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What Causes Basal and Squamous Cell Skin Cancers?

There are many known risk factors for basal and squamous cell skin cancers, but it’s not always clear exactly how these factors might cause cancer.

Most basal cell and squamous cell skin cancers are caused by repeated and unprotected skin exposure to ultraviolet (UV) rays from sunlight, as well as from man-made sources such as tanning beds. UV rays can damage the DNA inside skin cells and cause changes in genes.

How DNA damage can cause cancer

DNA is the chemical in each of our cells that makes up our genes, which control how our cells function. We usually look like our parents because they are the source of our DNA. But our genes affect more than just how we look.

Some genes help control when our cells grow, divide into new cells, repair mistakes in DNA, or cause cells to die when they’re supposed to. If these genes aren’t working properly, it can lead to cells growing out of control. For example:

  • Changes in genes that normally help cells grow, divide, or stay alive can lead to these genes being more active than they should be, causing them to become oncogenes. These genes can result in cells growing out of control.
  • Genes that normally help keep cell division under control or cause cells to die at the right time are known as tumor suppressor genes. Changes that turn off these genes can result in cells growing out of control.
  • Some genes normally help repair mistakes in a cell’s DNA. Changes that turn off these DNA repair genes can result in the buildup of DNA changes within a cell, which might lead to them growing out of control.

Any of these types of DNA changes might lead to cells growing out of control and forming a tumor. To learn more, see Oncogenes, Tumor Suppressor Genes, and DNA Repair Genes.

Gene changes that can lead to basal or squamous skin cancer

Researchers don’t yet know all of the DNA changes that result in basal or squamous cell skin cancer, but they have found that in many skin cancers the cells have changes in tumor suppressor genes or DNA repair genes.

The gene most often changed in squamous cell cancers is the TP53 tumor suppressor gene. This gene normally causes cells with damaged DNA to die. When TP53 is altered, these abnormal cells may live longer and might go on to become cancerous.

Genes often mutated in basal cell cancers include the PTCH1 or PTCH2 genes, which are part of the “hedgehog” signaling pathway inside cells. These are tumor suppressor genes that normally help keep cell growth in check, so changes in one of these genes can allow cells to grow out of control. People who have basal cell nevus syndrome (Gorlin syndrome), which is often inherited from a parent and results in getting many basal cell cancers, have an altered PTCH1 gene in all the cells of their body.

These are not the only gene changes that play a role in the development of skin cancer. There are many others as well.

People with xeroderma pigmentosum (XP) have a high risk for skin cancer. XP is a rare, inherited condition resulting from a change in one of the XP (ERCC) genes, which leads to a defect in one of the proteins that normally helps repair DNA damage. Because people with XP are less able to repair DNA damage caused by sunlight, they often develop many cancers on sun-exposed areas of their skin.

The link between squamous cell skin cancer and infection with some types of HPV (human papillomavirus) also involves DNA and genes. These viruses have genes that affect growth-regulating proteins of infected skin cells. This can cause skin cells to grow too much and to not die when they’re supposed to.

Scientists are studying other links between DNA changes and skin cancer. A better understanding of how damaged DNA leads to skin cancer might be used to design medicines to overcome or repair that damage.

The American Cancer Society medical and editorial content team

Our team is made up of doctors and oncology certified nurses with deep knowledge of cancer care as well as editors and translators with extensive experience in medical writing.

Christensen SR, Wilson LD, Leffell DJ. Chapter 90: Cancer of the Skin. In: DeVita VT, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology. 11th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2019.

National Cancer Institute. Genetics of Skin Cancer (PDQ®)–Health Professional Version. 2023. Accessed at on August 22, 2023.

Wu PA. Epidemiology, pathogenesis, clinical features, and diagnosis of basal cell carcinoma. UpToDate. 2023. Accessed at on August 22, 2023.

Xu YG, Aylward JL, Swanson AM, et al. Chapter 67: Nonmelanoma Skin Cancers. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, eds. Abeloff’s Clinical Oncology. 6th ed. Philadelphia, Pa: Elsevier; 2020.

Last Revised: October 31, 2023

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