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Background Cancer cells can proliferate indefinitely through telomere maintenance mechanisms. These mechanisms include telomerase-dependent elongation, mediated by  TERT  activation, and alternative lengthening of telomeres (ALT), linked to loss of  ATRX  or  DAXX . Methods We analyzed the telomeric content of 89,959 tumor samples within the Foundation Medicine dataset and investigated the genomic determinants of high telomeric content, linking them to clinical outcomes, when available. Results Telomeric content varied widely by disease type with leiomyosarcoma having the highest and Merkel cell carcinoma having the lowest telomeric content. In agreement with previous studies, telomeric content was significantly higher in samples with alterations in  TERC ,  ATRX,  and  DAXX . We further identified that amplifications in two genes,  RAD21  and  HGF , were enriched in samples with high telomeric content, which was confirmed using the PCAWG/ICGC dataset. We identified the minimal amplified region associated with high telomeric content for  RAD21  (8q23.1–8q24.12), which excludes  MYC , and for  HGF  (7q21.11). Our results demonstrated that  RAD21  and  HGF  exerted an additive telomere lengthening effect on samples with existing alterations in canonical genes previously associated with telomere elongation. Furthermore, patients with breast cancer who harbor  RAD21  alterations had poor median overall survival and trended towards higher levels of Ki-67 staining. Conclusions This study highlights the importance of the role played by  RAD21  (8q23.1–8q24.12) and  HGF  (7q21.11) in the lengthening of telomeres, supporting unlimited replication in tumors. These findings open avenues for work aimed at targeting this crucial pathway in tumorigenesis.

A pan-cancer landscape of telomeric content shows that RAD21 and HGF alterations are associated with longer telomeres