Individuals with an inherited form of skin cancer often have a poor prognosis. However, an international group of researchers has recently published findings demonstrating that the type of immunotherapy that was awarded the 2018 Nobel Prize in Physiology or Medicine is particularly effective in this patient group.1

Congenital mutations of the CDKN2A gene are the strongest known risk factors for inherited skin cancer. According to previous research, individuals with melanoma who carry mutations in this gene also have a poor prognosis.

Melanoma that has metastasized has a limited response to traditional chemotherapy. In recent years, new immunological treatments have appeared that many melanoma patients respond well to. Such so-called immune checkpoint inhibitors treat cancer by inhibiting braking mechanisms in the immune system.


Hildur Helgadottir, MD, PhD, Karolinska Institute.

In a new study, researchers at the Karolinska Institute and elsewhere have examined how effective immunological checkpoint therapy is for individuals with inherited CDKN2A mutation and metastatic melanoma. The results were compared with previous large-scale studies in which melanoma patients were treated with immunotherapy.

“We saw that the mutation carriers with metastatic melanoma responded surprisingly well to immunotherapy,” says study leader Hildur Helgadottir, MD, PhD, of the Karolinska Institute’s department of oncology-pathology. “This is good news, particularly for this otherwise vulnerable patient group.”

Almost two-thirds of the 19 patients with CDKN2A mutations included in the study responded to the treatment in a way that the tumors shrank or, as was the case in a third of the patients, disappeared completely. Going by earlier studies the expected response was that just over one third would respond to the treatment, and that the tumors would disappear in only 1 in 15 patients.

The researchers also discovered that melanoma tumors with a CDKN2A mutation had a larger number of mutations compared to tumors with no CDKN2A mutation. A possible explanation for the good therapeutic efficacy, according to the researchers, is that CDKN2A mutated tumor cells with many mutations become so unlike healthy cells that the immune system finds them easier to recognize as foreign.

“Our conclusion from the study is that CDKN2A mutation carriers with metastatic melanoma have good chances of responding to immunotherapy, which can be associated with the fact that tumors with a CDKN2A mutation seem to have a tendency to accrue even more mutations, although this relationship requires further investigation,” says Helgadottir.

The study was performed in cooperation with researchers at Lund University and Gothenburg University, and researchers in Barcelona, Genoa, Leiden, and Sidney.


  1. Helgadottir H, Ghiorzo P, van Doorn R, et al. Efficacy of novel immunotherapy regimens in metastatic melanoma patients with germline CDKN2A mutations. J Med Genet. Epub before print, October 5, 2018; doi: 10.1136/jmedgenet-2018-105610.