A number sign (#) is used with this entry because of evidence that tumor predisposition syndrome-3 (TPDS3) is caused by heterozygous germline mutation in the POT1 gene (606478) on chromosome 7q31.

Tumor predisposition syndrome-3 (TPDS3) is an autosomal dominant disorder characterized by an increased risk for the development of various types of benign and malignant neoplasms throughout life, with age-dependent penetrance. The age of tumor onset is usually in adulthood, although there is genetic anticipation and childhood onset has been reported. Affected individuals can develop neoplasms involving epithelial, mesenchymal, and neuronal tissues, as well as clonal hematopoietic syndromes, including lymphoid and myeloid cancers. The disorder is associated with elongated telomeres, which likely results in extended cellular longevity and age-associated accumulation of somatic driver mutations in other genes, such as JAK2 (147796). Inheritance of the disorder shows incomplete penetrance (DeBoy et al., 2023).

For a discussion of genetic heterogeneity of TPDS, see TPDS1 (614327).

For a discussion of genetic heterogeneity of cutaneous malignant melanoma (CMM), see 155600. For a discussion of genetic heterogeneity of glioma, see GLM1 (137800).

Robles-Espinoza et al. (2014) reported 4 unrelated families in which at least 2 members developed cutaneous malignant melanoma. Two patients developed non-melanoma cancers, and several family members had a history of non-melanoma cancers, suggesting increased susceptibility to a range of cancers.

Bainbridge et al. (2015) reported 3 unrelated families in which at least 2 members had adult-onset glioma, either an astrocytoma or an oligodendroglioma. In 2 families, several other family members had different cancers, including lung cancer, kidney cancer, and leukemia. None of the families had a history of melanoma.

Wong et al. (2019) reported 4 affected individuals from 3 unrelated families of Jewish descent with TPDS3. The probands in all families had melanoma, and some affected family members also developed chronic lymphocytic leukemia, thyroid cancer, and cutaneous T-cell lymphoma. All tumors were adult-onset. Examination of melanoma and nevi tissue from 2 of the patients showed accumulation of somatic events in several driver genes, many of which were involved in the MAPK pathway.

DeBoy et al. (2023) identified 21 patients from 8 unrelated families who developed various types of benign or malignant neoplasms associated with heterozygous germline mutations in the POT1 gene. Mutation carriers had increased telomere length compared to their noncarrier relatives. Mutation carriers developed a spectrum of tumor types, including melanoma, thyroid, glioblastoma, oligoastrocytoma, uterine fibroids, soft-tissue sarcomas, desmoid tumors, renal cell carcinoma, urothelial carcinoma, colorectal carcinoma, and hematopoietic neoplasms, such as B-cell leukemia and lymphoma, T-cell lymphoma, and myeloproliferative disorders. Analysis of peripheral T cells showed that 5 (28%) of 18 POT1 mutation carriers had evidence of increased clonality (clonal hematopoiesis of indeterminate potential, CHIP), including 4 persons with no history of hematologic cancer. Flow cytometry confirmed the presence of atypical or clonal T-cell populations in 4 of 5 of these individuals; all 5 were also incidentally identified as having clonal B-cell populations. In another analysis, 8 (67%) of 12 POT1 mutation carriers had clonal hematopoiesis of indeterminate potential (CHIP). In the clones in the carriers, DNMT3A (602769) was the most commonly somatically mutated gene, followed by JAK2, particularly V617F (147796.0001). The JAK2 V617F mutations were myeloid-derived and expanded longitudinally with age. In some cases, DNMT3A mutations were shared across myeloid and lymphoid lineages, supporting their having arisen in a primitive progenitor. Phylogenetic inference of colonies derived from single-cell hematopoietic progenitors in 2 related POT1 mutation carriers yielded results consistent with driver CHIP mutations arising early in life (e.g., before 4 years of age in one 74-year-old carrier). These findings suggested that driver-carrying lineages are long-lived in POT1 mutation carriers and that long telomere length provides a selective advantage that sustains clonal evolution. Of note, delayed graying of the hair was reported in 6 mutation carriers who were over the age of 70.

