Danielle Castillo
City of Hope National Medical Center
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Featured researches published by Danielle Castillo.
Cancer | 2015
Cynthia Villarreal-Garza; Rosa María Alvarez-Gomez; Carlos Pérez-Plasencia; Luis A. Herrera; Josef Herzog; Danielle Castillo; Alejandro Mohar; Clementina Castro; Lenny Gallardo; Dolores Gallardo; Miguel Santibáñez; Kathleen R. Blazer; Jeffrey N. Weitzel
Frequent recurrent mutations in the breast and ovarian cancer susceptibility (BRCA) genes BRCA1 and BRCA2 among Hispanics, including a large rearrangement Mexican founder mutation (BRCA1 exon 9‐12 deletion [ex9‐12del]), suggest that an ancestry‐informed BRCA‐testing strategy could reduce disparities and promote cancer prevention by enabling economic screening for hereditary breast and ovarian cancer in Mexico.
Urologia Internationalis | 2001
P. López Cubillana; E. Martínez Barba; A. Prieto; G. Server Pastor; J. Sola; J.A. Nicolás; J.A. García Hernández; G. Gómez Gómez; P. Martínez Pertusa; M. Pérez Albacete; V. Bañón; P. Valdelvira; Antonio Guardiola; Danielle Castillo; E. Cao; Jennifer Alonso
Background: Any carcinoma of prostatic origin which is not an acinary adenocarcinoma of the prostate is considered to be an atypical carcinoma. One member of this group of atypical prostatic tumors is the oat-cell carcinoma, or small cell carcinoma (SCC) of the prostate. This variety of carcinoma constitutes the histologic basis of <1% of all prostatic neoplasms. Methods: Between 1992 and 1997, four patients were diagnosed with SCC of the prostate at our hospital. In 3 of the 4 cases, the histopathological diagnosis was pure SCC, and in the 4th case there was a component of prostatic adenocarcinoma associated with the SCC. At the time of diagnosis, extracapsular extension of the tumor was present in all 4 cases, with T3 or higher stages in all of them (T3AN₀M1, T3AN₀M₀, T3BN₀M1, and T4N₀M₀). Because of the presence of extracapsular extension, radiotherapy and radical surgery were ruled out for all 4 patients. They were all offered systemic chemotherapy with cyclophosphamide (1 g/m2), doxorubicin (50 mg/m2) and vincristine (1.2 mg/m2). This therapeutic protocol was carried out in only 2 cases. Results: Survival was <1 year in the 3 patients with pure SCC, and the patient with a mixed tumor is alive with detectable disease 9 months after diagnosis. Conclusions: This poor vital prognosis in SCC stresses the need for early diagnosis a timely and appropriate therapeutic intervention in this condition.
Journal of the National Cancer Institute | 2018
Thomas P. Slavin; Lily Ravel Van Tongeren; Carolyn E Behrendt; Ilana Solomon; Christina Rybak; Bita Nehoray; Lili Kuzmich; Mariana Niell-Swiller; Kathleen R. Blazer; Shu Tao; Kai Yang; Julie O. Culver; Sharon Sand; Danielle Castillo; Josef Herzog; Stacy W. Gray; Jeffrey N. Weitzel
Background In germline genetic testing, variants from understudied ancestries have been disproportionately classified as being of uncertain significance. We hypothesized that the rate of variant reclassification likewise differs by ancestry. Methods Nonbenign variants in actionable genes were collected from consenting subjects undergoing genetic testing at two Southern California sites from September 1996 through December 2016. Variant reclassifications were recorded as they were received, until February 2017 or reclassification to benign. Excluding duplicate variants (same ancestry, laboratory, classification), generalized linear models for the hereditary breast cancer genes (BRCA1/2) and other variants investigated whether rate of reclassification differed for seven categories of ancestry compared with non-Hispanic European. Models took into account laboratory, year, gene, sex, and current classification (handled as a time-dependent covariate) and were adjusted for multiple hypothesis testing. Results Among 1483 nonbenign variants, 693 (46.7%) involved BRCA1/2. Overall, 268 (18.1%) variants were reclassified at least once. Few (9.7%) reclassified variants underwent a net upgrade in pathogenicity. For BRCA1/2 variants, reclassification rates varied by ancestry and increased over time, more steeply for ancestries with lower initial rates (African, Ashkenazi, Chinese) than for ancestries whose initial rates were high (Middle Eastern) or similar to non-Hispanic European (non-Chinese Asian, Native American, Hispanic). In contrast, reclassification rates of non-BRCA1/2 variants did not vary over time but were elevated for most minority ancestries except non-Chinese Asian and Native American. Conclusions For nonbenign variants in cancer-related genes, the rates at which reclassifications are issued vary by ancestry in ways that differ between BRCA1/2 and other genes.
