POT1 Tumor Predisposition

Excerpt

Clinical characteristics: POT1 tumor predisposition (POT1-TPD) is characterized by an increased lifetime risk for multiple cutaneous melanomas, sarcomas (particularly cardiac angiosarcomas), chronic lymphocytic leukemia (CLL), and gliomas. Additional solid tumors and hematologic neoplasms (e.g., thyroid cancer) have been reported in individuals with POT1-TPD. 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; in addition, monthly self-examination should be encouraged. Annual whole-body MRI beginning at age 18 years, or earlier depending on personal and family history of non-cutaneous, non-brain malignancies. Annual complete blood count with differential beginning at age 18 years to screen for CLL. Annual comprehensive physical examination including examination of lymph nodes. 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; 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 years.

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 individuals with 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. Clinical manifestations of POT1-TPD cannot be predicted in heterozygous family members because the full phenotypic spectrum and penetrance of POT1-TPD are unknown. Once the germline POT1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.