POT1 Tumor Predisposition

In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993.
[updated ].


Clinical characteristics: POT1 tumor predisposition (POT1-TPD) is characterized by an increased lifetime risk for multiple cutaneous melanomas, chronic lymphocytic leukemia (CLL), angiosarcoma (particularly cardiac angiosarcomas), and gliomas. Additional cancers (e.g., colorectal cancer, thyroid cancer, breast angiosarcomas) have been reported in individuals with POT1-TPD but with very limited evidence. The age of onset for first primary cutaneous melanoma ranges from 15 to 80 years. The majority of POT1 associated cancers are diagnosed in adulthood.

Diagnosis/testing: The diagnosis of POT1-TPD is established in a proband with suggestive findings and a heterozygous germline pathogenic variant in POT1 identified by molecular genetic testing.

Management: Treatment of manifestations: The treatments for POT1-TPD tumors are those used in standard practice.

Surveillance: Full skin examination by a dermatologist beginning at age 18 years at least every six months with excision of any lesions suspicious for melanoma; consider exams every three months in individuals with multiple atypical nevi, history of melanoma, and/or family history of melanoma. CBC with differential annually beginning at age 18 years to screen for CLL. Annual comprehensive physical examination including examination of lymph nodes. Whole-body MRI annually in families fulfilling Li-Fraumeni syndrome or Li-Fraumeni-like criteria beginning at age 18 years; Consider whole-body MRI every one to two years depending on personal and family history of non-cutaneous, non-brain malignancies. Consider brain MRI every one to two years beginning at age 18 years depending on family history of glioma.

Agents/circumstances to avoid: Tanning bed use and unprotected sun exposure. Avoid radiation in diagnostic procedures.

Evaluation of relatives at risk: Molecular genetic testing for the familial POT1 pathogenic variant should be offered to first-degree relatives to identify those who would benefit from early surveillance and intervention. Although molecular genetic testing for POT1-TPD is generally not recommended for at-risk individuals younger than age 18 years, a history of early cancers in the family may warrant predictive testing prior to age 18.

Genetic counseling: POT1-TPD is inherited in an autosomal dominant manner. To date, most individuals diagnosed with POT1-TPD have an affected parent; the proportion of POT1-TPD caused by a de novo pathogenic variant is unknown. Each child of an individual with POT1-TPD has a 50% chance of inheriting the POT1 pathogenic variant. It is important to note that clinical manifestations of POT1-TPD cannot be predicted in heterozygous family members because the full phenotypic spectrum and penetrance of POT1-TPD are unknown. The types of POT1-related tumors can vary among different members of the same family and current evidence is limited to disease-focused studies. Once the germline POT1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for POT1-TPD and preimplantation genetic testing are possible.

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