1. Skin cancer panel

Skin cancer panel

February 02, 2018

Disease synonyms

Skin cancer, Malignant melanoma, MM, Familial malignant melanoma, Basal-cell cancer, BCC, Squamous-cell cancer, SCC, Cutaneous malignant melanoma, CMM, Basal cell nevus syndrome, BCNS, Gorlin syndrome, Nevoid basal cell carcinoma syndrome, NBCCS

Inheritance pattern

Autosomal dominant

Clinical features

Skin cancer is one of the most common types of cancer. The main types of skin cancers are: basal-cell cancer (BCC), squamous-cell cancer (SCC), and melanoma.

Basal cell carcinoma

About 80% of skin cancers develop in the basal cells, which are located in the lower epidermis 1. Basal cell carcinoma most often develops on the head and neck and it is caused primarily by exposure to the sun or radiation therapy.

Squamous cell carcinoma

Around 20% of skin cancers develop in the squamous cells of the epidermis 2. Squamous cell carcinoma is usually caused by sun exposure, but it can also develop in skin which has been burned, damaged by chemicals, or exposed to x-rays. The most common location of squamous cell carcinoma are areas near a long-standing scar, lips and skin outside the mouth, anus, and vagina. About 2-5% of squamous cell carcinomas 2 spread to other parts of the body, which makes this form of skin cancer more likely to spread than basal cell carcinoma.


Malignant melanoma (MM) is one of the most aggressive human malignancies. Melanoma starts in melanocytes, and it is the third most common cancer among women aged 20-39 years and the second most common cancer in men aged 20-39 years 3, 4, 6. The incidence rates differ among Caucasian populations, from 35 per 100 000 in Australia 3 to 7-10 per 100 000 in the United States 4 and Western Europe 5.

About 10% of melanoma cases have a family history of disease 3, 4, 6. Pathogenic variants in the CDKN2A, CDK4, MC1R, MITF genes and others (see Table 1) can lead to a higher risk of developing melanoma 6. Melanomas may develop in skin which appears to be healthy or near a previously existing skin lesion. Melanoma also may occur in unexposed areas of the skin, including the palms, soles of the feet, and perineum. Several risk factors increase the likelihood of developing melanoma, including the following:

  • Ultraviolet (UV) light exposure
  • Presence of multiple skin moles
  • Race and skin color (the risk for Caucasians is higher than for African Americans)
  • Family history of melanoma
  • Older age
  • Xeroderma pigmentosum

Certain skin lesions are considered to be precursor lesions of melanoma, including the following nevi:

  • Common acquired nevus
  • Dysplastic nevus
  • Dongenital nevus
  • Cellular blue nevus

Greatly elevated risk factors of cutaneous melanoma include the following:

  • Changing mole
  • Dysplastic nevi in familial melanoma
  • More than 50 nevi, 2 mm or greater in diameter

Moderately elevated risk factors of cutaneous melanoma include the following:

  • One family member with melanoma
  • Previous history of melanoma
  • Sporadic dysplastic nevi
  • Congenital nevus

Slightly elevated risk factors of cutaneous melanoma include the following:

  • Immunosuppression
  • Sun sensitivity
  • History of acute, severe, blistering sunburns
  • Freckling

There are a number of genes in which inherited variants can contribute to melanoma (see Table 1). Two of the genes most frequently associated with melanoma are the CDKN2A gene (cyclin - dependent kinase inhibitor 2A) and the CDK4 gene (cyclin - dependent kinase 4) 3, 6, 7. The CDKN2A and CDK4 genes encode proteins which play a role in cell division and growth. The CDKN2A protein is a tumor suppressor, while CDK4 is a protein kinase which regulates cell division and growth cycle. Variants in the CDKN2A gene have been found in approximately 20-50% of families with melanoma, while CDK4 variants have been found in fewer families 7. Germline variant frequencies in CDKN2A show considerable variation among members of melanoma families: from 46% in French familial melanoma families 8, 18% in US familial melanoma 9 to 8% of cases among Swedish families 10

Genetic polymorphisms in the gene encoding melanocortin-1 receptor (MC1R) increase susceptibility to this form of cutaneous malignant melanoma. Also, there is a strong relationship between MC1R variants and hair color and skin type. MC1R variants were found in 72% of persons with melanoma 12, 13, and 3 alleles previously associated with red hair, R151C, R160W and D294H 14, doubled the risk of melanoma for each additional allele carried.

Variants in the MITF gene on chromosome 3p14.1-p12.3 increases susceptibility to cutaneous malignant melanoma type 8. Germline missense substitution in MITF, E318K, was shown to occur at a significantly higher frequency in patients affected with melanoma, renal cell carcinoma (RCC), or both cancers when compared with controls 15. Overall, the E318K carriers had a higher than 5-fold increased risk of developing melanoma, RCC, or both cancers 15.

