Esteban Astiazaran Symonds

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• Astiazaran-Symonds, E., Ney, G. M., Higgs, C., Oba, L., Srivastava, R., Livinski, A. A., Rosenberg, P. S., & Stewart, D. R. (2023). Cancer in Costello syndrome: a systematic review and meta-analysis. British journal of cancer, 128(11), 2089-2096.
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  Costello syndrome (CS) is a cancer-predisposition disorder caused by germline pathogenic variants in HRAS. We conducted a systematic review using case reports and case series to characterise cancer risk in CS.
• Feng, J., Karnes, J. H., & Symonds, E. A. (2023). Visualization and Quantification of the Association Between Breast Cancer and Cholesterol in the All of Us Research Program.. Cancer Informatics. doi:10.1177/11769351221144132
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  Epidemiologic evidence for the association of cholesterol and breast cancer is inconsistent. Several factors may contribute to this inconsistency, including limited sample sizes, confounding effects of antihyperlipidemic treatment, age, and body mass index, and the assumption that the association follows a simple linear function. Here, we aimed to address these factors by combining visualization and quantification a large-scale contemporary electronic health record database (the All of Us Research Program). We find clear visual and quantitative evidence that breast cancer is strongly, positively, and near-linearly associated with total cholesterol and low-density lipoprotein cholesterol, but not associated with triglycerides. The association of breast cancer with high-density lipoprotein cholesterol was non-linear and age dependent. Standardized odds ratios were 2.12 (95% confidence interval 1.9-2.48), P = 5.6 × 10-31 for total cholesterol; 1.99 (1.75-2.26), P = 2.6 × 10-26 for low-density lipoprotein cholesterol; 1.69 (1.3-2.2), P = 9.0 × 10-5 for high-density lipoprotein cholesterol at age < 56; and 0.65 (0.55-0.78), P = 1.2 × 10-6 for high-density lipoprotein cholesterol at age ⩾ 56. The inclusion of the lipid levels measured after antihyperlipidemic treatment in the analysis results in erroneous associations. We demonstrate that the use of the logistic regression without inspecting risk variable linearity and accounting for confounding effects may lead to inconsistent results.
• Feng, J., Symonds, E. A., & Karnes, J. H. (2023). Visualization and Quantification of the Association Between Breast Cancer and Cholesterol in the All of Us Research Program. Cancer informatics, 22, 11769351221144132.
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  Epidemiologic evidence for the association of cholesterol and breast cancer is inconsistent. Several factors may contribute to this inconsistency, including limited sample sizes, confounding effects of antihyperlipidemic treatment, age, and body mass index, and the assumption that the association follows a simple linear function. Here, we aimed to address these factors by combining visualization and quantification a large-scale contemporary electronic health record database (the All of Us Research Program). We find clear visual and quantitative evidence that breast cancer is strongly, positively, and near-linearly associated with total cholesterol and low-density lipoprotein cholesterol, but not associated with triglycerides. The association of breast cancer with high-density lipoprotein cholesterol was non-linear and age dependent. Standardized odds ratios were 2.12 (95% confidence interval 1.9-2.48),  = 5.6 × 10 for total cholesterol; 1.99 (1.75-2.26),  = 2.6 × 10 for low-density lipoprotein cholesterol; 1.69 (1.3-2.2),  = 9.0 × 10 for high-density lipoprotein cholesterol at age 
• Goldstein, A. M., Qin, R., Chu, E. Y., Elder, D. E., Massi, D., Adams, D. J., Harms, P. W., Robles-Espinoza, C. D., Newton-Bishop, J. A., Bishop, D. T., Harland, M., Holland, E. A., Cust, A. E., Schmid, H., Mann, G. J., Puig, S., Potrony, M., Alos, L., Nagore, E., , Millán-Esteban, D., et al. (2023). Association of germline variants in telomere maintenance genes ( and ) with spitzoid morphology in familial melanoma: A multi-center case series. JAAD international, 11, 43-51.
