Introduction – Loss of function variants in TMEM127 are associated with predisposition to pheochromocytomas (PCC), and the TMEM127 tumor spectrum may also include paragangliomas (PGL) and renal cell carcinoma (RCC). Due to the rarity of reported TMEM127 pathogenic and likely pathogenic variants (PVs), data on tumor prevalence and corresponding surveillance recommendations remain limited. This study aimed to characterize tumor types associated with PVs in TMEM127 from a cohort of 400 patients tested at a commercial laboratory and compare them with tumor frequencies in SDHA and SDHB heterozygotes.
Methods – We conducted a retrospective clinical data review of patients heterozygous for a PV in TMEM127 who underwent hereditary cancer predisposition testing at a single diagnostic testing laboratory from 2015-2025. TMEM127 PVs were detected in 382 probands who underwent multi-gene panel testing (MGPT) of 2-91 genes; an additional 18 had single-site analysis for familial TMEM127 variants. Individuals with PVs in other PGL/PCC-associated genes were excluded from analysis. Tumor frequencies among individuals with TMEM127 PVs were compared to a MGPT-negative dataset using Fischer’s exact test. Additionally, tumor frequencies among internally identified, panel-tested SDHA and SDHB heterozygotes were compared to the MGPT-negative dataset.
Results – Among 400 probands with TMEM127 PVs, 215 had a personal history of cancer (53.75%). TMEM127+ probands were significantly more likely to have a personal history of PCC than MGPT-negative probands (OR=31.49, CI 16.4-60.5, p<0.001). The majority of probands diagnosed with PCC (n=18), were diagnosed before age 50 (67%) and ranged from (23-68). Eight probands were diagnosed with renal cancer; none were diagnosed before age 50, and there was no significant difference between RCC prevalence in TMEM127-positive vs MGPT-negative cohorts (OR=1.44, CI 0.67-3.10, p=0.35). The frequency of PGL development (n=2) in TMEM127 PVs relative to MGPT-negative patients approached but did not meet statistical significance (OR 5.8, CI 1.3-26.3, p=0.058). Only one patient had two TMEM127-spectrum primaries, both of which were PGL. The frequency of glioblastoma (n=1) was not significantly different between TMEM127 PVs and MGPT-negative group (OR=1.99, CI 0.26-15.04, p=0.41). Family history was provided for 363 probands. Sixty-two (28.8%) reported a family history of PCC, PGL, brain cancer/tumor, or renal cancer, including 20 first-degree relatives (FDR) and 36 second-degree relatives (SDR). The most common tumor reported in FDRs was PCC (n=12). Renal cancers were reported in 7 FDR and SDRs, and, surprisingly, brain cancer/tumors were reported in 37 of these relatives (including 1 FDR and 4 SDRs reported to be diagnosed with glioblastoma, specifically). No PGL diagnoses were reported in FDR or SDRs. Relative to MGPT-negative probands, PCC risk for TMEM127 heterozygotes fell between that of SDHA and SDHB (OR 14.39, CI 7.2-28.8, p<0.0001; OR 110.7, CI 65.3-187.9, p<0.0001; respectively).
Conclusion – With the inclusion of this gene in multigene panel testing (MGPT) for hereditary cancer risk, these individuals are being identified at an increased frequency. This retrospective cohort corroborates previously published data that PCC is the most frequent tumor type in TMEM127 heterozygotes and, importantly, demonstrates that the risk of developing PCC in TMEM127 heterozygotes falls between that of SDHB and SDHA PV heterozygotes. Our findings support screening for PCC similar to that recommended for SDHB heterozygotes and highlight the need for consensus guidelines to support patient access to these screenings. Further studies to evaluate the association with PGL, RCC, glioblastoma, and other tumor types are warranted.
VIEW THE PUBLICATION
VIEW THE POSTER