AnteMEL – Skin Melanoma Polygenic Risk Score Test

Science behind AnteMEL

Overview and Purpose of the AnteMEL Test

AnteMEL is a genetic test that assesses the personalized risk of developing melanoma using a polygenic risk score. AnteMEL is one of the tools for the prevention and early detection of melanoma. The purpose of the AnteMEL test is to reduce the risk of premature mortality due to melanoma by primary and secondary prevention.

AnteMEL has been developed as a laboratory test by healthcare and medtech company Antegenes (License number L05386).

AnteMEL test uses data from genome-wide single nucleotide polymorphisms (SNPs) to evaluate individual polygenic risks of developing melanoma. This approach is based on the technology of polygenic risk scores. SNPs used in the risk score either increase or decrease the risk. AnteMEL combines the number of risk-increasing and lowering SNPs in the genome and their effects, which are summed up to form an overall estimate. Each SNP has little impact on the overall risk of melanoma but combining the effects of individual SNPs contributes to a clinically significant assessment of the total risk.

The risk model is based on peer-reviewed international research and has been evaluated and validated using anonymous population data of the UK Biobank.

AnteMEL is used to determine the carrier status of genetic variants that affect the patient’s individual risk and are combined into a polygenic risk assessment, and the 10-year probability of developing the disease. Individual patient risk is put into context with the population background data and estimates about the genetic risks of individuals of the same sex, age, and nationality. The final report also includes information about other clinical risk factors that are not included in the polygenic risk estimation.

The test report is made available to the patient and submitted to the Estonian E-Health system. If the patient has been referred to Antegenes by a healthcare service provider then the results can also be shared with the treating physician.

Target Population

AnteMEL test is recommended for men and women between the ages of 18 and 70.

AnteMEL Test Development

The polygenic risk scores and their risk differentiation estimations were validated using anonymous data from the UK Biobank. Based on large-scale genetic data, various risk prediction models published in the international scientific literature were compared, and the prediction accuracy of the best performing model was evaluated on independent data.

The risk score underlying AnteMEL is derived from Fritsche et al. 2019 (1), which combines genetic variants known to be associated with melanoma in the NHGRI-EBI GWAS Catalog (2) with those found in the Michigan Genomics Initiative. The risk score underlying AnteMEL is tailored for practical use. AnteMEL uses 28 melanoma-related SNPs to estimate personalized risk scores.

Interpretations based on individual risk scores are dependent on population data. AnteMEL estimates the distribution of individual risk levels relative to the rest of the population, using the population distribution and the risk differentiation between patients estimated during validation on UK Biobank data. The patient’s 10-year population-based risk is calculated using Choudhury et al. absolute risk model (3). The absolute risk model applies the risk differentiation estimates from UK Biobank. The absolute risk model additionally uses patient sex, age and country-based epidemiological information including overall melanoma incidence and morbidity, and overall mortality information.

Clinical recommendations of AnteMEL are based on evidence-based data on melanoma risk factors and prevention measures and the corresponding recommendations of international organizations that are tailored to the individual risk estimate from the test.

AnteMEL Test Methodology

AnteMEL test uses a non-invasive buccal swab method to collect and isolate a patient’s DNA.

The genetic material is analyzed either using second-generation genotyping or sequencing-based methods. The standard procedure includes the use of Illumina Global Screening Array-24 (GSA) v3.0 chip and Illumina iSCAN sequencer for genotyping. This workflow genotypes the ~762 000 markers on the GSA chip by following the Illumina Infinium HTS (high-throughput screening) protocol (Illumina Inc, http://www.illumina.com; Document # 15045738 v04).

The test can also use information from other microarrays and sequencing approaches that output DNA data broadly covering the human genome.

Antegenes performs the risk assessment based on imputed genotype data. Quality-controlled markers resulting from genotyping are imputed using a 1000G panel with reference to the human genome GRCh37.

AnteMEL Test Limitations

• AnteMEL test is not used to diagnose melanoma.
• An elevated risk estimated by the AnteMEL test does not mean that the patient will develop melanoma during their lifetime. Also, a moderate or lower risk does not mean that the patient will not develop the disease.
• AnteMEL test is patient-specific and does not assess the risk of the patient’s family and relatives, i.e.polygenic risk score-based disease risks may not be transmitted directly from parents to children.
• AnteMEL test does not analyze rare pathogenic mutations in single genes that significantly increase the risk of melanoma, such as CDKN2A, MC1R, CDK4, TP53, PTEN, BAP1, POT1, ACD, PARK2, TERF2IP, TERT, BRCA1, BRCA2, RB1, and others. Therefore, we recommend additional counseling and testing for the monogenic mutations, if:

1. The patient’s biological relative has a monogenic mutation in a gene predisposed to melanoma (CDKN2A, MC1R, CDK4, TP53, PTEN, BAP1, POT1, ACD, PARK2, TERF2IP, TERT, BRCA1, BRCA2, RB1);
2. Many of the patient’s biological relatives have had melanoma diagnosed;
3. The patient’s biological relatives have had three or more tumors associated with hereditary cancer syndromes.

• The AnteMEL test is based on the most up-to-date scientific data, which may, however, be supplemented and changed in the future as additional information becomes available. The field of genetics is constantly evolving, which may lead to changes in risk assessments over time, as well as changes in test selection recommendations and clinical recommendations based on test results.
• Different polygenic risk scores predicting risks of the same trait may give different estimates of the individual’s risks due to differences in the genetic variants included in the models and their weights.
• The results of this test should be applied in context with other relevant clinical data. In addition to the possible genetic predisposition, other risk factors also influence the risk of melanoma.