5579-8572","authenticated-orcid":false,"given":"Dong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4049-010X","authenticated-orcid":false,"given":"Zhi","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,4]]},"reference":[{"key":"3731_CR1","doi-asserted-by":"publisher","first-page":"R253","DOI":"10.1530\/ERC-11-0170","volume":"18","author":"J Welander","year":"2011","unstructured":"Welander, J., Soderkvist, P. & Gimm, O. 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