Cancer Genetics and Cytogenetics | 2017
Thomas P. Slavin; Susan L. Neuhausen; Christina Rybak; Ilana Solomon; Bita Nehoray; Kathleen R. Blazer; Mariana Niell-Swiller; Aaron Adamson; Yate-Ching Yuan; Kai Yang; Sharon Sand; Danielle Castillo; Josef Herzog; Xiwei Wu; Shu Tao; Tanya Chavez; Yanghee Woo; Joseph Chao; Pamela Mora; Darling Horcasitas; Jeffrey N. Weitzel
Few susceptibility genes for gastric cancer have been identified. We sought to identify germline susceptibility genes from participants with gastric cancer from an international hereditary cancer research network. Adults with gastric cancer of any histology, and with a germline DNA sample (n = 51), were retrospectively selected. For those without previously identified germline mutations (n = 43), sequencing was performed for 706 candidate genes. Twenty pathogenic or likely pathogenic variants were identified among 18 participants. Eight of the 18 participants had previous positive clinical testing, including six with CDH1 pathogenic or likely pathogenic variants, and two with pathogenic MSH2 and TP53 variants. Of the remaining 10, six were in BRCA1 DNA damage response pathway genes (ATM, ATR, BRCA2, BRIP1, FANCC, TP53), other variants were identified in CTNNA1, FLCN, SBDS, and GNAS. Participants identified with pathogenic or likely pathogenic variants were younger at gastric cancer diagnosis than those without, 39.1 versus 48.0 years, and over 50% had a close family member with gastric cancer (p-values < 0.0001). In conclusion, many participants were identified with mutations in clinically-actionable genes. Age of onset and family history of gastric cancer were mutation status predictors. Our findings support multigene panels in identifying gastric cancer predisposition.
Genetics in Medicine | 2018
Jeffrey N. Weitzel; Elizabeth C. Chao; Bita Nehoray; Lily Ravel Van Tongeren; Holly LaDuca; Kathleen R. Blazer; Thomas P. Slavin; D A B M D Facmg; Tina Pesaran; Christina Rybak; Ilana Solomon; Mariana Niell-Swiller; Jill S. Dolinsky; Danielle Castillo; Aaron M. Elliott; Chia-Ling Gau; Virginia Speare; Kory Jasperson
PurposeBlood/saliva DNA is thought to represent the germ line in genetic cancer-risk assessment. Cases with pathogenic TP53 variants detected by multigene panel testing are often discordant with Li-Fraumeni syndrome, raising concern about misinterpretation of acquired aberrant clonal expansions (ACEs) with TP53 variants as germ-line results.MethodsPathogenic TP53 variants with abnormal next-generation sequencing metrics (e.g., decreased ratio (<25%) of mutant to wild-type allele, more than two detected alleles) were selected from a CLIA laboratory testing cohort. Alternate tissues and/or close relatives were tested to distinguish between ACE and germ-line status. Clinical data and Li-Fraumeni syndrome testing criteria were examined.ResultsAmong 114,630 multigene panel tests and 1,454 TP53 gene-specific analyses, abnormal next-generation sequencing metrics were observed in 20% of 353 TP53-positive results, and ACE was confirmed for 91% of cases with ancillary materials, most of these due to clonal hematopoiesis. Only four met Chompret criteria. Individuals with ACE were older (50 years vs. 33.7; P = 0.02) and were identified more frequently in multigene panel tests (66/285; 23.2%) than in TP53 gene-specific tests (6/68; 8.8%, P = 0.005).ConclusionACE confounds germ-line diagnosis, may portend hematologic malignancy, and may provoke unwarranted clinical interventions. Ancillary testing to confirm germ-line status should precede Li-Fraumeni syndrome management.
