Clinical Guidance

POT1 tumor predisposition (POT1-TPD) is associated with an increased risk for multiple cutaneous melanomas, sarcomas (particularly cardiac angiosarcomas), chronic lymphocytic leukemia (CLL), and gliomas. Additional cancers have been reported in individuals with a germline POT1 pathogenic variant. However, due to limited data it is unclear if these cancers are specifically associated with POT1 germline pathogenic variants. The general experience, however, is that there is a great diversity of tumor types within and between families. Cutaneous melanoma is the most commonly reported malignancy in individuals with POT1-TPD. The age of onset for first primary cutaneous melanoma ranges from 15 to 80 years .

Source: GeneReviews — "POT1 Tumor Predisposition"

Penetrance

The penetrance of POT1-TPD is currently unknown. Initial studies suggest a very high penetrance but are subject to a selection bias for research cohorts/families. In more than half of reported families only the proband was tested. Many individuals with germline POT1 variants were ascertained based on a strong family history of cancer from tumor-specific consortiums (e.g., The Gliogene Consortium, UK National Study of Colorectal Cancer Genetics, UK Familial Melanoma Study).

Source: GeneReviews — "POT1 Tumor Predisposition"

Differential Diagnosis

Other genes known to be associated with predisposition to cutaneous melanoma, sarcoma, and/or glioma are listed in .

Table 2.

Autosomal Dominant Tumor Predisposition Syndromes of Interest in the Differential Diagnosis of POT1 Tumor Predisposition

Cancer Type(s) | Gene(s) | Tumor Predisposition Syndrome/ Comment

Cutaneous melanoma

| BAP1 | BAP1 tumor predisposition syndrome

BRCA2

| BRCA1- and BRCA2-associated hereditary breast and ovarian cancer

CDK4 | Susceptibility to cutaneous malignant melanoma 3 (OMIM 609048)

CDKN2A

| Hereditary melanoma/pancreatic cancer syndrome (See CDKN2A Cancer Predisposition.)

MITF | Susceptibility to cutaneous malignant melanoma 8 (OMIM 614456)

PTEN | PTEN hamartoma tumor syndrome (incl Cowden syndrome)

TERT | Susceptibility to cutaneous malignant melanoma 9 (OMIM 615134)

Source: GeneReviews — "POT1 Tumor Predisposition"

Clinical Guidance

To date, there is no evidence that UV light contributes to the pathogenesis of POT1-TPD-associated melanoma. However, individuals with POT1-TPD should be counseled against tanning bed use, as well as unprotected sun exposure, which are known risk factors for melanoma development. It is currently unknown whether ionizing radiation poses an increased risk to individuals with POT1-TPD, but because of the need for lifelong surveillance, it seems reasonable to avoid radiation in diagnostic procedures and instead recommend MRI or ultrasonography.

Source: GeneReviews — "POT1 Tumor Predisposition"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "POT1 Tumor Predisposition"