POT1 tumor predisposition: a broader spectrum of associated malignancies and proposal for additional screening program

Protection of Telomeres Protein 1 (POT1) gene is located on chromosome 7 (7q31.33) and POT1 protein is an essential subunit of the shelterin telemore binding complex. It binds to the telomeric overhangs, preventing the activation of DNA damage response at telomeres and regulating telomere length. POT1 pathogenic variants (PV) can present with different phenotypes. Some variants cause telomere truncations leading to dysfunctional telomeres and telomeric syndromes, while others allow telomere elongation, prolonging cellular lifespan and facilitating acquisition of somatic mutations. Loss of the tumour-suppressive mechanism of telomere shortening leads to clonal expansion and genomic instability, increasing cancer risk. POT1 tumour predisposition syndrome (POT1-TPD) is autosomal dominant and associated with increased risks of cutaneous melanoma (CM), chronic lymphocytic leukaemia (CLL), angiosarcoma (mostly cardiac), and gliomas. Other cancers, including colorectal cancer (CRC), thyroid cancer, other soft tissue sarcomas (STS), osteosarcomas, breast and lung cancers, and lymphoid/myeloid proliferative diseases have also been associated, though these are not yet part of formal surveillance recommendations. Penetrance is unknown as only several hundred probands have been tested, so the full phenotypic spectrum remains to be defined. Diagnosis relies on detecting a heterozygous germline POT1 PV. Suspicion should be raised in individuals with multiple CM, a core POT1-TPD cancer and a close relative with a POT1-TPD cancer, or when a somatic POT1 PV is found in tumor sequencing. No targeted treatments currently exist; management follows tumor-specific standards. Cell-line studies suggest longer telomeres and POT1 upregulation may confer radioresistance, motivating exploration of POT1/telomerase inhibitors to enhance radiosensitivity. Most tumors related to POT1 PV are diagnosed in adulthood; the earliest first primary reported is at age 15. Surveillance is recommended from adulthood or two years earlier than the youngest diagnosis in the family. Expert-opinion recommendations include annual comprehensive physical exam with lymph node assessment, regular full-skin examinations, annual complete blood count, and consideration of annual or biennial whole-body MRI based on family history (including brain MRI in families with kidney cancer). This study aims to expand the tumor spectrum in three POT1-PV families beyond previously described associations, to inform testing criteria, surveillance, and genetic counselling.

The paper contextualizes POT1-TPD within existing literature: POT1 is a shelterin component involved in telomere maintenance; specific germline PVs predispose to cancers including CM, CLL, cardiac angiosarcoma, and gliomas. Additional reports have linked POT1 PVs to CRC, thyroid cancer, other STS and osteosarcomas, breast and lung cancers, and to elevated risks of lymphoid and myeloid proliferative diseases. Surveillance guidance is currently based on expert opinion rather than formal guidelines. Experimental studies suggest that longer telomeres and POT1 upregulation may confer resistance to radiotherapy, indicating potential utility of POT1 and telomerase inhibitors. The penetrance and full phenotypic spectrum are still being defined in the literature.

Study setting: Genetics center (Julie Domingues). Ethical approval was obtained; the study adhered to the Declaration of Helsinki. All participants provided written informed consent for genetic testing and publication. Design and participants: Three multigenerational families (two with four generations, one with five) were ascertained through index cases referred for oncogenetic counselling due to personal cancer history. Clinical data were collected from medical records, direct interviews, and self/family reports. Genetic testing: Index cases of Families A and B underwent clinical exome sequencing covering 4,867 genes associated with Mendelian diseases. The Family C index case underwent an oncogenic gene panel including POT1. Identified POT1 familial variants were used to guide targeted testing of relatives (pre-symptomatic testing when appropriate). Family members were offered testing based on indication and willingness. Analysis and follow-up: Pedigrees were constructed; cancer histories were cataloged. Carriers were enrolled in surveillance per current recommendations (including dermatologic exams, blood counts, and consideration of whole-body and brain MRI depending on family history). Testing occurred between 2019 and 2023.