The transmission pattern of TPDS3 in the families reported by DeBoy et al. (2023) was consistent with autosomal dominant inheritance. There is an age-dependent penetrance and genetic anticipation, as well as incomplete penetrance.

In 9 affected members of 4 unrelated families with TPDS3 manifest as cutaneous malignant melanoma, Robles-Espinoza et al. (2014) identified 4 different heterozygous mutations in the POT1 gene (606478.0001-606478.0004). The mutations were found by whole-exome sequencing. In vitro functional expression studies showed that the mutations disrupted POT1 telomere binding, resulting in significantly longer telomere length in mutation carriers compared to melanoma patients without POT1 mutations. Robles-Espinoza et al. (2014) suggested that the mutations may promote uncapping of telomeres, telomere length extension, and chromosomal aberrations, thereby promoting tumorigenesis. The families were among 105 families with melanoma studied, thus accounting for 4% of the cohort.

In affected members of 7 Italian families with TPDS3 manifest as malignant melanoma, Shi et al. (2014) identified heterozygous mutations in the POT1 gene (see, e.g., 606478.0005-606478.0007). The mutations were found by whole-exome sequencing. One mutation (S270N; 606478.0005) showed a founder effect in 5 Italian families. Cells from mutation carriers showed increased telomere lengths and numbers of fragile telomeres compared to controls, suggesting that perturbation of telomere maintenance is involved in tumorigenesis. Sequencing the POT1 gene in 768 Italian melanoma cases and 768 controls showed a significant increase in burden for rare exonic variants among cases compared to controls (16 carriers among cases and 3 carriers among controls; odds ratio of 5.4, p = 0.0021). Subsequent sequencing of the POT1 gene in 3 other populations identified germline missense variants (see, e.g., 606478.0008) in families of American and French origin. Functional studies were not performed for any variant identified by Shi et al. (2014) .

In affected members of 3 unrelated families with gliomas, Bainbridge et al. (2015) identified 3 different heterozygous mutations in the POT1 gene (606478.0009-606478.0011). Two families had members with histories of other cancers, although none had melanoma, and several unaffected family members carried the mutation, consistent with incomplete penetrance. Functional studies of the variants were not performed, but there was evidence that mutation carriers had a higher telomere content compared to those without the mutation. The families were ascertained from a larger cohort of 55 glioma families who underwent whole-exome sequencing.

In 4 affected individuals from 3 unrelated families of Jewish descent with TPDS3, Wong et al. (2019) identified a heterozygous I78T mutation in the POT1 gene (606478.0006). The mutation segregated with the disorder in the families, although there was evidence of incomplete penetrance. In vitro functional studies showed that the variant impaired POT1 binding to telomere-like probes. Expression of the mutation into cells in vitro resulted in elongated telomeres. The probands in all families had melanoma, and some affected family members also developed chronic lymphocytic leukemia, thyroid cancer, and cutaneous T-cell lymphoma. All tumors were adult-onset. Examination of melanoma and nevi tissue from 2 of the patients showed accumulation of somatic events in several driver genes, many of which were involved in the MAPK pathway. Haplotype analysis suggested a founder effect.

In affected members of 8 unrelated families with TPDS3 with various types of hematopoietic and non-hematopoietic benign and malignant neoplasms, DeBoy et al. (2023) identified heterozygous germline mutations in the POT1 gene (see, e.g., 606478.0014-606478.0016). The mutations, which were confirmed by Sanger sequencing, segregated with the disorder in the families, with some evidence of incomplete penetrance. The mutations were either absent from or found at a low frequency in the gnomAD database. Patient cells showed decreased POT1 expression and defective binding to telomere DNA, consistent with a loss of function and haploinsufficiency. Mutation carriers, even those without tumors, had long telomeres compared to non-mutation carriers. DeBoy et al. (2023) concluded that loss of the tumor suppressor mechanism of telomere shortening resulting from POT1 haploinsufficiency may support the expansion of clonal populations, leading to an elevated risk of cancer.