Harvind S. Chahal

Risk Factors for Basal Cell Carcinoma Among Patients With Basal Cell Nevus Syndrome: Development of a Basal Cell Nevus Syndrome Patient Registry.

Importance Patients with basal cell nevus syndrome (BCNS) have a greater risk of developing numerous basal cell carcinomas (BCCs). Risk factors influencing the wide variation in tumor burden are poorly understood. Objective To describe the burden of BCCs in patients with BCNS in the United States and identify potential risk factors for BCCs. Design, Setting, and Participants Prospective clinical registry with data collected from September 2014 to March 2016. Participants were recruited from a mailing list of patients with BCNS at Children’s Hospital Oakland Research Institute and Basal Cell Carcinoma Nevus Syndrome Life Support Network. Patients of all ages with a diagnosis of BCNS were eligible for enrollment. Participants completed a clinical questionnaire on their disease characteristics and risk factors. Main Outcomes and Measures Number of BCCs in the past 2 years and over lifetime (disease burden), risk factors for BCCs. Results A consecutive sample of the first 141 participants was included (34% [100 of 297] response rate from paper survey, 23% [41 of 179] from online survey; 85 [60%] female; mean age at start of study, 53 [range, 8-83] years; 131 [93%] white). In the previous 2 years, participants reported a mean of 25 BCCs (median, 11; range, 0-250). Over their lifetime, participants reported a mean of 257 BCCs (median, 160; range, 0-2200). Univariate analysis identified age (odds ratio [OR], 1.05; 95% CI, 1.03-1.07; P < .001), number of sunburns (OR, 1.05; 95% CI, 1.00-1.10; P = .047), and history of radiation exposure (OR, 2.26; 95% CI, 1.02-5.03; P = .046) as potential risk factors for lifetime BCC severity. On multivariate analysis, only age (OR, 1.04; 95% CI, 1.02-1.07; P < .001) and number of sunburns (OR, 1.06; 95% CI, 1.00-1.11; P = .04) were statistically significant. In our adjusted models, BCC burden increased by 4% per year of age and by 6% per number of sunburns. Conclusions and Relevance Patients with BCNS have a high burden of BCCs. Age and number of sunburns were significantly associated with the severity of lifetime BCC. Further interventions to prevent and treat BCCs in patients with BCNS are needed.

Association study of genetic variation in DNA repair pathway genes and risk of basal cell carcinoma

DNA repair plays a critical role in protecting the genome from ultraviolet radiation and maintaining the genomic integrity of cells. Genetic variants in DNA repair‐related genes can influence an individuals DNA repair capacity, which may be related to the risk of developing basal cell carcinoma (BCC). We comprehensively assessed the associations of 2,965 independent single‐nucleotide polymorphisms (SNPs) across 165 DNA repair pathway genes with BCC risk in a genome‐wide association meta‐analysis totaling 17,187 BCC cases and 287,054 controls from two data sets. After multiple testing corrections, we identified three SNPs (rs2805831 upstream of XPA: OR = 0.93, P = 1.35 × 10−6; rs659857 in exon of MUS81: OR = 1.06, P = 3.09 × 10−6 and rs57343616 in 3′ UTR of NABP2: OR = 1.11, P = 6.47 × 10−6) as significantly associated with BCC risk in meta‐analysis, and all of them were nominally significant in both data sets. Furthermore, rs659857 [T] was significantly associated with decreased expression of MUS81 mRNA in the expression quantitative trait locus (eQTL) analysis. Our findings suggest that the inherited common variation in three DNA repair genes—XPA, MUS81 and NABP2—may be involved in the development of BCC. To our knowledge, our study is the first report thoroughly examining the effects of SNPs across DNA repair pathway genes on BCC risk based on a genome‐wide association meta‐analysis.

