MIAMI (FRONTLINE MEDICAL NEWS) – Although rare, patients who present with one or more skin cancers characteristic of those associated with loss of the BAP1 tumor suppressor protein may be at elevated risk for more aggressive uveal melanomas and other cancers such as kidney cancer and mesothelioma. For this reason, dermatologists who recognize the lesions and telltale pattern of this inherited mutation within families can do a great service, encouraging education, genetic counseling, and referral of patients to a nearby cancer center, according to Hensin Tsao, MD, PhD.

BAP1 is a mixed-tumor syndrome. These patients are getting melanoma and mesothelioma, kidney cancer and ocular melanoma,” Dr. Tsao said at the 2018 Orlando Dermatology Aesthetic and Clinical Conference.

“And melanoma becomes a window and opportunity to screen and identify these other mutations. And as with all cancer syndromes, we want to screen earlier.”

The BAP1-associated skin lesions can emerge when patients are relatively young, even as teenagers. The melanoma and renal cell cancers also can have an early onset, said Dr. Tsao, director of the melanoma genetics program at Massachusetts General Hospital, Boston. The skin lesion itself can be a tipoff for a BAP1 germline mutation. In general, they are small, dome shaped – not flat like a superficial basal cell – rarely pigmented and appear “orangey translucent.” Dr. Tsao added: “When you start seeing them, you’ll recognize them. However, to be sure, you’re going to have to biopsy to know what is going on.”

In one patient he described, the pattern of malignancies in the patient’s family was a hint that she had a BAP1 mutation, Dr. Tsao said. The proband had melanoma starting at age 31 years, a squamous cell carcinoma at 35 years, and basal cell carcinoma at age 40 years. “She had nine ‘nevoid melanomas’ over the years. Nevoid melanomas are rare, and with nine in a row, you know something odd is going on.” Dr. Tsao and his team performed a series of sentinel lymph node biopsies that ruled out metastasis. “What is also interesting is the father had ocular melanoma, which is what got us to thinking about BAP1 mutations in this family.” A sister who developed melanoma and a brother who also was diagnosed with melanoma plus kidney cancer at age 45 years were further clues to the germline mutation.

No longer ‘condemned proteins’

Under normal circumstances, BAP1 is a tumor suppressor protein involved in cellular process called “ubiquitination.” Often, ubiquitination serves to identify proteins “condemned” for destruction by the proteasome system. The BAP1 protein acts through a molecular relay and removes ubiquitin polypeptide groups on the protein. “In the absence of BAP1, proteins often linger longer because they accumulate ubiquitin groups, or alternatively, the protein’s function is somehow altered by mechanisms we don’t quite understand yet,” Dr. Tsao explained.

In someone with a relevant mutation that destroys this BAP1 function, the ubiquitin compounds fail to be removed. “In the case of BAP1 protein loss, cancers can proliferate. “All the families described so far [with inherited BAP1 alterations] have a harmful mutations that kill this protein somehow,” Dr. Tsao said.

Once a dermatologist suspects a BAP1 mutation–associated cancer, they can order a BAP1 nuclear stain to confirm diagnosis. Formal documentation of a germline mutation, however, requires genetic testing of blood DNA.

A family history lesson

Ask patients not only about history of melanoma in their family, including if any close relative was diagnosed with eye melanoma, Dr. Tsao suggested. “We had an opportunity to look at cutaneous and ocular melanoma families. Overall, if your family has an ocular melanoma along with cutaneous melanoma, the risk of being a BAP1 mutation–bearing family is greater.” In addition, he and his colleagues did a case control study with Ivana K. Kim, MD , at the Massachusetts Eye and Ear Infirmary in Boston, and found people with metastatic ocular melanoma were more likely to have BAP1 mutations, compared with those with nonmetastatic ocular melanoma.

“The fear is, of course, patient who are BAP1 mutation carriers might be predisposed to more lethal variants of uveal melanoma.”

Although taking a family history is essential, some patients may be unfamiliar with mesothelioma. “So ask about any unusual lung cancers or eye cancers,” Dr. Tsao suggested. “And if it looks like there is an aggregation of rare tumors, get them to a nearby cancer center [for further work-up]. Mesothelioma is difficult to treat and a horrible disease,” he added. “So if there is any chance you can [catch] the mesothelioma early, that’s good.”

He also cautioned against over interpretation of patient reports about family malignancies, in part because lung and breast cancers are relatively common. “Sometimes, when you see a family with lung or breast cancers, it could just be a chance association since these are quite common in the general population.” In other words, determining if a lung cancer in a family with melanoma is an association beyond chance can take some “pretty large numbers to prove.”

In contrast, “the number of kidney cancers among BAP1 families I do believe are out of proportion with normal population expectations,” Dr. Tsao added.

Follow-up and genetic counseling

There is no standard protocol for follow-up once a patient is identified with a BAP1 mutation. “I refer them for uveal, kidney, and/or lung cancer evaluation and see them back two to four times a year for skin checks.”

A meeting attendee suggested that management of a patient with melanoma might not differ based on genetic-testing results. “I agree with you that I don’t need to know the genetic status within these families to help with their cutaneous melanomas,” Dr. Tsao replied. “But the question becomes, are there other internal malignancies you’re not screening for appropriately?”

Another attendee asked about genetic counseling. “I encourage genetic counseling since dermatologists often don’t have time to take at detailed family history of all cancers and ages of onset,” Dr. Tsao said. “Genetic counselors can help sort out the strength of the genetic pedigree in a family. My residents usually ask if someone has a history of melanoma in their family, and that’s it. But there is a big difference between having a cousin with melanoma and three brothers with melanoma.”