Variants in mismatch repair genes (MMR genes: MLH1, MSH2, MSH6, PMS1, PMS2) are also associated with melanoma 16. In a group of patients affected with melanoma,  variants were identified in several MMR genes: deletion of MSH2 exon 12 and/or exon 13, deletion of exons 15 and a6 of the MLH1 gene. The deletion of exons results in loss of MLH1 and MSH2 protein function. Point variants in both the MLH1 and MSH2 genes were not found in any of the patients affected with melanoma. In addition, MMR genes expression was decreased in melanoma brain metastases in the majority of patients affected.

Basal cell nevus syndrome is caused by variants in the PTCH1 gene. The Drosophila 'Patched' gene PTCH1 encodes a transmembrane protein which represses transcription in specific cells of genes encoding members of the TGF-beta and Wnt pathway signaling proteins. Nevoid basal cell carcinoma syndrome is characterized by the development of multiple jaw keratocysts and/or basal cell carcinomas. Approximately 60% of individuals have a recognizable appearance with macrocephaly, frontal bossing, coarse facial features, and facial milia. Sequencing analysis of exons 2-23 with intron-exon junctions and one of the splice forms of exon 1 detects pathogenic variants in 50-85% of individuals with typical clinical findings of NBCCS. Individuals and families with no other features aside from multiple BCCs have a very small probability of having a PTCH1 pathogenic variant 17, 18.

Susceptibility to cutaneous malignant melanoma is also conferred by pathogenic variants in the POT1, XRCC3, and other genes (see Table 1).

Table 1: Genes included in CENTOGENE´s Skin cancer panel:

Gene OMIM chr. locus % of pathogenic variants Allelic disorders
9p21.3 40% of MM 3, 6, 7 Melanoma and neural system tumor syndrome (155755); Pancreatic cancer/melanoma syndrome (606719); Melanoma, cutaneous malignant 2 (155601)
2p21 ~1%-3% for Lynch syndrome 19 HNPCC 8 (613244); Diarrhea 5, with tufting enteropathy, congenital (613217)
16q24.3 Variants in 72% of Australian melanoma families 12, 13 Melanoma, cutaneous malignant, 5 (613099); UV-induced skin damage (266300); Skin/hair/eye pigmentation 2 (266300); Albinism oculocutaneous type II (203200)
3p13 10%-20% for WS2 20 Several families reported 19 COMMAD syndrome (617306); Tietz albinism-deafness syndrome (103500); Waardenburg syndrome type 2A, WS2A (193510); Melanoma, cutaneous malignan
3p22.2 50% for CRC 16 HNPCC2 (609310); Mismatch repair cancer syndrome (276300); Muir-Torre syndrome (158320)
2p21-p16 40% for CRC 16 HNPCC1 (120435); Mismatch repair cancer syndrome (276300); Muir-Torre syndrome (158320)
2p16.3 7%-10% for CRC 16 HNPCC5 (614350); Mismatch repair cancer syndrome (276300); Endometrial cancer, familial (608089)
2q32.2 <1% for CRC 16 Mismatch repair cancer syndrome (276300)
7p22.1 <5% for CRC 16 HNPCC4 (614337); Mismatch repair cancer syndrome (276300)
7q31.33 Several families 21 Melanoma, cutaneous malignant, susceptibility to, 10 (615848); Glioma susceptibility 9 (616568)
9q22.32 >85% for basal cell carcinoma 17, 18 Basal cell carcinoma, somatic (605462); Basal cell nevus syndrome (109400); Holoprosencephaly 7 (610828)
14q32.33 Several families 6, 7 Melanoma, cutaneous malignant, 6 (613972); Breast cancer, susceptibility to (114480)

Treatment of skin cancers includes surgery and adjuvant therapy, which includes immunotherapy, interferon alfa, chemotherapy and palliative local therapy. Early diagnosis is of the highest significance for rapid treatment, health preservation, and survival.

CENTOGENE experts have designed the Skin cancer panel, targeted which includes these genes: CDKN2A, EPCAM, MC1R, MITF, MLH1, MSH2, MSH6, PMS1, PMS2, POT1, PTCH1.

Differential diagnosis

The differential diagnosis of skin cancer-related disorders – depending on the major symptoms in the initial case – includes the following diseases:

  • Benign melanocytic lesions
  • Dysplastic nevus
  • Squamous cell carcinoma
  • Metastatic tumors to the skin
  • Lentigo maligna melanoma

Diagnostic strategy

CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage. 

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for skin cancer using NGS Panel targeted towards this specific phenotype:

Step 1: Next Generation sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Skin cancer panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no pathogenic variant is identified after analysis of the skin cancer panel, we further recommend CentoCancer panel and/or MLPA analysis of relevant genes.

Referral reasons

The following individuals are candidates for skin cancer panel gene testing:

  • Individuals with a family history of skin cancer and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling skin cancer
  • Individuals with a negative but suspected family history, in order to perform proper genetic counseling.

Test utility

Sequencing, deletion/duplication of skin cancer related genes should be performed in all individuals suspected of having skin cancer. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of pathogenic variants, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of skin cancer, identify at-risk family members, provide information about reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.

More information on CENTOGENE´s genetic tests for Skin cancer can be found in our genetic test catalogue.