Multiplex melanoma families are enriched for polygenic risk

Area of Science:

• Genetics
• Dermatology
• Cancer Research

Background:

• Cutaneous melanoma exhibits familial clustering, influenced by environmental factors like UV radiation and genetic predisposition.
• Genetic risks include rare, high-penetrance mutations and common, low-penetrance variants.
• Known high-penetrance mutations explain only half of familial melanoma cases, leaving the cause of remaining clustering unknown.

Purpose of the Study:

• To investigate the role of cumulative small-effect genetic variants in familial melanoma clustering.
• To assess polygenic risk scores in families with melanoma but without known high-penetrance mutations.

Main Methods:

• Utilized a polygenic risk score for cutaneous melanoma.
• Compared polygenic load in families lacking known high-penetrance mutations against unrelated melanoma cases and healthy controls.
• Performed whole-genome sequencing on germline DNA from 51 individuals across 21 families.

Main Results:

• Family members showed a significantly higher mean polygenic load for cutaneous melanoma compared to unrelated cases and controls (P < 1.5 × 10⁻⁵ and P < 6.3 × 10⁻⁴⁵).
• Whole-genome sequencing identified a CDKN2A p.G101W mutation in one family but no other high-penetrance genes.
• The majority of families studied had low polygenic risk scores.

Conclusions:

• Familial melanoma clustering can result from the combined effect of numerous common, low-penetrance genetic variants.
• This suggests that complex disorders like melanoma arise from multiple predisposing factors, including both rare high-penetrance mutations and cumulative small-effect alleles.