Short NK- and Naïve T-Cell Telomere Length Is Associated with Thyroid Cancer in Childhood Cancer Survivors: A Report from the Childhood Cancer Survivor Study

Tsz Kwong Man, Geraldine Aubert, Melissa A. Richard, Wanda LeJeune, Elmira Hariri, Tatiana Goltsova, Amos Gaikwad, Yan Chen, Jillian Whitton, Wendy M. Leisenring, Michael A. Arnold, Joseph P. Neglia, Yutaka Yasui, Leslie L. Robison, Gregory T. Armstrong, Smita Bhatia, Maria M. Gramatges

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

BACKGROUND: Survivors of childhood cancer are at risk for therapy-related subsequent malignant neoplasms (SMN), including thyroid SMN. Telomere length (TL) is associated with cancer risk, but the relationship between TL and SMN risk among survivors is less clear.

METHODS: We conducted a nested, matched case-control study of radiation-exposed 15-year+ adult survivors of childhood cancer with thyroid SMN (cases) and without SMN (controls). Forty-six cases were matched to 46 controls by primary diagnosis, chemotherapy (yes/no), radiation field, and follow-up duration. Lymphocyte TL (LTL) was measured by telomere flow-FISH cytometry using blood samples banked at a mean of 38.9 years (cases), 39.2 years (controls). Genetic variation in telomere genes was assessed by whole genome sequencing. Point estimates for LTL <10th percentile were determined for cases and controls.

RESULTS: Cases had shorter median LTL than controls in three out of four leukocyte subsets. Cases were more likely to have NK cell LTL <10th percentile ( P = 0.01), and 2.8-fold more likely to have naïve T-cell LTL <10th percentile than controls (CI, 1.07-8.78). Five out of 15 cases with a rare indel or missense variant had naïve T-cell LTL <10th percentile, compared with one out of eight controls.

CONCLUSIONS: Long-term survivors have shorter than expected LTL, a finding that is more pronounced among survivors with thyroid SMN.

IMPACT: The long-term impact of childhood cancer treatment on immune function is poorly understood. Our findings support immune function studies in larger survivor cohorts to assess long-term deficits in adaptive and innate immunity that may underlie SMN risk.

Original languageEnglish (US)
Pages (from-to)453-460
Number of pages8
JournalCancer Epidemiology Biomarkers and Prevention
Volume31
Issue number2
DOIs
StatePublished - Feb 2022

Bibliographical note

Funding Information:
The authors would like to thank Dr. Alison Bertuch for her critical review of this manuscript, and the survivors and families who participate in the CCSS. This work was supported by the Texas Children’s Cancer and Hematology Centers Flow Cytometry Core Laboratory, the Texas Children’s Cancer and Hematology Centers Bioinformatics Core Laboratory, and the Baylor College of Medicine Human Genome Sequencing Center. This work was supported by the NCI at the NIH (R01 CA194473: M.M. Gramatges, Principal Investigator). CCSS was supported by the NCI at the NIH (U24 CA55727: G.T. Armstrong, Principal Investigator), the St. Jude Children’s Research Hospital Cancer Center Support (CORE) grant (CA21765, C. Roberts, Principal Investigator), and the American Lebanese-Syrian Associated Charities (ALSAC).

Funding Information:
G. Aubert reports other support from Repeat Diagnostics Inc. (RDx) during the conduct of the study. W.M. Leisenring reports grants from NIH during the conduct of the study. L.L. Robison reports grants from NCI during the conduct of the study. G.T. Armstrong reports grants from NIH during the conduct of the study. No disclosures were reported by the other authors.

Publisher Copyright:
© 2021 American Association for Cancer Research.

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