Study Examines Rate of Inherited Cancer Risk in Individuals with Melanoma

Results of a recent study on germline predisposition in oncologic and dermatologic melanoma cohorts conducted by Pauline Funchain, MD, an oncologist and cancer genomics expert who co-founded the Genomics Clinic at Cleveland Clinic, showed a 15.3% germline positive rate.

Dr. Funchain presented the findings in a poster discussion session at the 2022 American Society of Clinical Oncology Annual Meeting.

Motivation behind the study

When Dr. Funchain began caring for patients at the Cleveland Clinic Taussig Cancer Center, she noticed that many of them had a family history of cancer – and not just melanoma.

“At the time, many people were interested in multiple melanomas running in a family, but what we were seeing in clinic was melanoma and breast cancer or kidney cancer or pancreatic cancer,” says Dr. Funchain.

A review of the literature suggested that it’s rare for patients with familial atypical multiple mole melanoma (FAMMM) syndrome, multiple primary melanomas and early age of onset – all known to be associated with germline CDKN2A/CDK4 pathogenic variants – to carry germline alterations, so Dr. Funchain decided to conduct a more expansive study.

“Instead of offering testing for only melanoma-specific genes, we broadened it out to cancer-related genes,” she says. “That expanded the number of genes we looked at from 12 to 85. Our purpose was to understand what percentage of people with melanoma have an inherited cancer risk.”

Methods and data analysis

The study compared the overall prevalence of germline cancer predisposition in a large prospective oncologic cohort to other defined cohorts of individuals with melanoma with available germline data.

Individuals who presented to the medical oncology clinic with a diagnosis of melanoma and a personal or family history of multiple cancers were offered germline testing with a commercially available, next-generation sequencing panel. Selection criteria included:

• An individual with a melanoma diagnosed at 35 years of age or younger
• Two or more melanomas in an individual or family
• An individual with a melanoma and other cancer(s)
• An individual with a melanoma with at least two other cancers in first- or second-degree relatives

Dr. Funchain and her colleagues performed a comparative analysis of germline next-generation sequencing data from three additional selected and non-selected melanoma datasets.

Study results

In addition to the 15.3% germline positive rate, other key findings include the following:

• Genes previously associated with inherited melanoma (BAP1, BRCA 1/2, CDKN2A, MITF, TP53) comprised less than one-third of germline pathogenic/likely pathogenic variants.
• The majority of germline variants were in cancer predisposition genes such as BRIP1, CHEK2, MSH2, MLH1, RAD51C and BLM, which are not traditionally associated with melanoma.

“There is a much broader set of genes associated with melanoma that runs in families than we previously thought,” says Dr. Funchain. “They are genes we haven’t been looking for in the melanoma population, such as genes typically associated with Lynch syndrome.”

Clinical implications

Based on the study results, Dr. Funchain recommends that clinicians obtain a family and personal history of cancer from individuals with melanoma and refer them for broad panel-based germline testing.

“The traditional wisdom is that if an individual has an inherited melanoma gene, it doesn’t really change management of the patient because they routinely see dermatologists,” she says. “However, because the genes identified in patients with melanoma are related to other cancers, that does change management and possible treatment.”

Dr. Funchain has seen the benefit of genetic testing and counseling first-hand. One of her patients with melanoma who underwent germline testing discovered he carried a mutation in one of the BRCA genes. His daughter subsequently tested positive, so she had a baseline mammogram at a younger age than is normally recommended. It revealed early-stage breast cancer.

“If she had waited until the average age to have a routine mammogram, her providers may have caught the cancer too late to effectively treat it,” says Dr. Funchain.

Since completing the study, Dr. Funchain and her colleagues have opened a clinical trial to look at the efficacy of PCR inhibitors on patients with melanoma caused by homologous recombination deficiency.