The combination of genetic profiling and histological techniques improves the diagnostic and personalization of the treatment against melanoma

Dr. Juan Angel Recio, head of the Biomedical Research in Melanoma group at the Vall d'Hebron Institute of Research (VHIR) and Dr.Vicenç Garcia-Patos, head of the Dermatology Department) have studied the genetic alterations and tumoral evolution in a patient with Nevus of Ota who developed a skin malignant melanoma, comparing them with other melanocytic lesions molecularly related, the blue nevus. The results, published in Pigment Cell and Melanoma Research and Oncotarget suggest the need of the combination of histological and genetic techniques for the correct diagnosis of many of these cases.

Nevus of Ota is a skin and eye disease which consists in a hyper pigmentation that affects the skin of a sector of the face and eye, following the path of the trigeminal nerve. It is produced by a proliferation of cells called melanocytes, which are increased in size and number in these lesions. Although they are rare, it has been described that, as uveal melanomas and blue nevus, contain mutations in the gene GNAQ, and there is a risk that it may become malignant and fatal.

The study is based on the case of a patient aged 28 who attended the specialist because the sebaceous cyst that had been diagnosed 12 years ago had begun to grow in the last 6 months. The dermatologist decided to remove the cyst, but the result was that it was a malignant skin melanoma.

After a few months, the patient came recommended to Vall d'Hebron to monitor her case and oncologists Dr. Javier Cortés and Dr. Eva Muñoz-Cosuelo found that the tumour had developed in the same place occupied by a Nevus of Ota located under the hair. At this stage the team of Dr. Recio analyzed the tumour histopathology (Dr. Berta Ferrer, Pathology Department) and its molecular characteristics, and they found that the tumour had developed from the malignant transformation of the benign lesion (Nevus of Ota) probably carried since birth. A year later the patient developed a new tumour in exactly the same area where the first was removed. The histological and genetic analysis of the new tumour made by Dr. Recio in collaboration with Dr. Ana Vivancos, head of Cancer Genomics Group at the Vall d’Hebron Institute of Oncology (VHIO), revealed that it was genetically different to the primary. According to the researcher, "tracking the evolution of the patient revealed tumoural heterogeneity of the melanoma in the malignant disease progression." Keeping in mind this evolution of the tumour is important, as targeted cancer therapies are based on the detection of genetic alterations in one or more genes.

Given the development observed in this type of skin cancer, Dr. Recio ensures that knowledge of the tumour and mutations which coexist in the same tumour cell "is essential to understand the convergent mechanisms involved in the progression, establish the prognosis and manage effective therapies.”

After this case, researchers analyzed the evolution of mutations involved in the malignization of related lesions, blue nevus, since these share with the Nevus of Ota and uveal melanomas the mutations that start the lesion (GNAQ). The analysis of the melanoma developed from the nevus of Ota showed the same malignant mutation observed in uveal melanomas, which prevented BAP1 protein activity. Instead, the blue nevus had not that mutation, despite being also related to the possibility of malignant and fatal ending.

To determine what was happening, the researchers looked at the malignant cells of blue nevus with histological techniques and found that indeed the BAP 1 protein was present but it could not perform its normal function because it was delocalized. Instead of being in the core of the cell, it was located in the cytoplasm. So these tumours had selected in their malignant evolution a different mechanism to achieve the same end, inactivating BAP1. Therefore, Dr. Recio said that "genetics is sometimes not enough for the correct diagnostic or prognosis", since in this case the gene was not mutated, but it could not perform its function properly.

Thanks to the investigation of her case, the patient could receive a personalized treatment according to the particularities of her disease. Currently the patient is clear of disease.