Adenomatoid tumors of the male and female genital tract are defined by TRAF7 mutations that drive aberrant NF-kB pathway activation

Our plain-English summary of Adenomatoid tumors of the male and female genital tract are defined by TRAF7 mutations that drive aberrant NF-kB pathway activation, by B. Goode, N.M. Joseph, M. Stevers, et al (Modern Pathology, 2018).

The study

• Authors: B. Goode, N.M. Joseph, M. Stevers, J. Van Ziffle, C. Onodera, E. Talevich, J.P. Grenert, I. Yeh, B.C. Bastian, J.J. Phillips, K. Garg, J.T. Rabban, C. Zaloudek, D.A. Solomon
• Journal: Modern Pathology
• Published: 2018;31(4):660-673
• Cited by: 83 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Adenomatoid tumors are the most common neoplasm of the epididymis, and histologically similar adenomatoid tumors also commonly arise in the uterus and fallopian tube. To investigate the molecular pathogenesis of these tumors, we performed genomic profiling on a cohort of 31 adenomatoid tumors of the male and female genital tracts. We identified that all tumors harbored somatic missense mutations in the TRAF7 gene, which encodes an E3 ubiquitin ligase belonging to the family of tumor necrosis factor receptor-associated factors (TRAFs). These mutations all clustered into one of five recurrent hotspots within the WD40 repeat domains at the C-terminus of the protein. Functional studies in vitro revealed that expression of mutant but not wild-type TRAF7 led to increased phosphorylation of nuclear factor-kappa B (NF-kB) and increased expression of L1 cell adhesion molecule (L1CAM), a marker of NF-kB pathway activation. Immunohistochemistry demonstrated robust L1CAM expression in adenomatoid tumors that was absent in normal mesothelial cells, malignant peritoneal mesotheliomas and multilocular peritoneal inclusion cysts. Together, these studies demonstrate that adenomatoid tumors of the male and female genital tract are genetically defined by TRAF7 mutation that drives aberrant NF-kB pathway activation.

In plain English

This laboratory study examined the genes of adenomatoid tumors, genital tract growths presumed to arise from mesothelial (lining) cells. The article does not study asbestos. The authors sequenced 31 tumors from 28 patients (7 men with tumors of the epididymis and 21 women with tumors of the fallopian tube or uterus) from University of California, San Francisco archives spanning 1994 to 2016. All 31 tumors carried a mutation in a gene called TRAF7 that was present only in the tumor. In lab-grown human cells, mutated TRAF7, but not the normal form, increased signs of activity in a signaling pathway called NF-kB. A marker of that pathway, L1CAM, stained in all 8 adenomatoid tumors tested. It stained in none of 7 normal mesothelium samples, 7 malignant peritoneal mesotheliomas or 6 multilocular peritoneal inclusion cysts. Ten of 25 patients with available history had immune dysregulation, including autoimmune disease, HIV infection or immunosuppressive therapy after organ transplant. The authors concluded that TRAF7 mutation defines these tumors and that it likely acts at least partly through NF-kB activation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Genomic profiling (targeted DNA sequencing) of archived tumor and matched normal tissue, with in vitro cell experiments and immunohistochemistry
• Who was studied: 31 adenomatoid tumors from 28 patients (7 male, 21 female; ages 31 to 72, median 47) from the University of California, San Francisco pathology archives, 1994 to 2016. For L1CAM staining: 8 adenomatoid tumors, 7 normal mesothelium samples, 7 malignant peritoneal mesotheliomas and 6 multilocular peritoneal inclusion cysts
• Exposure: No asbestos exposure was studied. The study examined TRAF7 gene mutations in the tumors. It also recorded patients' history of immune dysregulation, including immunosuppressive therapy after organ transplant, but did not measure an exposure-related risk.
• Main results:
  • All 31 tumors had a tumor-specific (somatic) missense mutation in TRAF7
  • The most common mutation, p.S561R, was found in 13 of 31 tumors (42%). The second most common, p.H521R, was found in 11 of 31 tumors (35%).
  • 9 of 31 tumors (29%) had mutations in at least one additional gene
  • None of the adenomatoid tumors had alterations in BAP1, NF2 or CDKN2A, which the authors say characterize most malignant mesotheliomas
  • In 293T cells, mutant but not wild-type TRAF7 increased phosphorylation of the p65 subunit of NF-kB and increased L1CAM protein
  • L1CAM staining was positive in 8 of 8 adenomatoid tumors and in 0 of 7 normal mesothelium samples, 0 of 7 malignant peritoneal mesotheliomas and 0 of 6 multilocular peritoneal inclusion cysts
  • 10 of 25 patients (40%) with available clinical history had a history of immune dysregulation (autoimmune disease, HIV infection or immunosuppressive therapy after organ transplant)
  • No patient had a recurrence after a median follow-up of approximately 12 months
• The authors' conclusion: The authors concluded that TRAF7 mutation is a defining genetic alteration of adenomatoid tumors of the epididymis, fallopian tube and uterus. They suggested these mutations lead to the tumors at least in part through activation of NF-kB signaling.
• Limitations the authors state:
  • One MED12 mutation found in a uterine adenomatoid tumor may have come from contamination by an adjacent leiomyoma (a fibroid)
  • The authors state that further studies are needed to fully explain how TRAF7 mutations cause these tumors

Topics

Medical terms in this study, explained in our Lexicon: Adenomatoid Tumor, Neoplasm, Epididymis, Necrosis, Immunohistochemistry, Mesothelial Cells, Peritoneal Mesothelioma.

Related studies

• Well-differentiated papillary mesothelioma of the peritoneum is genetically defined by mutually exclusive mutations in TRAF7 and CDC42 — M. Stevers, J.T. Rabban, et al. (2019)
• TRAF7 mutations and immunohistochemical study of uterine adenomatoid tumor compared with malignant mesothelioma — H. Itami, T. Fujii, et al. (2021)
• Histogenesis and classification of mesonephric tumors of the female and male genital system and relationship to benign so-called adenomatoid tumors (mesotheliomas); a comparative histological study — G. Teilum (1954)
• PAX8 and PAX2 immunostaining facilitates the diagnosis of primary epithelial neoplasms of the male genital tract — G.X. Tong, L. Memeo, et al. (2011)
• Absence of estrogen immunoreactivity in adenomatoid tumors of male reproductive system — J.I. Lopez, F.I. Aranda (1990)
• Palliation of male genital cancers — C.J. Shukla, M. Shabbir, et al. (2010)

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