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Sunday, December 22, 2019

Publication in Modern Pathology

 2019 Dec 19. doi: 10.1038/s41379-019-0424-4. [Epub ahead of print]

Next-generation sequencing implicates oncogenic roles for p53 and JAK/STAT signaling in microcystic adnexal carcinomas.

Chan MP1,2,3Plouffe KR4,5,6Liu CJ4,5Palanisamy N7Carskadon S7Zhao L8Nazarian RM9Durham AB10,11Johnson TM10,11Andea AA4,10,11Patel RM4,10,11Lowe L4,10,11Fullen DR4,10,11Brown NA4Tomlins SA4,11,5,6Udager AM4,5Harms PW12,13,14,15.

Author information

1
Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA. mpchan@med.umich.edu.
2
Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA. mpchan@med.umich.edu.
3
Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA. mpchan@med.umich.edu.
4
Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.
5
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
6
Strata Oncology, Ann Arbor, MI, USA.
7
Department of Urology, Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, USA.
8
Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
9
Dermatopathology Unit, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
10
Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.
11
Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
12
Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA. paulharm@med.umich.edu.
13
Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA. paulharm@med.umich.edu.
14
Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA. paulharm@med.umich.edu.
15
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA. paulharm@med.umich.edu.

Abstract

Microcystic adnexal carcinoma is a locally aggressive sweat gland carcinoma characterized by its infiltrative growth and histopathologic overlap with benign adnexal tumors, often posing challenges to both diagnosis and management. Understanding the molecular underpinnings of microcystic adnexal carcinoma may allow for more accurate diagnosis and identify potential targetable oncogenic drivers. We characterized 18 microcystic adnexal carcinomas by targeted, multiplexed PCR-based DNA next-generation sequencing of the coding sequence of over 400 cancer-relevant genes. The majority of cases had relatively few (less than 8) prioritized somatic mutations, and lacked an ultraviolet (UV) signature. The most recurrent mutation was TP53 inactivation in four (22%) tumors. Frame-preserving insertions affecting the kinase domain of JAK1 were detected in three (17%) cases, and were nonoverlapping with TP53 mutations. Seven (39%) cases demonstrated copy number gain of at least one oncogene. By immunohistochemistry, p53 expression was significantly higher in microcystic adnexal carcinomas with TP53 mutations compared with those without such mutations and syringomas. Similarly, phospho-STAT3 expression was significantly higher in microcystic adnexal carcinomas harboring JAK1 kinase insertions compared with those with wild-type JAK1 and syringomas. In conclusion, microcystic adnexal carcinomas are molecularly heterogeneous tumors, with inactivated p53 or activated JAK/STAT signaling in a subset. Unlike most other nonmelanoma skin cancers involving sun-exposed areas, most microcystic adnexal carcinomas lack evidence of UV damage, and hence likely originate from a relatively photo-protected progenitor population in the dermis. These findings have implications for the biology, diagnosis, and treatment of microcystic adnexal carcinomas, including potential for therapeutic targeting of p53 or the JAK/STAT pathway in advanced tumors.
PMID:
 
31857679
 
DOI:
 
10.1038/s41379-019-0424-4

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