Cancer Genetics and Cytogenetics | 2017
Annette Y. Sunga; Charite Ricker; Carin R. Espenschied; Danielle Castillo; Marilena Melas; Josef Herzog; Sarah A. Bannon; Marcia Cruz-Correa; Patrick M. Lynch; Ilana Solomon; Stephen B. Gruber; Jeffrey N. Weitzel
Lynch syndrome (LS), the most common hereditary colorectal cancer syndrome, is caused by mismatch repair (MMR) gene mutations. However, data about MMR mutations in Hispanics are limited. This study aims to describe the spectrum of MMR mutations in Hispanics with LS and explore ancestral origins. This case series involved an IRB-approved retrospective chart review of self-identified Hispanic patients (n = 397) seen for genetic cancer risk assessment at four collaborating academic institutions in California, Texas, and Puerto Rico who were evaluated by MMR genotyping and/or tumor analysis. A literature review was conducted for all mutations identified. Of those who underwent clinical genetic testing (n = 176), 71 had MMR gene mutations. Nine mutations were observed more than once. One third (3/9) of recurrent mutations and two additional mutations (seen only once) were previously reported in Spain, confirming the influence of Spanish ancestry on MMR mutations in Hispanic populations. The recurrent mutations identified (n = 9) included both previously reported mutations as well as unique mutations not in the literature. This is the largest report of Hispanic MMR mutations in North America; however, a larger sample and haplotype analyses are needed to better understand recurrent MMR mutations in Hispanic populations.
Cancer Research | 2017
Thomas P. Slavin; Stacy W. Gray; Lily Ravel Van Tongeren; Ilana Solomon; Christina Rybak; Bita Nehoray; Lili Kuzmich; Mariana Niell-Swiller; Kathleen R. Blazer; Kai Yang; Julie O. Culver; Sharon Sand; Danielle Castillo; Josef Herzog; Jeffrey N. Weitzel
BACKGROUND: Clinicians who provide genetic cancer risk assessment (GCRA) are dependent on laboratory reporting of germline results to inform cancer screening and treatment recommendations. Efforts to enhance variant classification and harmonization, such as ClinVar, will lead to an increase in the number of variants being reclassified. Given that the impact of variant reclassification on care is unknown, we evaluated the frequency and clinical impact of variant reclassification on individuals seen for GCRA. METHODS: We retrospectively evaluated data on 7,356 participants enrolled through the Clinical Cancer Genomics Community Research Network (CCGCRN) at City of Hope and Olive View Medical Center from September 1996- October 2016. RESULTS: 4,969 commercial genetic tests yielded a total of 1,610 variants of any category, of which 181 unique variants in 20 genes were reclassified. BRCA1 and BRCA2 (BRCA) and mismatch repair genes comprised 73.5% and 5.5% of the genes reclassified, respectively. Reclassification impacted 225 individuals (97% women) from 217 families; 89% of these individuals (n=201) had a personal history of cancer. The interval between initial report and variant reclassification averaged 3 years (17 days- 13 years). Minorities had higher reclassification rates as compared to non-Hispanic white participants (P = 0.0149). Of the 181 unique reclassifications, 164 (90.6%) of variants were downgraded. Sixteen reclassifications led to changes in clinical care. Thirteen variants carried by 15 individuals were upgraded from a variant of uncertain significance (VUS) to likely pathogenic or pathogenic (10 BRCA, 3 MLH1 or MSH2). These reclassifications prompted additional prophylactic surgical interventions (i.e., bilateral salpingo-oophorectomy), specialist referrals, and surveillance recommendations for at risk patients and family members. Three variants (NBN p.Arg215Trp, PTEN p.Ala79Thr, and MET c.1200+2T>C) were downgraded from likely pathogenic or pathogenic