Telomere length of both parents contributes to heritable POT1 cancer-predisposition syndrome

Abstract

Germline mutations in POT1 are linked to familial cancer predisposition, and somatic POT1 mutations occur recurrently in tumors. These mutations promote oncogenesis by enabling aberrant telomere elongation. For inherited POT1 mutations, a critical question is the extent to which elongated telomeres are transmitted to the next generation from the POT1 carrier parent and whether the inherited excessively long telomeres elevate cancer risk. Using a nanopore sequencing approach that provides haplotype-specific telomere length measurements, we examined telomere inheritance in families harboring POT1 mutations. We found that individuals preferentially inherit their longest telomeres from the carrier parent, consistent with extensive telomere elongation in the carrier germline, whereas comparatively short telomeres are predominantly inherited from the non-carrier parent. Analysis of carrier and non-carrier siblings further showed that telomeres inherited from both parents are elongated in POT1 carriers, with the shortest telomeres undergoing preferential elongation. These findings support a potential mechanism of genetic anticipation in which POT1 mutations progressively reduce the likelihood that short telomeres capable of enforcing telomere-based tumor suppression are inherited from the carrier parent. Together, our results demonstrate that telomeres inherited from both parents jointly shape telomere-based tumor suppressive barriers. Summary sentenceAllele specific nanopore sequencing reveals that POT1 mutations reshape germline and somatic telomere dynamics, uncovering a novel mechanism of generational anticipation driven by preferential elongation of short inherited telomeres.