Pathogenic Loss-of-Function Germline TERT Mutations in Patients With Solid Tumors.

Dyskeratosis congenita, the original telomere syndrome, was clinically described more than 100 years ago on the basis of individuals who presented with a distinct rash, abnormal nails, and whitening of the tongue.[1] From this rare syndrome, our clinical and molecular understanding of telomere syndromes has evolved and has now expanded to include aplastic anemia, myelodysplastic syndrome, and pulmonary fibrosis.[2]-[5] The identification of patients with telomere syndromes is of significant clinical importance because these patients are exquisitely sensitive to alkylating chemotherapeutic agents and ionizing radiation.[6]-[8] Patients with telomere syndromes may manifest overt or subtle clinical findings.[5] Moreover, for patients with both obvious and subtle telomere syndromes, exquisite treatment sensitivities have been reported.[6],[7] Although only one in 1,571 individuals in this series of patients with advanced cancer showed a germline I TERT i mutation, this could translate to more than 1,000 patients diagnosed with malignancies a year in the United States who may have increased therapeutic sensitivities. Moreover, multiple I TERT i single nucleotide polymorphisms have been shown to be associated with telomere length and breast and ovarian cancer risk.[31] All this information together with telomere lengths may provide insights for stratifying patients with regard to age at presentation, outcome, and tumor evolution. Future studies that interrogate for germline mutations in other genes implicated in telomere biology (ie, I CTC1 i , I DKC1 i , I NHP2 i , I NOP10 i , I TERC i , I TINF2 i , I RTEL1 i ) in the setting of cancer may reveal additional individuals with potential therapeutic sensitivities. [Extracted from the article]
Copyright of JCO Precision Oncology is the property of American Society of Clinical Oncology and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)