Pathogenic Loss-of-Function Germline <i>TERT</i> Mutations in Patients With Solid Tumors

Walsh, Michael F.; Sacca, Rosalba; Wildman, Temima; Amoroso, K.; Kennedy, Jennifer A.; Zhang, Liying; Birsoy, Ozge; Mandelker, Diana; Steinsnyder, Zoe; Latham, Alicia; Carlo, Maria I.; Cadoo, Karen A.; Kemel, Yelena; Stadler, Zsofia K.; Offit, Kenneth

doi:10.1200/po.19.00230

Cited by 2 publications

(1 citation statement)

References 28 publications

(31 reference statements)

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“…Such a result could be due to biases contributed by omitted or suppressor variables during univariate analysis, so we sought to determine which variables may be affecting the impact of TERT mutations on survival. TERT mutations result in increased TERT reactivation and telomerase activity, which results in a more active DNA damage response and reduced sensitivity to DNA damaging treatments such as radiation [ 9 , 23 , 24 ]. Thus, patients with TERT mutations may require higher doses of radiation to achieve improved survival outcomes.…”

Section: Discussionmentioning

confidence: 99%

Impact of CDKN2A/B, MTAP, and TERT Genetic Alterations on Survival in IDH Wild Type Glioblastomas

et al. 2022

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Purpose Poor outcomes in IDH wild-type (IDHwt) glioblastomas indicate the need to determine which genetic alterations can indicate poor survival and guidance of patient specific treatment options. We sought to identify the genetic alterations in these patients that predict for survival when adjusting particularly for treatments and other genetic alterations. Methods A cohort of 167 patients with pathologically confirmed IDHwt glioblastomas treated at our institution was retrospectively reviewed. Next generation sequencing was performed for each patient to determine tumor genetic alterations. Multivariable cox proportional hazards analysis for overall survival (OS) was performed to control for patient variables. Results CDKN2A, CDKN2B, and MTAP deletion predict for worse OS independently of other genetic alterations and patient characteristics (hazard ratio [HR] 2.192, p = 0.0017). Patients with CDKN2A copy loss (HR 2.963, p = 0.0037) or TERT mutated (HR 2.815, p = 0.0008) glioblastomas exhibited significant associations between radiation dose and OS, while CDKN2A and TERT wild type patients did not. CDKN2A deleted patients with NF1 mutations had worse OS (HR 1.990, p = 0.0540), while CDKN2A wild type patients had improved OS (HR 0.229, p = 0.0723). Patients with TERT mutated glioblastomas who were treated with radiation doses < 45 Gy (HR 3.019, p = 0.0010) but not those treated with ≥ 45 Gy exhibited worse OS compared to those without TERT mutations. Conclusion In IDHwt glioblastomas, CDKN2A, CDKN2B, and MTAP predict for poor prognosis. TERT and CDKN2A mutations are associated with worse survival only when treated with lower radiation doses, thus potentially providing a genetic marker that can inform clinicians on proper dose-fractionation schemes.

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Section: Discussionmentioning

confidence: 99%