Melanoma, Cutaneous Malignant, Susceptibility To, 10

A number sign (#) is used with this entry because susceptibility to cutaneous malignant melanoma-10 (CMM10) is conferred by heterozygous mutation in the POT1 gene (606478) on chromosome 7q31.

Mutation in the POT1 gene can also caused glioma susceptibility-9 (GLM9; 616568).

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

Clinical Features

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.

Inheritance

The transmission pattern of CMM10 in the families reported by Shi et al. (2014) was consistent with autosomal dominant inheritance and incomplete penetrance.

Molecular Genetics

In 9 affected members of 4 unrelated families with cutaneous malignant melanoma-10, 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 CMM10, 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 CMM 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) .