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  Spitzoid morphology in familial melanoma has been associated with germline variants in , a telomere maintenance gene (TMG), suggesting a link between telomere biology and spitzoid differentiation.
• Hanson, H., Astiazaran-Symonds, E., Amendola, L. M., Balmaña, J., Foulkes, W. D., James, P., Klugman, S., Ngeow, J., Schmutzler, R., Voian, N., Wick, M. J., Pal, T., Tischkowitz, M., & Stewart, D. R. (2023). Response to Stern. Genetics in medicine : official journal of the American College of Medical Genetics, 101030.
• Hanson, H., Astiazaran-Symonds, E., Amendola, L. M., Balmaña, J., Foulkes, W. D., James, P., Klugman, S., Ngeow, J., Schmutzler, R., Voian, N., Wick, M. J., Pal, T., Tischkowitz, M., Stewart, D. R., & , A. P. (2023). Management of individuals with germline pathogenic/likely pathogenic variants in CHEK2: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genetics in medicine : official journal of the American College of Medical Genetics, 25(10), 100870.
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  Although the role of CHEK2 germline pathogenic variants in cancer predisposition is well known, resources for managing CHEK2 heterozygotes in clinical practice are limited.
• Sargen, M. R., Kim, J., Potjer, T. P., Velthuizen, M. E., Martir-Negron, A. E., Odia, Y., Helgadottir, H., Hatton, J. N., Haley, J. S., Thone, G., Widemann, B. C., Gross, A. M., Yohe, M. E., Kaplan, R. N., Shern, J. F., Sundby, R. T., Astiazaran-Symonds, E., Yang, X. R., Carey, D. J., , Tucker, M. A., et al. (2023). Estimated Prevalence, Tumor Spectrum, and Neurofibromatosis Type 1-Like Phenotype of CDKN2A-Related Melanoma-Astrocytoma Syndrome. JAMA dermatology, 159(10), 1112-1118.
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  Knowledge about the prevalence and tumor types of CDKN2A-related melanoma-astrocytoma syndrome (MAS) is limited and could improve disease recognition.
• Astiazaran-Symonds, E., Graham, C., Kim, J., Tucker, M. A., Ingvar, C., Helgadottir, H., Pastorino, L., van Doorn, R., Sampson, J. N., Zhu, B., Bruno, W., Queirolo, P., Fornarini, G., Sciallero, S., Carter, B., Hicks, B., Hutchinson, A., Jones, K., Stewart, D. R., , Chanock, S. J., et al. (2022). Gene-Level Associations in Patients With and Without Pathogenic Germline Variants in and Pancreatic Cancer. JCO precision oncology, 6, e2200145.
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  Pancreatic ductal adenocarcinoma (PDAC) is a component of familial melanoma due to germline pathogenic variants (GPVs) in . However, it is unclear what role this gene or other genes play in its etiology.
• Astiazaran-Symonds, E., Kim, J., Haley, J. S., Kim, S. Y., Rao, H. S., Genetics Center, R., Carey, D. J., Stewart, D. R., & Goldstein, A. M. (2022). A Genome-First Approach to Estimate Prevalence of Germline Pathogenic Variants and Risk of Pancreatic Cancer in Select Cancer Susceptibility Genes. Cancers, 14(13).
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  Patients with germline pathogenic variants (GPV) in cancer predisposition genes are at increased risk of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer. The genes most frequently found to harbor GPV in unselected PDAC cases are , , , , and . However, GPV prevalence and gene-specific associations have not been extensively studied in the general population. To further explore these associations, we analyzed genomic and phenotypic data obtained from the UK Biobank (UKB) and Geisinger MyCode Community Health Initiative (GHS) cohorts comprising 200,600 and 175,449 participants, respectively. We estimated the frequency and calculated relative risks (RRs) of heterozygotes in both cohorts and a subset of individuals with PDAC. The combined frequency of heterozygous carriers of GPV in the general population ranged from 1.22% for to 0.05% for . The frequency of GPV in PDAC cases varied from 2.38% ( to 0.19% ( and . The RRs of PDAC were elevated for all genes except for and varied widely by gene from high () to low (, ). This work expands our understanding of the frequencies of GPV heterozygous carriers and associations between PDAC and GPV in several important PDAC susceptibility genes.