Correlates of multiple basal cell carcinoma in a retrospective cohort study: Sex, histologic subtypes, and anatomic distribution

To the editor: Basal cell carcinoma (BCC) is the most common malignancy in the United States. More than 41% of patients with 2 or more BCCs develop a subsequent BCC. Despite clinical awareness of risk factors for a second BCC, there remains a subset of individuals who develop significantly more BCCs than the average population. In this study, we sought to characterize the factors associatedwithhigh-frequency BCC, including sex, anatomic site, and histologic site. We performed a retrospective cohort study of all biopsy specimens of BCCs between June 2005 and May 2015 at Stanford Hospital and Clinics, comprising 4943 BCCs and affecting a total of 2407 patients. A final cohort of 1419 patients had 5 or more years of continuous follow-up at Stanford, of whom 60.7% (n1⁄4 862) weremale and 39.3% (n1⁄4 557) were female (Supplemental Table I; available at http:// www.jaad.org). During the 10-year period, 46.7% of patients (n 1⁄4 662) had 2 or more BCCs and 5% had 6 or more BCCs (termed ‘‘high-frequency BCCs’’). In our cohort, BCCs were most commonly located on the head and neck (55.7%), followed by the trunk (28.0%), the extremities (15.9%), and the genitalia (0.1%). The most common histologic subtype was nodular (57.1%), followed by superficial (19.5%) and infiltrative (14.1%). Patients with 6 or more BCCs were more likely to have BCCs on the trunk than those with a single BCC (P 1⁄4 .011). Similarly, as the number of BCCs increased, they were more likely to be of the superficial subtype as compared with the subtypes in patients with a single BCC (P1⁄4 .007). The anatomic and histologic subtype of high-frequency BCCs were consistent with prior case series on multiple BCCs. As the number of BCCs increased, the proportion of male patients increased, from 57.1% of those with 1 BCC to 62.1% with 2 to 5 BCCs to 79.3% with 6 or more BCCs (Fig 1). With the use of generalized logistic regression, adjusted for age, race, and followup duration, male sex was associatedwith a 1.18-fold increase in risk of 2 or more BCCs (P 1⁄4 .007) and a 2.40-fold increase in risk of 6 or more BCCs (P \ .001) (Table I). The increased risk of highfrequency BCCs followed a nonlinear change with each incremental BCC (Supplemental Fig 1; available at http://www.jaad.org).

Association between genetic variation within vitamin D receptor-DNA binding sites and risk of basal cell carcinoma

An increasing number of studies have reported a protective association between vitamin D and cancer risk. The vitamin D endocrine system regulates transcriptional programs involved in inflammation, cell growth and differentiation through the binding of vitamin D receptor (VDR) to specific VDR elements. However, limited attention has been given to the role of variation within VDR binding sites in the development of basal cell carcinoma (BCC). Across 2,776 previously identified VDR binding sites, we identified 2,540 independent single‐nucleotide polymorphisms (SNPs) and examined their associations with BCC risk in a genome‐wide association meta‐analysis totaling 17,187 BCC cases and 287,054 controls from two data sets. After multiple testing corrections, we identified two SNPs at new loci (rs16917546 at 10q21.1: odds ratio (OR) = 1.06, p = 3.16 × 10−7 and rs79824801 at 12q13.3: OR = 1.10, p = 1.88 × 10−5) for the first time as independently related to BCC risk in meta‐analysis; and both SNPs were nominally significant in two data sets. In addition, the SNP rs3769823 within VDR binding site at a previously reported BCC susceptibility locus (2q33.1, rs13014235) also exhibited a significant association (OR = 1.12, p = 3.99 × 10−18). A mutually adjusted model suggested that rs3769823 explained the signal in this region. Our findings support the hypothesis that inherited common variation in VDR binding sites affects the development of BCC.

Incidence ratio of basal cell carcinoma to squamous cell carcinoma equalizes with age

BCC, Basal cell carcinoma; SCC, squamous cell carcinoma. Data source: Dermatopathology reports for patients seen and biopsied at Stanford Hospital and Clinics, from June 2005 to June 2015. Among patients with BCC, roughly 58% were male and 90% were Caucasian; for SCC cases, these values are 62% and 85%, respectively. Cases defined as recurrences were excluded. For more information about this cohort, please contact the corresponding author (ksarin@stanford.edu). *Small sample size limits accuracy. J AM ACAD DERMATOL VOLUME 76, NUMBER 2 Research Letters 353