• Variants identified: Three known germline POT1 missense variants were detected in the families: • Family A: NC_000007.14(NM_015450.2):c.349C>T; p.Arg117Cys (likely pathogenic) • Family B: NC_000007.14(NM_015450.2):c.233T>C; p.Ile87Thr (likely pathogenic) • Family C: NC_000007.14(NM_015450.2):c.818G>A; p.Arg273Gln (likely pathogenic)
• Cohort: 37 individuals tested (51.4% female), median age 46 (22–81) years; 22 carried a POT1 PV.
• Family A: 27 relatives tested; 16 carriers (11 without cancer at testing). Six non-tested obligate carriers inferred. Tumors among carriers/obligate carriers included soft tissue sarcomas (including osteosarcoma and testicular leiomyosarcoma), two early-onset cardiac angiosarcomas (ages 28–29), CM, CRC, papillary thyroid carcinoma (PTC), leukemia/CLL, low-grade glioma detected on surveillance MRI, lung cancer, and a giant cell tumor of bone (benign). One glioblastoma case tested negative for the familial variant (phenocopy).
• Family B: Proband had two liposarcomas (age 73) and PTC (74). Two daughters were carriers; one had CM. Family history included leukemia, prostate, colon, lung, brain, breast, thyroid, and gastric cancers (mostly in untested relatives).
• Family C: Proband had early-onset prostate cancer (47) and a spinal cord tumor (57); carried p.Arg273Gln. Maternal side largely negative/untested; paternal side with multiple cancers (kidney, colon, breast, STS, and early-onset prostate cancers). Mother tested negative.
• Aggregate tumor spectrum across families: Typical POT1-TPD tumors observed (two CM, two cardiac angiosarcomas, one CLL, two brain tumors). Additional observations included six sarcomas other than angiosarcoma, one CRC and two PTC in carriers, multiple lung cancers (six individuals overall, including some carriers), and early-onset prostate cancers (three individuals across statuses: one carrier, one obligate carrier, one untested).
• Surveillance impact: A low-grade glioma was identified in a carrier via screening MRI, demonstrating potential utility of imaging surveillance.
• Literature concordance: Observations align with recent reports suggesting broader associations of POT1 PV with STS (beyond angiosarcoma), CRC, PTC, hematologic neoplasia, and possible prostate cancer susceptibility.

The findings reinforce the established association of POT1 PVs with CM, CLL, cardiac angiosarcoma, and gliomas, and support an expanded tumor spectrum that includes additional sarcoma subtypes, CRC, PTC, and potentially early-onset prostate cancer. Family A’s p.Arg117Cys aligns with prior reports linking POT1 PVs to sarcomas and melanoma, and revealed further tumors (brain tumors, leukemia/CLL). Family B’s p.Ile87Thr corresponds to prior associations with familial melanoma and hematologic neoplasms, and the family history suggests broader tumor types potentially related to POT1 PV, although many were untested. Family C’s p.Arg273Gln aligns with melanoma and clonal hematopoiesis risk reported in the literature; the family history includes kidney, colon, breast, STS, and early-onset prostate cancers, though causality cannot be established without testing. These results, together with literature, suggest POT1-TPD may be underdiagnosed under current testing criteria and that surveillance guidelines could be broadened. In particular, data support considering all sarcoma types (not only angiosarcoma) in testing criteria and surveillance. Early-onset prostate cancers observed raise the possibility of discussing earlier PSA-based screening on an individualized basis, given its non-invasive nature. The detection of a glioma via screening MRI illustrates the potential benefit of whole-body and brain MRI in selected carriers. Mechanistically, telomere elongation due to POT1 PVs can promote genomic instability and clonal evolution; experimental evidence of radioresistance tied to telomere biology suggests potential benefit of developing POT1/telomerase inhibitors to enhance radiosensitivity. Overall, the expanded phenotype influences genetic counselling, testing criteria, and surveillance planning for POT1 PV carriers, while emphasizing the need for larger, prospective studies to refine risk estimates and penetrance.

In three multigenerational families with germline POT1 PVs (p.Arg117Cys, p.Ile87Thr, p.Arg273Gln), the authors observed the canonical POT1-TPD cancers and a broader spectrum including multiple non-angiosarcoma sarcomas, CRC, PTC, and possible early-onset prostate cancer. One glioma was detected through surveillance MRI, underscoring clinical utility of imaging in carriers. These findings suggest POT1-TPD is likely underrecognized under current criteria and support considering all sarcoma types in testing and surveillance guidelines, with individualized consideration of earlier prostate cancer screening. The study advocates for updated clinical protocols and for large, prospective studies to define penetrance, tumor risks, and optimal surveillance for POT1 PV carriers.

• Small sample size and limited number of tested relatives in Families B and C.
• Incomplete cascade testing: not all relatives underwent genetic testing; many cancers occurred in untested individuals, limiting causal inference.
• Cancer histories for some relatives (especially earlier generations) were based on family reports, introducing potential inaccuracies.
• Short follow-up duration and relatively young age of many carriers under surveillance (1–4 years), limiting observation of incident cancers.
• Single-center, retrospective family-based design limits generalizability and precise risk quantification.