Showing papers by "Alisa M. Goldstein published in 2020"

Integrated analysis of genome-wide miRNAs and targeted gene expression in esophageal squamous cell carcinoma (ESCC) and relation to prognosis.

Abstract: Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer death worldwide and in China. We know miRNAs influence gene expression in tumorigenesis, but it is unclear how miRNAs affect gene expression or influence survival at the genome-wide level in ESCC. We performed miRNA and mRNA expression arrays in 113 ESCC cases with tumor/normal matched tissues to identify dysregulated miRNAs, to correlate miRNA and mRNA expressions, and to relate miRNA and mRNA expression changes to survival and clinical characteristics. Thirty-nine miRNAs were identified whose tumor/normal tissue expression ratios showed dysregulation (28 down- and 11 up-regulated by at least two-fold with P < 1.92E-04), including several not previously reported in ESCC (miR-885-5p, miR-140-3p, miR-708, miR-639, miR-596). Expressions of 16 miRNAs were highly correlated with expressions of 195 genes (P < 8.42E-09; absolute rho values 0.51–0.64). Increased expressions of miRNA in tumor tissue for both miR-30e* and miR-124 were associated with increased survival (P < 0.05). Similarly, nine probes in eight of 818 dysregulated genes had RNA expression levels that were nominally associated with survival, including NF1, ASXL1, HSPA4, TGOLN2, BAIAP2, EZH2, CHAF1A, SUPT7L. Our characterization and integrated analysis of genome-wide miRNA and gene expression in ESCC provides insights into the expression of miRNAs and their relation to regulation of RNA targets in ESCC tumorigenesis, and suggest opportunities for the future development of miRs and mRNAs as biomarkers for early detection, diagnosis, and prognosis in ESCC.

Insights into Genetic Susceptibility to Melanoma by Gene Panel Testing: Potential Pathogenic Variants in ACD, ATM, BAP1, and POT1

Abstract: The contribution of recently established or candidate susceptibility genes to melanoma missing heritability has yet to be determined. Multigene panel testing could increase diagnostic yield and better define the role of candidate genes. We characterized 273 CDKN2A/ARF and CDK4-negative probands through a custom-designed targeted gene panel that included CDKN2A/ARF, CDK4, ACD, BAP1, MITF, POT1, TERF2IP, ATM, and PALB2. Co-segregation, loss of heterozygosity (LOH)/protein expression analysis, and splicing characterization were performed to improve variant classification. We identified 16 (5.9%) pathogenic and likely pathogenic variants in established high/medium penetrance cutaneous melanoma susceptibility genes (BAP1, POT1, ACD, MITF, and TERF2IP), including two novel variants in BAP1 and 4 in POT1. We also found four deleterious and five likely deleterious variants in ATM (3.3%). Thus, including potentially deleterious variants in ATM increased the diagnostic yield to about 9%. Inclusion of rare variants of uncertain significance would increase the overall detection yield to 14%. At least 10% of melanoma missing heritability may be explained through panel testing in our population. To our knowledge, this is the highest frequency of putative ATM deleterious variants reported in melanoma families, suggesting a possible role in melanoma susceptibility, which needs further investigation.

Body mass index and height and risk of cutaneous melanoma: Mendelian randomization analyses.

Abstract: Background Height and body mass index (BMI) have both been positively associated with melanoma risk, although findings for BMI have been less consistent than height. It remains unclear, however, whether these associations reflect causality or are due to residual confounding by environmental and lifestyle risk factors. We re-evaluated these associations using a two-sample Mendelian randomization (MR) approach. Methods We identified single nucleotide polymorphisms (SNPs) for BMI and height from separate genome-wide association study (GWAS) meta-analyses. We obtained melanoma SNPs from the most recent melanoma GWAS meta-analysis comprising 12 874 cases and 23 203 controls. We used the inverse variance-weighted estimator to derive separate causal risk estimates across all SNP instruments for BMI and height. Results Based on the combined estimate derived from 730 SNPs for BMI, we found no evidence of an association between genetically predicted BMI and melanoma [odds ratio (OR) per one standard deviation (1 SD) (4.6 kg/m2) increase in BMI 1.00, 95% confidence interval (CI): 0.91–1.11]. In contrast, we observed a positive association between genetically-predicted height (derived from a pooled estimate of 3290 SNPs) and melanoma risk [OR 1.08, 95% CI: 1.02–1.13, per 1 SD (9.27 cm) increase in height]. Sensitivity analyses using two alternative MR methods yielded similar results. Conclusions These findings provide no evidence for a causal association between higher BMI and melanoma, but support the notion that height is causally associated with melanoma risk. Mechanisms through which height influences melanoma risk remain unclear, and it remains possible that the effect could be mediated through diverse pathways including growth factors and even socioeconomic status.

Ambient Ultraviolet Radiation and Sebaceous Carcinoma Incidence in the United States, 2000-2016.

Abstract: Sebaceous carcinoma (SC) is an aggressive skin tumor. Although ultraviolet radiation (UVR) is an important risk factor for some skin cancer types, no population-level study has evaluated for an association between UVR and SC risk. Herein, we examined satellite-based ambient UVR in relation to SC incidence using Surveillance, Epidemiology, and End Results 18 cancer registry data (2000-2016). There were 3503 microscopically confirmed cases of SC diagnosed during the study period. For non-Hispanic whites, there was an association between increasing ambient UVR and SC risk (incidence rate ratio [per UVR quartile] = 1.15, 95% confidence interval = 1.11 to 1.19; two-sided P < .001) including among individuals with and without putative Muir-Torre syndrome. In contrast, there was no association between ambient UVR and SC risk for other race and ethnicities. Our findings support a role for UVR in SC tumorigenesis, which suggests that photoprotection may reduce SC risk, particularly for high-risk populations (eg, Muir-Torre syndrome).

