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Having multiple diagnoses of basal cell carcinoma (BCC) is a clinical sign of an inherited cancer susceptibility that significantly increases the risk for internal malignancies such as melanoma, breast, colon, and prostate cancers, according to researchers.

Germline analysis of 29 DNA repair genes in 61 patients treated at a single institution for multiple BCCs between January 2005 and December 2015 showed that 19.7% harbored 13 pathogenic mutations in 12 DNA repair genes.

In patients with six or more BCCs, DNA repair deficiencies in APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2 were associated with a 3.5-fold increase of internal malignancy, said Kavita Y. Sarin, MD, PhD, of Stanford University Medical Center in California, and colleagues.

In addition, a parallel retrospective review of the medical insurance claims database Truven showed that from 2007 to 2011, 13,264 registered individuals with six or more BCCs had a 3.2-fold increase in other malignancies, the study authors reported online in the .

"The prevalence of these inherited mutations in DNA repair genes is even higher than those reported in individuals with life-threatening malignancies, including metastatic (11.8%), primary (18%), and stage I–III (10.7%, 14.6%)," they wrote. "Further studies are needed to determine if our findings are generalizable in independent cohorts."

The average number of BCCs per patient was 11, and 21 (34.4%) had a personal history of cancer: five invasive melanomas and five hematologic, two breast, two colon, and five prostate cancers. "The highest increase in risk was observed in melanoma and squamous cell carcinoma, likely due to shared ultraviolet light exposure."

The incidence of pathogenic mutation in DNA repair genes in patients with frequent BCCs was "shockingly high" compared with the general population (20% versus 3%), Sarin said in a news release." We're hopeful that this finding could be a way to identify people at an increased risk for a life-threatening malignancy before those cancers develop."

Patients with multiple BCC diagnoses may benefit from clinical screening for a family history of malignancy as well as multigene cancer-susceptibility panel testing, the researchers suggested, noting that the latter needs to be better understood before it can be widely implemented. The gene environment also needs to be characterized in patients with multiple BCCs to identify risk factors that may be independently associated with increased malignancy.

The researchers pointed out that more than 85% of individuals in the United States are age 55 or older when first diagnosed with . In the cohort of patients with high-frequency BCC, however, the first diagnosis of skin cancer occurred a decade earlier, at an average age of 44.1.

What's more, the team said, in 10 (16.4%) of the patients with multiple BCCs, skin cancer developed before the age of 30. This compares with 1.3% of the general population diagnosed with incident skin cancer before age 35. "The earlier onset of first skin cancer may suggest a higher contribution from genetic susceptibility in addition to increased environmental risk factors."

The investigators noted that an earlier longitudinal Danish in 190,000 individuals identified an increased risk of internal malignancy, including breast cancer and lymphoma, after the diagnosis of one or more BCCs.

'Broaden Pathophysiology Horizons'

Asked for his perspective, Adam Friedman, MD, of George Washington School of Medicine and Health Sciences in Washington, D.C., who was not affiliated with the research, said the findings "suggest we should broaden our pathophysiology horizons a little. This single study opens the door for and encourages further investigations but is not enough to merit more frequent cancer screenings, and the substantial physical and financial cost that would come with it."

Other than inherited syndromes such as Gorlin syndrome in which patients can develop both multiple BCCs and internal malignancy, "this is the first study I am aware of showing that a substantial percentage of individuals with multiple consecutive BCCs have germline mutations of DNA repair genes associated with other cancers," Friedman said.

Typically, BCCs are limited to the skin and resolved with local surgery, he pointed out. "We tend not to think of these malignancies as a component of a systemic picture."

A patient with multiple BCCs warrants having a thorough family history, said Friedman. In the patient with both multiple BCCs and a strong family history of internal malignancy, "we should simply be encouraging and facilitating proper age-related screenings."

Sarin and co-authors said their study has two key limitations: The genetic analysis was limited to 61 patients at a single institution, and the claims database did not have demographic and clinical data such as race and genetic testing results.

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