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

Abstract

Protection of Telomeres Protein 1 (POT1) protein is an essential subunit of the shelterin telomere binding complex, regulating telomere length. Some POT1 gene pathogenic variants (PV) lead to telomere elongation, genomic instability and higher risk of cancer. POT1 tumour predisposition syndrome (POT1-TPD) has autosomal dominant inheritance and unknown penetrance. It is associated with increased risk of cutaneous melanoma, chronic lymphocytic leukaemia, angiosarcoma and gliomas. In this work, we aim to describe a broader cancer phenotype related to POT1-TPD, in three families (two with a four generation pedigree, one with a five generation pedigree). The three index cases were referred to our oncogenetic centre for genetic counselling due to their personal history of cancer. Two underwent clinical exome sequencing of 4,867 genes associated with Mendelian genetic diseases, and another underwent gene panel sequencing including POT1, which identified three different POT1 PV: NC_000007.14(NM_015450.2):c.349C>T; NC_000007.14(NM_015450.2):c.233T>C and NC_000007.14(NM_015450.2):c.818G>A; already described in the literature. Referenced relatives, did a target genetic test (according to the POT1 PV identified in the family). In total, 37 individuals were tested (51.4% females), median age of 46 (22-81) years, with POT1 PV detected in 22. POT1-TPD was observed, but also a higher incidence of other cancers (other sarcomas, papillary thyroid cancer, early onset prostate cancer and leukaemia). These findings contribute to an increase in our knowledge about POT1 PV, and it can play a role in the definition of future POT1 PV screening criteria, POT1 carrier surveillance protocols (possibly considering screening for all types of sarcomas) and in genetic counselling.

Fig. 1. Family A - four generation pedigree with several family members affected with different primary cancers.

Family members with a cancer diagnosis are shown as filled symbol. All tested family members are marked in the pedigree, others were not tested. + : positive for NC_000007.14(NM_015450.2):c.349C>T variant; − : negative for NC_000007.14(NM_015450.2):c.349C>T variant; (+) : obligate carrier of NC_000007.14(NM_015450.2):c.349C>T variant.

Fig. 2. Family B - five generation pedigree with multiple family members affected with different primary cancers.

Family members with a cancer diagnosis are shown as filled symbol. All tested family members are marked in the pedigree, others were not tested. + : positive for NC_000007.14(NM_015450.2):c.233T>C variant; − : negative for NC_000007.14(NM_015450.2):c.233T>C variant; (+) : obligate carrier of NC_000007.14(NM_015450.2):c.233T>C variant.

Fig. 3. Family C - four generation pedigree with several family members affected with different primary cancers.

Family members with a cancer diagnosis are shown as filled symbol. All tested family members are marked in the pedigree, others were not tested. + : positive for NC_000007.14(NM_015450.2):c.818G>A variant; − : negative for NC_000007.14(NM_015450.2):c.818G>A variant; (+) : obligate carrier of NC_000007.14(NM_015450.2):c.818G>A variant.