Insights Into Basal Cell Carcinoma Gene Mutations

Ashley Wysong, MD, MS, is the founding chair of the department of dermatology at the University of Nebraska Medical Center in Omaha, NE, and the William W. Bruce, MD, distinguished chair of dermatology. A nationally recognized Mohs micrographic surgeon, Dr Wysong is the director of the skin cancer program at the Fred and Pamela Buffett Cancer Center where she is developing multidisciplinary programs in melanoma/sarcoma, high-risk nonmelanoma skin cancer (NMSC), Merkel cell carcinoma, cutaneous lymphoma, and supportive oncodermatology. Currently, she has an interest in identifying novel genetic mutations in skin cancer to help predict which tumors may be cured by localized treatments alone, and which are at higher risk for metastasis and death. She joined The Dermatologist to discuss her recent study, “Basal Cell Carcinoma [BCC] Gene Mutations Differ Between Asian, Hispanic, and Caucasian Patients: A Pilot Study.”¹

What was the reason you and your team conducted this study?
First and foremost, skin cancer is important to study as one in five Americans develop a form of skin cancer in their lifetime. If you add up all other cancers that we treat in the United States, there are four times as many skin cancers as all other cancers combined. In general, about 40% of Caucasian patients will develop skin cancer at some point in their life, compared with 5% of Hispanics, 4% of Asians, and 2% of African Americans. While a smaller proportion of skin cancer develops in persons of color, it accounts for a significant number of individuals and we have much to learn.

The reason our team became interested in patients with skin cancer and skin of color is because, in practice, we kept seeing non-Caucasian patients developing advanced and late stage tumors, often with delays in diagnosis at the time of presentation. Our team has been trying to understand more about the factors that help explain these differences in a true “bedside to bench” approach. In 2018 and 2019, we did a two-part comprehensive literature review of skin of color patients with melanoma and NMSC that was published in Dermatologic Surgery^2,3 that helped identify differences in clinical presentation. Since that time, a lot of our research on skin cancer in skin of color has shifted from epidemiologic to translational in nature.  Specifically, we are interested in understanding if there are differences in germline or somatic tumor mutations or expression that might explain racial and ethnic differences in skin cancer presentation and progression and could ultimately help improve management in the future.

This study’s results noted that there are “potential differences in the prevalence of somatic gene mutations for [patients with] BCC of different races and ethnicities.” What’s the significance of these findings?
When we talk about mutations within the body, there are two major types of mutations: germline and somatic (aka “sporadic”). Germline mutations are present in every cell in the body and are passed down through families. Germline mutations, in the context of cancer, can put patients at higher or lower risk for developing skin cancer and can help predict response to systemic medications and other therapies. Somatic mutations happen sporadically and are usually due to some sort of insult, which in the case of skin cancer is typically UV radiation, but there are other types of mutations patients can develop sporadically.

To the best of our knowledge, this is the first study to evaluate mutational differences in BCC from patients of different races and ethnicities. Specifically, this study was looking at somatic mutations, and found statistically significant differences between Asian, Caucasian, and Hispanic patients. One of the findings we found very interesting was that the proportion of UV-B mutations was significantly higher in Caucasian patients compared with Asian and Hispanic patients, suggesting that less UV radiation may be needed to cause malignant transformation in non-Caucasian patients and/or other pathways may be involved in carcinogenesis.

The other big and interesting finding is that the most commonly mutated genes were different between Asian, Hispanic, and Caucasian patients in BCC. This is especially important in light of novel targeted molecular therapies that are in use for patients with BCC. For example, no smoothened receptor (SMO) mutations were detected in the Hispanic cohort, which may affect tumor susceptibility to therapies such as vismodegib and sonidegib that inhibit SMO. Some of the lifesaving medications that we’re using now in oncology are targeted to specific mutations; if those mutations are different between races and ethnicities, the medications may not be equivalently effective. These potential mutational differences and their impact on gene expression are important to study in different races and ethnicities.

A major caveat is that this is a pilot study with a small number of patients (N=23). We’re now going back and trying to recruit and build larger cohorts of patients to further evaluate these findings. I hope that this study serves as an early first step to get people thinking about skin cancer in persons of color.

What should dermatologists consider when screening or treating patients with BCC in addition to different race and ethnic backgrounds?
High level, the vast majority of BCCs are treated with locally destructive or surgical techniques. For most BCCs, the mutational profile may not be important if we can surgically cure the tumor. Our findings become important in locally advanced or more aggressive BCCs to help potentially predict poor outcomes or response to targeted therapy. First and foremost, public health campaigns are essential in all populations to get the word out about warning signs for skin cancer, such as looking for growing, changing, bleeding, and nonhealing lesions. Early detection is key.

What additional research is needed to improve the treatment of BCC in Asian, Hispanic, and Caucasian patients?
Additional research is needed to follow up on the findings of this pilot project. Specifically, I think there is a tremendous opportunity utilizing novel genetic techniques to better understand how skin cancer, and other types of tumors and dermatologic conditions may differ by race and ethnicity both in terms of pathophysiology, progression/prognosis, and management.  In addition, our group is now looking beyond mutational differences into gene expression and differences in the tumor microenvironment.

What key takeaways would you like to leave with dermatologists regarding BCC gene mutations in Asian, Hispanic, and Caucasian patients?
We are at the tip of the iceberg here—it is an exciting time to be a dermatologist, because we’re just beginning to understand how we can utilize genetic information and precision medicine to guide work up and management of patients with skin conditions. We also need to recognize that this may differ based on race and ethnicity.

It is also important to recognize that if a dermatologist is treating a non-Caucasian patient with a more aggressive or locally advanced BCC and/or multiple tumors, the patient may present and respond to therapies differently. This is particularly important if patients will be receiving a molecular inhibitor or other systemic medications. I believe our work also highlights the importance of equal access and ensuring diverse populations are represented in clinical trials in our field.

References
"1. Lobl M, Hass B, Clarey D, Higgins S, Sutton A, Wysong A. Basal cell carcinoma gene mutations differ between Asian, Hispanic, and Caucasian patients: a pilot study.
J Drugs Dermatol. 2021;20(5):504-510. doi:10.36849/JDD.5884

2. Higgins S, Nazemi A, Chow M, Wysong A. Review of nonmelanoma skin cancer in African Americans, Hispanics, and Asians. Dermatol Surg. 2018;44(7):903-910. doi:10.1097/DSS.0000000000001547

3. Higgins S, Nazemi A, Feinstein S, Chow M, Wysong A. Clinical presentations of melanoma in African Americans, Hispanics, and Asians. Dermatol Surg. 2019;45(6):791-801. doi:10.1097/DSS.0000000000001759