# Cancer Genetics of Long Telomere Syndromes

> **NIH CA R01** · JOHNS HOPKINS UNIVERSITY · 2026 · $646,478

## Abstract

Abstract
This application focuses on understanding the genetic basis of a recently recognized cancer-prone syndrome
caused by long telomere length. It is driven by extended cellular longevity, a mechanism that is distinct from
tumor suppressor- and oncogene-mediated familial cancer syndromes. Telomere length is constrained in the
human population to a relatively narrow range and telomerase elongation is tightly regulated. Recent studies,
from multiple lines of evidence from our group and others, have uncovered that genetically-determined short
telomere length, at certain thresholds, is protective against most age-related malignancies. Exceptions include
squamous cancers that arise in the setting of T cell immune exhaustion, and myelodysplastic syndrome and
acute myeloid leukemia that arise in the setting of hematopoietic stem cell failure. These cancers occur at
significantly higher rates among individuals with Mendelian short telomere syndromes. The relatively lower risk
of other age-related malignancies in the short telomere syndromes has deep mechanistic underpinnings as
short telomere length mediates cellular senescence and apoptosis, thus limiting cancer evolution in nearly all
tumor-prone animal models. By contrast, there is emerging evidence that long telomere length is associated
with significantly increased cancer risk in the human population with common variants in telomere genes
increasing the risk for more than 28 malignancies. Our group recently reported on an autosomal dominant long
telomere syndrome caused by heterozygous mutations in POT1. Haploinsufficiency of POT1 enhances
telomerase elongation in vitro, and we found mediates ultra-long telomere length. POT1 mutation carriers with
long telomeres had high cancer penetrance, near 100% by age 60, and were prone to multiple malignancies
including melanoma, thyroid cancer, sarcoma, epithelial and hematologic malignancies. Alongside, they shared
a predilection to high rates of clonal hematopoiesis, which

## Key facts

- **NIH application ID:** 11300249
- **Project number:** 5R01CA292812-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Mary Y Armanios
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $646,478
- **Award type:** 5
- **Project period:** 2025-03-10T00:00:00 → 2030-02-28T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11300249

## Citation

> US National Institutes of Health, RePORTER application 11300249, Cancer Genetics of Long Telomere Syndromes (5R01CA292812-02). Retrieved via AI Analytics 2026-07-21 from https://api.ai-analytics.org/grant/nih/11300249. Licensed CC0.

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