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

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 wildtype 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.

Well-Differentiated Papillary Mesothelioma of the Peritoneum is Genetically Distinct from Malignant Mesothelioma

“…Copy-number loss of BAP1, CDKN2A/B, LAST1/2, and NF2 is frequently found in pleural mesothelioma 4,5 . 11 What is surprising in our results is the absence of the TRAF7 and CDC42 alterations reported by Yu et al 7 and Stevers et al 11 in WDPM and by the same group in adenomatoid tumors 31 . Alterations in TRAF7 has also been reported in malignant mesotheliomas 4,20,32…”

Adenomatoid tumour of the uterus is frequently associated with iatrogenic immunosuppression

“…Further studies are needed to determine the type of immunosuppression that is relevant to AT. Goode et al . recently reported six tubal ATs with clinical information, one of which arose in an immunosuppressed patient.…”

“…Goode et al . recently reported TRAF7 mutations in all 31ATs of the male and female that they analysed by targeted next‐generation DNA sequencing.…”

“…Goode et al 14 recently reported TRAF7 mutations in all 31ATs of the male and female that they analysed by targeted next-generation DNA sequencing. They further demonstrated that the TRAF7 mutation leads to aberrant NF-jB pathway activation.…”

“…A recent study by Wang et al 13 is among a few molecular studies that demonstrated the clonality of the cells lining the lymphatic vessel-like lumen of AT using human androgen receptor gene (HUMARA) assays. Another study by Goode et al 14 showed that the ATs commonly harbor somatic TRAF7 mutations, using targeted nextgeneration DNA sequencing. Taken together, the evidences on neoplastic nature of AT are accumulating.…”