Sebaceous Carcinoma Incidence and Survival Among Solid Organ Transplant Recipients in the United States, 1987-2017.

Abstract: Importance Risk of sebaceous carcinoma (SC), a rare skin cancer associated with Muir-Torre syndrome, is elevated among solid organ transplant recipients (SOTRs). However, population studies evaluating this association and assessing survival for posttransplant cases are lacking, and further understanding of SC epidemiology in this immunosuppressed population could provide etiologic and clinical insights. Objective To assess SC incidence and patient survival after solid organ transplantation. Design, Setting, and Participants This cohort study, conducted from January 1, 1987, to December 31, 2017, used data from the Transplant Cancer Match Study, which links transplant and cancer registry data for 17 states and 1 metropolitan area in the United States. Altogether, these registries account for approximately 46% of all US transplants. Data on demographic and transplant characteristics as well as induction and initial maintenance immunosuppressive therapies were obtained from the transplant registry. Standardized incidence ratios (SIRs) comparing SC incidence among SOTRs to the general population were calculated. Incidence rate ratios (IRRs) comparing SC risk between SOTR subgroups were calculated using multivariate Poisson regression. Cox regression was used to compare overall survival between SC cases in SOTRs and other individuals. Main Outcomes and Measures Sebaceous carcinoma incidence and overall patient survival after transplantation compared with the general population. Results A total of 326 282 transplant procedures were performed for 301 075 patients (No. [%] age at transplant, 126 550 [38.8%] aged 0-44 years; 82 394 [25.3%] aged 45-54 years; 82 082 [25.5%] aged 55-64 years; 35 256 [10.8%] aged ≥65 years; 201 354 male patients [61.7%]; 202 557 White patients [62.1%]). A total of 102 SCs were diagnosed in 301 075 SOTRs, corresponding to a 25-fold increased incidence (SIR, 24.8; 95% CI, 20.2-30.1). Incidence was especially elevated among lung recipients (SIR, 47.7; 95% CI, 20.6-94.0) and after a posttransplant diagnosis of cutaneous squamous cell carcinoma (SIR, 104.0; 95% CI, 62.8-163.0). Among SOTRs, factors independently associated with SC risk included male sex (IRR, 2.46; 95% CI, 1.48-4.07; P < .001), race/ethnicity (non-Hispanic Black vs non-Hispanic White, IRR, 0.28; 95% CI, 0.10-0.77; P = .01), older age (IRR, 7.85; 95% CI, 3.85-16.0; ≥65 vs 0-44 years; P < .001 for trend), use of thymoglobulin induction (IRR, 1.82; 95% CI, 1.16-2.86; P = .009), posttransplant cutaneous squamous cell carcinoma (IRR, 4.60; 95% CI, 2.67-7.94; P < .001), and longer time since transplant (IRR, 8.40; 95% CI, 3.94-17.90; ≥10 vs 0-1.9 years; P < .001 for trend). Muir-Torre syndrome–associated cancers were rare among both SOTRs and others with SC (3.3%-4.1%). Among patients with SC, prior transplantation was associated with increased overall mortality (adjusted hazard ratio, 2.09; 95% CI, 1.45-3.01), although few deaths were attributed to SC (4 of 92 SOTRs [4.3%]; 235 of 3585 non-SOTRs [6.6%]). Conclusions and Relevance Among SOTRs, results of this large cohort study suggest that SC was associated with measures of immunosuppression, and overall survival was worse than for other patients with SC. Findings also suggest a possible role for UV radiation in carcinogenesis.

Using whole-exome sequencing and protein interaction networks to prioritize candidate genes for germline cutaneous melanoma susceptibility.

Abstract: Although next-generation sequencing has demonstrated great potential for novel gene discovery, confirming disease-causing genes after initial discovery remains challenging. Here, we applied a network analysis approach to prioritize candidate genes identified from whole-exome sequencing analysis of 98 cutaneous melanoma patients from 27 families. Using a network propagation method, we ranked candidate genes by their similarity to known disease genes in protein-protein interaction networks and identified gene clusters with functional connectivity. Using this approach, we identified several new candidate susceptibility genes that warrant future investigations such as NGLY1, IL1RN, FABP2, PRKDC, and PROSER2. The propagated network analysis also allowed us to link families that did not have common underlying genes but that carried variants in genes that interact on protein-protein interaction networks. In conclusion, our study provided an analysis perspective for gene prioritization in the context of genetic heterogeneity across families and prioritized top potential candidate susceptibility genes in our dataset.

Histologic features of melanoma associated with germline mutations of CDKN2A, CDK4, and POT1 in melanoma-prone families from the United States, Italy, and Spain.

Abstract: Background CDKN2A, CDK4, and POT1 are well-established melanoma-susceptibility genes. Objective We evaluated melanoma histopathology for individuals with germline mutations of CDKN2A, CDK4, and POT1. Methods We assessed histopathology for melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) from the United States, Italy, and Spain. Comparisons between mutation carriers and noncarriers (no mutation) were adjusted for age, sex, Breslow depth, and correlations among individuals within the same family. Results Histologic slides were evaluated for 290 melanomas (139 from 132 noncarriers, 122 from 68 CDKN2A carriers, 10 from 6 CDK4 carriers, and 19 from 16 POT1 carriers). Superficial spreading was the predominant subtype for all groups. Spitzoid morphology (>25% of tumor) was observed in 10 of 15 invasive melanomas (67%) from POT1 carriers (P Limitations Limited sample sizes for rare melanoma-susceptibility syndromes (CDK4, POT1). Conclusion Spitzoid morphology was associated with POT1 mutations suggesting that telomere dysfunction (POT1 mutations) may contribute to spitzoid differentiation in melanocytic tumors.