to VUS. Prior to downgrade to VUS, 2 cases had unnecessary surveillance procedures. CONCLUSIONS: Since many genomic variants will be reclassified over time, it is critical that laboratories deliver prompt notification of reclassifications, and that providers involved in GCRA discuss the possibility of variant reclassification with patients and family members and collect patient/proxy information during informed consent so that re-contact is possible. Given the non-trivial effort required for variant reclassification and patient/participant re-contact, system-level interventions are needed to facilitate genomic reinterpretation and the return of results to individuals over time. Citation Format: Thomas P. Slavin, Stacy W. Gray, Lily R. Van Tongeren, Ilana Solomon, Christina Rybak, Bita Nehoray, Lili Kuzmich, Mariana Niell-Swiller, Kathleen R. Blazer, Kai Yang, Julie Culver, Sharon Sand, Danielle Castillo, Josef Herzog, Jeffrey N. Weitzel. Variant reclassifications in hereditary cancer genetics and their implications for clinical care [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4273. doi:10.1158/1538-7445.AM2017-4273
Cancer Epidemiology, Biomarkers & Prevention | 2017
Julyann Pérez-Mayoral; Adrian Cora-Morges; Krystel Gonzalez-Rosa; Jessica Hernandez; Danielle Castillo; Josef Herzog; Jeffrey N. Weitzel; Marcia Cruz-Correa
Introduction: Hereditary breast cancer accounts for up to 10% of breast cancer cases. These hereditary breast cases have been shown to be associated with mutations in the BRCA1 and BRCA2 genes. The prevalence and types of mutations in these genes varies depending on the population and ethnicity under study. Identification of such specific mutations allows for site specific testing. In the absence of knowledge of specific mutation information, entire gene sequencing is necessary in order to identify the putative mutations involved in the predisposition to increased risk. Objective: The objective of this project is to identify and annotate the mutations in BRCA1 and BRCA2 genes encountered in the Puerto Rican population which will allow for accessible genetic testing services to be offered. Methods: From January 2014 to May 2016, we recruited 46 women that met the National Comprehensive Cancer Network guidelines for breast cancer genetic testing. Among recruited participants, 18 were diagnosed with breast cancer, 8 with ovarian cancer, 1 with both breast and ovarian cancer and 19 had family history of breast or ovarian cancer suggestive of hereditary cancer. The recruited individuals were submitted to genetic testing, first by the Hispanel breast cancer mutation panel, developed at City of Hope Division of Clinical Cancer Genetics. If negative on the Hispanel, Sanger sequencing was performed to evaluate the whole genes and confirm results. Results: Our results showed 38 negative genetic testing for BRCA1/BRCA2, 4 variants of uncertain significance and 4 pathogenic mutations in the population under study. One pathogenic mutation was found in BRCA1 (BRCA1 exon15-16del) and 3 pathogenic mutations were found in BRCA2 (BRCA2 2022del5; BRCA2 4150G>T (E1308X); BRCA2 6027del4). Conclusion: The prevalence of mutations in this preliminary study is consistent with previous reports of BRCA mutations in Puerto Rico, which describe as BRCA2 as the most commonly mutated gene in the island. Additional studies are needed to fully elucidate the BRCA1/BRCA2 mutation spectrum in Puerto Rico for allowing the implementation of cost-effective and affordable genetic testing strategies for women in need. Citation Format: Julyann Perez-Mayoral, Adrian Cora-Morges, Krystel Gonzalez-Rosa, Jessica Hernandez, Danielle Castillo, Josef Herzog, Jeffrey Weitzel, Marcia Cruz-Correa. BRCA1 and BRCA2 mutations spectrum in Puerto Rican Hispanics. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B53.
