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Rule of three may be more effective than rule of two in melanoma testing

Compared with the rule of two for detecting melanoma, the rule of three was more effective in identifying genetic risk factors for the disease in a recent retrospective study.

The analysis included 1,032 patients who underwent genetic testing at two university hospitals in France during 2004 through 2015. The researchers aimed to reconsider the rule of two criteria for general population testing for melanoma, which was based on whether a first- or second-degree relative had a malignancy, or if the patient had two invasive cutaneous melanomas and/or related cancers.

The frequency of mutations in CDKN2A, CDK4 and BAP1 genes, which the researchers defined as high susceptibility, underwent analysis, as did the intermediate susceptibility gene MITF. Other parameters evaluated included histological subtype, age of the patient, dysplastic nevi syndrome and associated cancers on mutation rate. Cases with anamnestic uncertainty also were included.

Results indicated a mutation rate of 6.5%, with 67 patients carrying mutations. When the rule of three — defined as 3 primary melanomas or genetically related cancers — was applied, the incidence rate of mutations increased to 9.3% (P = .68).

The mutation rate increased again to 18% when a rule of four — where patients had four primary melanomas or related cancer — was applied (P < .001).

Among patients experiencing a first melanoma at an age younger than 40 years, the rule of two yielded a mutation identification rate of 12.1% (P = .12), while the rule of three yielded a rate of 18.2% (P = .001). When the rule of two was applied in patients younger than 40 years, it decreased the number of missed CDKN2A-mutated families compared with the rule of three (7 of 43 vs. 14 of 43).

The overall rate of anamnestic uncertainty was 8.5%. When this criterion was excluded, one mutation would have been missed, according to the findings. Withdrawal of anamnestic uncertainty would have led to the withdrawal of 23.8% of cases.

“We propose using the rule of [three] to recommend genetic testing in France and countries with low to moderate incidence of melanoma, except in families and patients with a first melanoma occurrence before age 40 years in whom the rule of [two] could be maintained,” the researchers concluded. – by Rob Volansky

Disclosures: The authors report no relevant financial disclosures.