Response to everolimus is seen in TSC-associated SEGAs and angiomyolipomas independent of mutation type and site in TSC1 and TSC2

David J. Kwiatkowski, Michael R. Palmer, Sergiusz Jozwiak, John Bissler, David Franz, Scott Segal, David Chen, Julian R. Sampson

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Abstract

Tuberous sclerosis complex is an autosomal dominant disorder that occurs owing to inactivating mutations in either TSC1 or TSC2. Tuberous sclerosis complex-related tumors in the brain, such as subependymal giant cell astrocytoma, and in the kidney, such as angiomyolipoma, can cause significant morbidity and mortality. Recently, randomized clinical trials (EXIST-1 and EXIST-2) of everolimus for each of these tuberous sclerosis complex-associated tumors demonstrated the benefit of this drug, which blocks activated mammalian target of rapamycin complex 1. Here we report on the spectrum of mutations seen in patients treated during these trials and the association between mutation and response. TSC2 mutations were predominant among patients in both trials and were present in nearly all subjects with angiomyolipoma in whom a mutation was identified (97%), whereas TSC1 mutations were rare in those subjects (3%). The spectrum of mutations seen in each gene was similar to those previously reported. In both trials, there was no apparent association between mutation type or location within each gene and response to everolimus. Everolimus responses were also seen at a similar frequency for the 16-18% of patients in each trial in whom no mutation in either gene was identified. These observations confirm the strong association between TSC2 mutation and angiomyolipoma burden seen in previous studies, and they indicate that everolimus response occurs regardless of mutation type or location or when no mutation in TSC1 or TSC2 has been identified.

Original languageEnglish (US)
Pages (from-to)1665-1672
Number of pages8
JournalEuropean Journal of Human Genetics
Volume23
Issue number12
DOIs
StatePublished - Dec 1 2015

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Angiomyolipoma
Mutation
Tuberous Sclerosis
Everolimus
Genes
Astrocytoma
Brain Neoplasms

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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Response to everolimus is seen in TSC-associated SEGAs and angiomyolipomas independent of mutation type and site in TSC1 and TSC2. / Kwiatkowski, David J.; Palmer, Michael R.; Jozwiak, Sergiusz; Bissler, John; Franz, David; Segal, Scott; Chen, David; Sampson, Julian R.

In: European Journal of Human Genetics, Vol. 23, No. 12, 01.12.2015, p. 1665-1672.

Research output: Contribution to journalArticle

Kwiatkowski, David J. ; Palmer, Michael R. ; Jozwiak, Sergiusz ; Bissler, John ; Franz, David ; Segal, Scott ; Chen, David ; Sampson, Julian R. / Response to everolimus is seen in TSC-associated SEGAs and angiomyolipomas independent of mutation type and site in TSC1 and TSC2. In: European Journal of Human Genetics. 2015 ; Vol. 23, No. 12. pp. 1665-1672.
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