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

• Published in: Genome medicine Vol. 14; no. 1; pp. 25 - 15
• Main Authors: Sharaf, Radwa, Montesion, Meagan, Hopkins, Julia F., Song, Jiarong, Frampton, Garrett M., Albacker, Lee A.
• Format: Journal Article
• Language: English
• Published: London BioMed Central 26.02.2022; BioMed Central Ltd; BMC
• Subjects: Analysis; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Breast; Cancer; Cancer Research; Cell Cycle Proteins - genetics; DNA-Binding Proteins - genetics; Genes; Hepatocyte Growth Factor - genetics; Hepatocyte Growth Factor - metabolism; HGF; Human Genetics; Humans; Medicine/Public Health; Metabolomics; Neoplasms - genetics; RAD21; Systems Biology; Telomerase; Telomerase - genetics; Telomere; Telomere - genetics; Telomere Homeostasis; Telomeres; TERC; Tumor; X-linked Nuclear Protein - genetics; DAXX; TERT; TERC; RAD21; HGF; ATRX; Breast; Tumor; ALT; Telomere
• ISSN: 1756-994X; 1756-994X
• DOI: 10.1186/s13073-022-01029-7

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.