C9ORF72 Mutation Linked to High Risk of Melanoma in ALS and FTLD Patients in Study

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by Alice Melão |

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skin cancer and genes

Amyotrophic lateral sclerosis (ALS) or frontotemporal lobar degeneration (FTLD) patients with the C9ORF72 mutation are at an unusually high risk of malignant skin cancer and should be monitored for it, a study suggests.

The study, “Increased risk of melanoma in C9ORF72 repeat expansion carriers: A case-control study,” was published in the journal Muscle & Nerve.

Previous studies have suggested that Parkinson’s, Alzheimer’s, and ALS can confer a protective effect against cancer. However, recent reports have found that the incidence of some types of cancer are higher-than-usual in the ALS population.

ALS and FTLD are considered to belong to the same disorder spectrum, sharing common disease-associated mutations, including the C9ORF72 gene expansion.

Several genes are thought to link neurodegenerative disorders with cancer, yet there is little information on the underlying mechanism that might explain this association.

Portuguese researchers recently explored the hypothesis that C9ORF72 mutation is linked to a higher prevalence of malignant skin cancer, also known as melanoma.

A total of 157 people diagnosed with primary FTLD and 32 with ALS were enrolled. Genetic analysis found that 62 patients had disease-associated mutations, including 39 people with C9ORF72 repeat expansions (63%), 3 with MAPT (5%) mutations, and 20 with GRN (32%) mutations.

The mean age of the entire study’s population was 63.8, but mutation carriers were significantly younger, with a mean age of 59.3.

Seven patients had a melanoma diagnosis, and six (86%) of them were carriers of a C9ORF72 repeat expansion. The remaining patient had no identified mutation.

Two others with the C9ORF72 expansion were found to have basal cell carcinoma, the most common form of skin cancer.

“Melanoma’s prevalence in C9ORF72 carriers is higher than that of basal cell carcinoma, which is the inverse of the general population,” the researchers wrote.

Overall, C9ORF72 carriers in this study were found to have 24.7-fold higher risk of developing melanoma compared to all other patients. Melanoma’s prevalence was also significantly higher in this patient group compared to those with other gene mutations.

Additional genetic analysis failed to detect additional mutations known to be linked to melanoma, further supporting a link between C9ORF72 repeat expansions and an increased risk of melanoma.

Researchers believe “that a common pathway is involved in the ALS/FTLD spectrum and melanoma development, in which C9ORF72 repeat expansions may play a role.”

Their findings also suggest that ALS or FTLD patients with a personal history of melanoma “may be at increased risk of carrying a C9ORF72 repeat expansion. … [and] genetic testing for C9ORF72 might be considered” for them — keeping in mind that all who are carriers “should undergo surveillance for skin changes,” the researchers wrote.