Cancer Research | 2016
Jeffrey N. Weitzel; Cynthia Villarreal-Garza; Kathleen R. Blazer; Josef Herzog; Danielle Castillo; Tanya Chavez; Ln Gallardo-Alvarado; Talia Wegman; Rosa Alvarez; Karla Unger; Maria E. Fernandez; Azucena Del Toro-Valero; Adrian Daneri Navarro; Abelardo Meneses; Luis Herrera Montalvo; Alejandro Mohar Betancourt; Lily Ravel Van Tongeren
Purpose: Access to genomic cancer risk assessment (GCRA) is standard of care in most developed countries, but is not readily available in Latin America. Following needs assessment, a dissemination and implementation intervention, including clinical training and application of inexpensive genomic tools, was used in Mexico to develop a model for vertical integration of GCRA among underserved populations in Latin America. Methods: A roundtable forum with 15 Latin American physicians representing Brazil, Colombia, Mexico, Puerto Rico and Peru was conducted to assess the state of GCRA services and barriers to implementation in these countries. The roundtable was conducted in Spanish, moderated by bilingual cancer genetics clinicians, recorded, transcribed, translated and thematically analyzed. The training resources of the City of Hope Clinical Cancer Genomics Community of Practice (CCGCoP), a flexible, multi-modal program of distance didactics, face-to-face case-based workshops and continuing practice support, were deployed to promote practitioner level GCRA competence among clinicians in Latin America. A common prospective registry protocol was implemented via the Cancer Genetics Community Research Network (CCGCRN), and an inexpensive BRCA screening tool (HISPANEL) was introduced to support GCRA services. HISPANEL sensitivity compared to full sequencing was estimated; quality/content of GCRA process was assessed; and downstream barriers to follow up care were identified. Results: Roundtable findings pointed to the need for a multi-level approach with GCRA training, cost-effective genetic testing, and an evidence-based foundation to support the development of policy, infrastructure and resources to implement and sustain GCRA services in Latin America. Post-training assessments for the 41 Latin American clinicians indicated significant increases in professional self efficacy and skills, and demonstrate the value of CCGCoP training and practice support; 19 alumni (representing 7 sites in Mexico, Peru, Colombia, Brazil and Puerto Rico) joined the CCGCRN. To date 1,010 patients have been accrued to the Latin American component of the CCGCRN cohort. The HISPANEL genomic tool demonstrated a clinical sensitivity of 68-77%, at a cost of
Cancer Research | 2016
Thomas P. Slavin; Kai Yang; Sharon Sand; Tanya Chavez; Danielle Castillo; Joseph Herzog; Ilana Solomon; Christina Rybak; Mariana Niell-Swiller; Bita Nehoray; Aaron Adamson; Kathleen R. Blazer; Susan L. Neuhausen; Jeffrey N. Weitzel
20 per case in Mexico, where site assessments demonstrated successful initiation of GCRA services and facilitated identification of barriers to follow up care. Conclusions: Innovative pairing of multi-modal GCRA training and practice support, combined with access to affordable genomic screening tools, demonstrates the potential for dissemination and implementation of GCRA to improve cancer prevention and control in Latin America. Future directions: address scalability; adapt to other countries; and develop a Spanish-language version of the training program to facilitate broader dissemination. Citation Format: Jeffrey N. Weitzel, Cynthia Villarreal-Garza, Kathleen R. Blazer, Josef Herzog, Danielle Castillo, Tanya Chavez, Lenny Gallardo-Alvarado, Talia Wegman, Rosa Alvarez, Karla Unger, Maria Fernandez, Azucena del Toro-Valero, Adrian Daneri Navarro, Abelardo Meneses, Luis Herrera Montalvo, Alejandro Mohar Betancourt, Lily van Tongeren, Cancer Genomics Community Research Network. Dissemination and implementation of genomic cancer risk assessment in Latin America via innovative pairing of clinical training and genomic tools. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3465.