A cohort analysis of 79 patients with five or more cutaneous melanomas turned up markedly elevated polygenic risk scores and no single high-penetrance variant explaining most cases. The work appears in the August 2026 issue of the Journal of Investigative Dermatology, Volume 146, Issue 8, Pages 2057-2060, framed by a commentary from Andrew D. King and David E. Fisher.

Researchers built the cohort to address a recurring clinical puzzle: patients with multiple primary melanomas who test negative on the standard germline panel. They excluded anyone carrying pathogenic variants in the established susceptibility set (CDKN2A, CDK4, BAP1, TERT, POT1, ACD, TERF2IP, TINF2), then layered two assays. Whole-exome sequencing scanned for rare coding variants. SNP array genotyping fed polygenic risk scores for each individual.

The aim was to test whether cumulative low-to-moderate risk alleles, not a hidden monogenic driver, could explain multiple primary melanoma in this subgroup.

The clinical pull is real. Cutaneous melanoma arises from UVR exposure layered on inherited susceptibility ranging from common low-penetrance variants in pigmentation, nevus count, and telomere biology to rare high-penetrance variants in the canonical susceptibility genes. Patients with multiple primaries skew toward the rare-variant end, but a large subgroup sits in the negative-panel gray zone.

Who was in the cohort?

Of 79 participants, 29 (37%) were female. Mean age at first melanoma diagnosis sat at 43.9 years, with a range of 7 to 73. Each patient carried at least five histologically confirmed in situ or invasive cutaneous melanomas. Lentigo maligna melanoma fell outside the inclusion criteria.

The QIMR Berghofer Human Research Ethics Committee approved the protocol. Samples came from blood or saliva collected with Oragene DNA kits. Twelve of the 79 had previously appeared in early-onset cutaneous melanoma or combined cutaneous-uveal cohorts.

What did the genetic data show?

MC1R risk alleles turned up significantly enriched across the cohort. MC1R sits at the center of pigmentation biology and is the classic low-to-moderate-penetrance locus for melanoma. Polygenic risk scores ran markedly higher than in population-based melanoma cases.

Variants of uncertain or moderate effect surfaced in pigmentation and DNA damage response genes, but no single rare variant carried the multiple primary melanoma phenotype for most patients.

The takeaway: stacked common alleles do the heavy lifting here. A pattern emerged on the other end: people who did carry rare potentially pathogenic variants in cancer genes tended to land lower on the polygenic risk scale.

The authors read this as complementary genetic architectures, with high-polygenic-risk and rare-variant pathways sitting on opposite ends of the same risk spectrum.

What does this change for clinicians?

Practitioners seeing patients with a stack of primary melanomas and a negative germline panel shouldn't assume an undiscovered high-penetrance driver is running the show. It's the cumulative burden of low- and moderate-risk alleles, captured by PRS, that explains much of the risk here.

Pathogenic CDKN2A variants appear in only 1–2% of unselected melanoma cases but explain roughly 40% of high-density families, which makes the negative-panel cohort clinically distinct from familial clusters. The data argue for combining polygenic risk scores with rare-variant panels when stratifying multiple primary melanoma patients.

Referral pathways that end at negative germline testing may need a PRS add-on to flag high-risk individuals for intensified surveillance. Patients with five or more primaries and no identified PV now have a plausible alternative explanation to offer them.

What are the limits?

The analysis excluded lentigo maligna melanoma and ran on a relatively small, high-burden subset. Twelve participants had appeared in prior cohorts, which can shift allele frequencies.

Conflict disclosures list honoraria to one author from Metaoptima and travel support from L'Oréal, both unrelated to this work. Funding came from Australia's National Health and Medical Research Council (APP1195581) and the Warwick L Morison Professorship of Dermatology at UNSW.

Larger, ancestry-diverse cohorts will decide whether PRS thresholds translate across populations, and whether combined PRS-plus-rare-variant scoring becomes standard of care for multiple primary melanoma surveillance.