• Astiazaran-Symonds, E., & Goldstein, A. M. (2021). A systematic review of the prevalence of germline pathogenic variants in patients with pancreatic cancer. Journal of gastroenterology, 56(8), 713-721.
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  The genetics of pancreatic ductal adenocarcinoma (PDAC) is complex with patients reported to harbor germline pathogenic variants (PVs) in many different genes. PDAC patients with familial pancreatic cancer (FPC) are more likely to carry germline PVs but there is no consensus main gene involved in FPC. We performed a systematic review of publications from PubMed and Scopus reporting PVs in patients with FPC, sporadic pancreatic cancer (SPC) and unselected cohorts of PDAC patients undergoing genetic testing and calculated a cumulative prevalence of PVs for each gene evaluated across these three groups of patients. When available, variants in the selected publications were reclassified according to the American College of Medical Genetics and Genomics classification system and used for prevalence calculations if classified as pathogenic or likely pathogenic. We observed an increased prevalence of PVs in FPC compared to SPC or unselected PDAC patients for most of the 41 genes reported. The genes with the highest prevalence of carriers of PVs in FPC were ATM, BRCA2, and CDKN2A. BRCA2 and ATM showed the highest prevalence of PVs in both SPC and unselected PDAC cohorts. Several genes with the highest prevalence of PVs are involved in breast and ovarian cancer suggesting strong overlap with underlying genetics in these disorders but no single gene was predominant. More research is needed to further understand the risk of PDAC associated with these many diverse genes.
• Xiao, C., Astiazaran-Symonds, E., Basu, S., Kisling, M., Scaglia, F., Chapman, K. A., Wang, Y., Vockley, J., & Ferreira, C. R. (2020). Mitochondrial energetic impairment in a patient with late-onset glutaric acidemia Type 2. American journal of medical genetics. Part A, 182(10), 2426-2431.
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  Glutaric acidemia type 2 (GA2), also called multiple acyl-CoA dehydrogenase deficiency, is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism resulting in excretion of multiple organic acids and glycine conjugates as well as elevation of various plasma acylcarnitine species (C4-C18). It is caused by mutations in the ETFA, ETFB, or ETFDH genes which are involved in the transfer of electrons from 11 flavin-containing dehydrogenases to Coenzyme Q (CoQ ) of the mitochondrial electron transport chain (ETC). We report a patient who was originally reported as the first case with primary myopathic CoQ deficiency when he presented at 11.5 years with exercise intolerance and myopathy that improved after treatment with ubiquinone and carnitine. At age 23, his symptoms relapsed despite increasing doses of ubiquinone and he was shown to have biallelic mutations in the ETFDH gene. Treatment with riboflavin was started and ubiquinone was changed to ubiquinol. After 4 months, the patient recovered his muscle strength with normalization of laboratory exams and exercise tolerance. Functional studies on fibroblasts revealed decreased levels of ETFDH as well as of very long-chain acyl-CoA dehydrogenase and trifunctional protein α. In addition, the mitochondrial mass was decreased, with increased formation of reactive oxygen species and oxygen consumption rate, but with a decreased spared respiratory capacity, and decreased adenosine triphosphate level. These findings of widespread dysfunction of fatty acid oxidation and ETC enzymes support the impairment of a larger mitochondrial ETC supercomplex in our patient.
• López, P. D., Andreias, L., Astiazarán-Symonds, E., & Chalabi, J. (2017). Fabry Disease: An Uncommon Cause of Renal Failure. The American journal of medicine, 130(9), e389-e390.