title: Porocarcinomas harbor recurrent HRAS-activating mutations and tumor suppressor inactivating mutations.
abstract: Porocarcinomas are a rare eccrine carcinoma with significant metastatic potential. Oncogenic drivers of porocarcinomas have been underexplored, with PIK3CA-activating mutation reported in 1 case. We analyzed 5 porocarcinomas by next-generation sequencing using the DNA component of the Oncomine Comprehensive Assay, which provides data on copy number changes and mutational events in 126 cancer-relevant genes through multiplex polymerase chain reaction. We detected an average of 3.3 high-confidence nonsynonymous mutations per tumor (range, 1-6), including a spectrum of oncogenic activation and tumor suppressor inactivation events. Tumor suppressor mutations included TP53 (4/5, 80%), RB1 (3/5, 60%), ATM (2/5, 40%), ARID1A (1/5, 20%), and CDKN2A (1/5, 20%). In 4 (80%) of 5 tumors, at least 1 potential oncogenic driver was identified. Activating HRAS mutations were detected in 2 (40%) of 5, including G13D and Q61L hotspot mutations. Mutations of EGFR were identified in 2 (40%) of 5; these mutations have been previously reported in cancer but did not affect classic activation hotspot sites. EGFR and HRAS mutations were mutually exclusive. HRAS mutations were detected by targeted sequencing in a minority of benign eccrine poromas (2/17; 11.7%), suggesting that HRAS activation may rarely be an early event in sweat gland neoplasia. Together, our data suggest roles for HRAS and EGFR as drivers in a subset of poroma and porocarcinoma. TP53 and RB1 inactivation events are also likely to contribute to tumorigenesis. These findings suggest that porocarcinomas display diversity with respect to oncogenic drivers, which may have implications for targeted therapy in metastatic or unresectable cases.
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, MI 48109; Department of Dermatology, University of Michigan Health System, Ann Arbor, MI 48109; Michigan Center for Translational Pathology, University of Michigan Health System, Ann Arbor, MI 48109.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Harms
authors.affiliation: Department of Dermatology, University of Michigan Health System, Ann Arbor, MI 48109; Michigan Center for Translational Pathology, University of Michigan Health System, Ann Arbor, MI 48109.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Hovelson
authors.affiliation: Department of Dermatology, University of Michigan Health System, Ann Arbor, MI 48109; Michigan Center for Translational Pathology, University of Michigan Health System, Ann Arbor, MI 48109.
authors.forename: Andi K
authors.initials: AK
authors.lastname: Cani
authors.affiliation: Department of Dermatology, University of Michigan Health System, Ann Arbor, MI 48109; Michigan Center for Translational Pathology, University of Michigan Health System, Ann Arbor, MI 48109.
authors.forename: Kei
authors.initials: K
authors.lastname: Omata
authors.affiliation: Department of Dermatology, University of Michigan Health System, Ann Arbor, MI 48109; Michigan Center for Translational Pathology, University of Michigan Health System, Ann Arbor, MI 48109.
authors.forename: Michaela J
authors.initials: MJ
authors.lastname: Haller
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, MI 48109.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, MI 48109; Department of Dermatology, University of Michigan Health System, Ann Arbor, MI 48109.
authors.forename: David
authors.initials: D
authors.lastname: Arps
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, MI 48109; Department of Dermatology, University of Michigan Health System, Ann Arbor, MI 48109.
authors.forename: Rajiv M
authors.initials: RM
authors.lastname: Patel
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, MI 48109; Department of Dermatology, University of Michigan Health System, Ann Arbor, MI 48109.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Fullen
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, MI 48109.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, MI 48109; Michigan Center for Translational Pathology, University of Michigan Health System, Ann Arbor, MI 48109.
authors.forename: Javed
authors.initials: J
authors.lastname: Siddiqui
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, MI 48109; Department of Dermatology, University of Michigan Health System, Ann Arbor, MI 48109.
authors.forename: Aleodor
authors.initials: A
authors.lastname: Andea
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, MI 48109; Michigan Center for Translational Pathology, University of Michigan Health System, Ann Arbor, MI 48109; Department of Urology, University of Michigan Health System, Ann Arbor, MI 48109; Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor, MI 48109. Electronic address: tomlinss@umich.edu.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D057090:Eccrine Porocarcinoma / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D018773:Genes, erbB-1 / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D013544:Sweat Gland Neoplasms / Q000235:genetics*; D055815:Young Adult
chemical_list: C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Epidermal growth factor receptor; HRAS; Porocarcinoma; Poroma; RB1; TP53