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Association of BRAF V600E Status of Incident Melanoma and Risk for a Second Primary Malignancy: A Population-Based Study

Cutis. 2022 September;110(3):150-154,E2-E3 | doi:10.12788/cutis.0607
September 6, 2022|Cutis
Soogan C. Lalla, MBChB, FRCP;Anagha Bangalore Kumar, MBBS;Julia S. Lehman, MD;Christine M. Lohse, MS;Jerry D. Brewer, MD, MS
Author and Disclosure Information

From the Mayo Clinic, Rochester, Minnesota. Drs. Lalla and Brewer are from the Department of Dermatology, Dr. Bangalore Kumar is from the Department of Immunology, Dr. Lehman is from the Division of Anatomic Pathology, and Ms. Lohse is from the Division of Biomedical Statistics and Informatics.

The authors report no conflict of interest.

This study was made possible by using the resources of the Rochester Epidemiology Project, which is supported by the National Institute on Aging of the National Institutes of Health (NIH) under Award Number R01AG034676. BRAF staining of histopathology slides was supported by the Department of Dermatology at the Mayo Clinic, Rochester, Minnesota. Dr. Kumar was supported by the NIH grant T32 GM008685-20. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.

Correspondence: Jerry D. Brewer, MD, MS, Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (Brewer.Jerry@mayo.edu).doi:10.12788/cutis.0607

Mutations of the BRAF oncogene occur in both melanomas and several other cancers. Our objective was to determine if mutant BRAF V600E expression in a population-based cohort of patients with melanoma was associated with the development of a second primary malignancy of any type. Using the resources of the Rochester Epidemiology Project, we retrospectively identified 380 patients aged 18 to 60 years who were diagnosed with an incident melanoma from 1970 through 2009. We reviewed individual medical records to identify second primary malignancies. We evaluated mutant BRAF V600E expression from available melanoma tissue specimens and assessed its association with the development of a second primary malignancy. BRAF V600E expression in melanomas is associated with an increased risk for basal cell carcinoma (BCC).

Practice Points

  • Dermatologists should be aware of the long-term risk of second primary malignancies after an incident melanoma.
  • BRAF mutations occur in melanomas and several other cancers. Our study found that melanoma BRAF V600E expression is associated with an increased risk for basal cell carcinomas.

The 5- and 10-year cumulative incidences of all second primary malignancies excluding second primary melanoma were similar between BRAF-positive and BRAF-negative melanoma, but the 15- and 20-year cumulative incidences were greater for the BRAF-positive cohort. This could reflect the association of BRAF expression with BCCs and the increased likelihood of their occurrence with cumulative sun exposure and advancing age. BRAF expression was associated with the development of BCCs, but the reason for this association was unclear. BRAF-mutated melanoma occurs more frequently on sun-protected sites,20 whereas sporadic BCC generally occurs on sun-exposed sites. However, BRAF-mutated melanoma is associated with high levels of ambient UV exposure early in life, particularly birth through 20 years of age,21 and we speculate that such early UV exposure influences the later development of BCCs. The lack of an association between BRAF positivity and the development of other specific cancers is possibly because the mutation is somatic and not inherited or germline, as with the CDKN2A mutation, and/or because of the small size of our cohorts.

Development of BRAF-Mutated Cancers—It currently is not understood why the same somatic mutation can cause different types of cancer. A recent translational research study showed that in mice models, precursor cells of the pancreas and bile duct responded differently when exposed to PIK3CA and KRAS oncogenes, and tumorigenesis is influenced by specific cooperating genetic events in the tissue microenvironment. Future research investigating these molecular interactions may lead to better understanding of cancer pathogenesis and direct the design of new targeted therapies.22,23

Regarding environmental influences on the development of BRAF-mutated cancers, we found 1 population-based study that identified an association between high iodine content of drinking water and the prevalence of T1799A BRAF papillary thyroid carcinoma in 5 regions in China.24 Another study identified an increased risk for colorectal cancer and nonmelanoma skin cancer in the first-degree relatives of index patients with BRAF V600E colorectal cancer.25 Two studies by institutions in China and Sweden reported the frequency of BRAF mutations in cohorts of patients with melanoma.26,27

Additional studies investigating a possible association between BRAF-mutated melanoma and other cancers with larger numbers of participants than in our study may become more feasible in the future with increased routine genetic testing of biopsied cancers.

Study Limitations—Limitations of this retrospective epidemiologic study include the possibility of ascertainment bias during data collection. We did not account for known risk factors for cancer (eg, excessive sun exposure, smoking). The Olmsted County population is mostly White, and residents have relatively easy access to health care; these factors should be considered when generalizing the results to other populations. Basal cell carcinomas are common skin cancers, and there may be other risk factors influencing the development of BCCs in our cohort. BRAF mutation analysis was available in only a small number of patients (n=380; aged 18–60 years), which would have reduced our capacity to identify statistically significant associations. A positive BRAF result did not differentiate between high and low expression levels, but expression levels may affect patient outcomes. One study showed that high BRAF expression correlated with significantly poorer overall (P=.009) and disease-specific 5-year survival (P=.007) for 232 patients with primary melanoma.28

The main clinical implications from this study are that we do not have enough evidence to recommend BRAF testing for all incident melanomas, and BRAF-mutated melanomas cannot be associated with increased risk for developing other forms of cancer, with the possible exception of BCCs. Future research should assess BRAF mutation status of any second primary malignancies that arise after an incident BRAF-positive melanoma.

Conclusion

Physicians should be aware of the risk for a second primary malignancy after an incident melanoma, and we emphasize the importance of long-term cancer surveillance. The association between BRAF expression in incident melanomas and a higher rate of BCC development may provide indirect evidence that high levels of UV light exposure in early life can increase the risk for BCCs later. Although BRAF mutations occur in several nonmelanoma cancers, further studies are needed to determine whether BRAF tissue expression in melanoma affects the development of other cancers.

Acknowledgment—We thank Ms. Jayne H. Feind (Rochester, Minnesota) for assistance with study coordination.

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