Hyunje G. Cho

Lateral Pharyngeal Wall Tension After Maxillomandibular Advancement for Obstructive Sleep Apnea Is a Marker for Surgical Success: Observations From Drug-Induced Sleep Endoscopy

PURPOSE The efficacy of maxillomandibular advancement (MMA) for obstructive sleep apnea (OSA) with anatomic airway changes has previously been studied using static imaging and endoscopy in awake subjects. The aim of the present study was to use drug-induced sleep endoscopy (DISE) to evaluate the dynamic upper airway changes in sleeping subjects before and after MMA and their association with the surgical outcome. PATIENTS AND METHODS This was a retrospective cohort study of subjects with OSA who had undergone MMA at the Stanford University Sleep Surgery Division from July 2013 to July 2014. The subjects were included if perioperative polysomnography and DISE had been performed. The predictor variable was the perioperative DISE velum-oropharynx-tongue-epiglottis score. The outcome variables were the apnea-hypopnea index (AHI), oxygen-desaturation index (ODI), and Epworth Sleepiness Scale (ESS). A subgroup analysis was performed for the subjects who had undergone primary and secondary MMA. The statistical analyses included Cronbachs α coefficient, the McNemar test, and the independent Student t test. The P value was set at <.01. RESULTS A total of 16 subjects (15 males, 1 female) were included in the present study, with an average age of 47 ± 10.9 years and body mass index of 29.4 ± 5.1 kg/m(2). Significant post-MMA decreases were found in the AHI (from 59.8 ± 25.6 to 9.3 ± 7.1 events/hr) and ODI (from 45 ± 29.7 to 5.7 ± 4.1 events/hr; P < .001). Greater improvement in the AHI occurred in the primary MMA group (P = .022). The post-MMA change in airway collapse was most significant at the lateral pharyngeal wall (P = .001). The subjects with the most improvement in lateral pharyngeal wall collapsibility demonstrated the largest changes in the AHI (from 60.0 ± 25.6 events/hr to 7.5 ± 3.4 events/hr) and ODI (from 46.7 ± 29.8 to 5.3 ± 2 events/hr; P = .002). CONCLUSIONS Using DISE, we observed that after MMA, the greatest reduction in upper airway collapsibility is seen at the lateral pharyngeal wall of the oropharynx, followed by the velum, and then the tongue base. The stability of the lateral pharyngeal wall is a marker of surgical success after MMA using the AHI, ODI, and ESS.

Two-stage genome-wide association study identifies a novel susceptibility locus associated with melanoma

Genome-wide association studies have identified 21 susceptibility loci associated with melanoma. These loci implicate genes affecting pigmentation, nevus count, telomere maintenance, and DNA repair in melanoma risk. Here, we report the results of a two-stage genome-wide association study of melanoma. The stage 1 discovery phase consisted of 4,842 self-reported melanoma cases and 286,565 controls of European ancestry from the 23andMe research cohort and the stage 2 replication phase consisted of 1,804 melanoma cases and 1,026 controls from the University of Texas M.D. Anderson Cancer Center. We performed a combined meta-analysis totaling 6,628 melanoma cases and 287,591 controls. Our study replicates 20 of 21 previously known melanoma-loci and confirms the association of the telomerase reverse transcriptase, TERT, with melanoma susceptibility at genome-wide significance. In addition, we uncover a novel polymorphism, rs187843643 (OR = 1.96; 95% CI = [1.54, 2.48]; P = 3.53 × 10−8), associated with melanoma. The SNP rs187842643 lies within a noncoding RNA 177kb downstream of BASP1 (brain associated protein-1). We find that BASP1 expression is suppressed in melanoma as compared with benign nevi, providing additional evidence for a putative role in melanoma pathogenesis.

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.

Melanoma risk prediction using a multilocus genetic risk score in the Women's Health Initiative cohort

Background: Single‐nucleotide polymorphisms (SNPs) associated with melanoma have been identified though genome‐wide association studies. However, the combined impact of these SNPs on melanoma development remains unclear, particularly in postmenopausal women who carry a lower melanoma risk. Objective: We examine the contribution of a combined polygenic risk score on melanoma development in postmenopausal women. Methods: Genetic risk scores were calculated using 21 genome‐wide association study–significant SNPs. Their combined effect on melanoma development was evaluated in 19,102 postmenopausal white women in the clinical trial and observational study arms of the Womens Health Initiative dataset. Results: Compared to the tertile of weighted genetic risk score with the lowest genetic risk, the women in the tertile with the highest genetic risk were 1.9 times more likely to develop melanoma (95% confidence interval 1.50‐2.42). The incremental change in c‐index from adding genetic risk scores to age were 0.075 (95% confidence interval 0.041‐0.109) for incident melanoma. Limitations: Limitations include a lack of information on nevi count, Fitzpatrick skin type, family history of melanoma, and potential reporting and selection bias in the Womens Health Initiative cohort. Conclusion: Higher genetic risk is associated with increased melanoma prevalence and incidence in postmenopausal women, but current genetic information may have a limited role in risk prediction when phenotypic information is available.

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.

Azathioprine and risk of multiple keratinocyte cancers

To the Editor: Chronic medication-induced immunosuppression is a known risk factor for keratinocyte cancer (KC). To determine which immunosuppressants are most significantly associated with increased KC, we retrospectively analyzed 3398 subjects with a biopsy finding of squamous cell cancer (SCC) or basal cell cancer (BCC) by using 8002 pathology reports at Stanford Hospital and Clinics between 2005 and 2015. We excluded reports of residual or recurrent skin cancers (Supplementary Materials and Methods; available at http://www.jaad.org). We subdivided our cohort into 3 groups on the basis of the number of KCs developed over 10 years: (1) 1 KC, (2) 2 to 5 KCs, and (3) more than 6 KCs. In the cohort, 60.1% developed 1 KC, 31.8% developed 2 to 5 KCs, and 8.1% developed 6 or more KCs. A comparable distribution was observed for BCC and SCC frequency. Overall, patients with 6 or more BCCs or SCCs represented the top 5% of the respective cohorts. A total of 572 out of 3398 subjects with KCs had 6months or more use of immunosuppressant medications, including azathioprine (n1⁄4 39), mycophenolate mofetil (n1⁄4 158), cyclosporine (n1⁄4 103), sirolimus (n1⁄4 50), and tacrolimus

Frequent basal cell cancer development is a clinical marker for inherited cancer susceptibility

Innate DNA repair mechanisms play a critical role in protecting skin keratinocytes from UV mutagenesis and skin cancer development. We hypothesized that individuals who develop frequent skin cancers may harbor germline defects in DNA repair genes and have increased predisposition to internal malignancies. We enrolled 61 patients with unusually frequent basal cell carcinoma (BCC) development, seen at Stanford Hospital and Clinics from January 2005 until December 2015, for germline analysis of 29 DNA repair genes. In parallel, a case-control retrospective review was performed to interrogate the association of malignancies with frequent BCC development in a large US medical insurance claims database (Truven), which included 13,264 individuals with 6 or more BCCs from 2007 to 2011. 19.7% of the frequent BCC cohort harbored pathogenic mutations in DNA repair genes: APC, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, and PALB2. Individuals with 6 or more BCCs had an increased risk of other malignancies, with a 3.5-fold increase in the frequent BCC cohort and a 3.2-fold increase in the Truven database. Individuals who developed frequent BCCs have an increased prevalence of germline mutations in DNA repair genes and increased malignancy risk. Our data implicate frequent BCC development as an external marker of inherited cancer risk.