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1.
Artigo em Inglês | MEDLINE | ID: mdl-31491540

RESUMO

BACKGROUND: Atopic dermatitis (AD) is a common chronic relapsing skin disease. Genetic variants have been associated with skin barrier function and immune regulation. Thymic stromal lymphopoietin (TSLP), an immune regulator, has been previously associated with AD. OBJECTIVES: To fine map TSLP and evaluate associations with the onset and persistence of AD. METHODS: TSLP variation was determined using targeted massively parallel sequencing in a longitudinal cohort of children with AD. Evaluations included linkage disequilibrium and the persistence of AD for as many as 10 years of follow-up. The association between the presence of AD and rs1898671 variation was evaluated in a second independent cohort. RESULTS: The minor variant frequency for rs1898671 was 23.5% (95% CI, 21.4%-25.8%). This variant was not in linkage disequilibrium with other TSLP variants in the longitudinal cohort (n = 741). White children with AD were less likely to have rs1898671 variant (odds ratio [OR], 1.41; 95% CI, 1.20-1.66) than Genome Aggregation Database controls. Children with AD and the rs1898671 variant during follow-up were more likely to have remission than children who were wild type for rs1898671 (OR, 1.56; 95% CI, 1.26-1.91). In the second cohort (n = 585), the rs1898671 variant was less prevalent in those with AD than those without. The protective effect was greater in rs1898671 heterozygotes (OR, 1.91; 95% CI, 1.34-2.75) than homozygotes (OR, 1.28; 95% CI, 0.61-2.70). CONCLUSION: TSLP and specifically rs1898671 are important in the pathogenesis of AD and could represent a potential clinical target for the development of therapies to treat individuals with AD.

2.
Cell ; 178(4): 933-948.e14, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398344

RESUMO

Interferon-gamma (IFNG) augments immune function yet promotes T cell exhaustion through PDL1. How these opposing effects are integrated to impact immune checkpoint blockade (ICB) is unclear. We show that while inhibiting tumor IFNG signaling decreases interferon-stimulated genes (ISGs) in cancer cells, it increases ISGs in immune cells by enhancing IFNG produced by exhausted T cells (TEX). In tumors with favorable antigenicity, these TEX mediate rejection. In tumors with neoantigen or MHC-I loss, TEX instead utilize IFNG to drive maturation of innate immune cells, including a PD1+TRAIL+ ILC1 population. By disabling an inhibitory circuit impacting PD1 and TRAIL, blocking tumor IFNG signaling promotes innate immune killing. Thus, interferon signaling in cancer cells and immune cells oppose each other to establish a regulatory relationship that limits both adaptive and innate immune killing. In melanoma and lung cancer patients, perturbation of this relationship is associated with ICB response independent of tumor mutational burden.

3.
Arch Dermatol Res ; 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31372728

RESUMO

Atopic dermatitis (AD) is a common illness that most commonly originates in childhood, but can be seen in all ages. Filaggrin (FLG) loss of function variants have been associated with the onset and severity of atopic dermatitis and are the most common genetic association with AD. Previous studies have shown variability in the frequency of FLG variants. We have recently demonstrated that previous FLG genotyping methods were inadequate for proper genotyping. In this concise report, we show that genotyping using a popular older informatics program is problematic. In fact, publications that used the older program likely do not properly capture all FLG variants.

4.
Mol Genet Genomic Med ; 7(9): e898, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31376244

RESUMO

BACKGROUND: While there is increasing interest in sharing genetic research results with participants, how best to communicate the risks, benefits and limitations of research results remains unclear. METHODS: Participants who received genetic research results answered open and closed-ended questions about their experiences receiving results and interest in and advantages and disadvantages of a web-based alternative to genetic counseling. RESULTS: 107 BRCA1/2 negative women with a personal or family history of breast cancer consented to receive genetic research results and 82% completed survey items about their experience. Most participants reported there was nothing they disliked (74%) or would change (85%) about their predisclosure or disclosure session (78% and 89%). They most frequently reported liking the genetic counselor and learning new information. Only 24% and 26% would not be willing to complete predisclosure counseling or disclosure of results by a web-based alternative, respectively. The most frequently reported advantages included convenience and reduced time. Disadvantages included not being able to ask questions, the risk of misunderstanding and the impersonal nature of the encounter. CONCLUSION: Most participants receiving genetic research results report high satisfaction with telephone genetic counseling, but some may be willing to consider self-directed web alternatives for both predisclosure genetic education and return of results.

5.
JAMA Dermatol ; 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31365035

RESUMO

Importance: Atopic dermatitis (AD) is a common chronic illness that has been associated with variation in the filaggrin gene (FLG). Four variants are most often evaluated. Objectives: To comprehensively describe and compare results from targeted sequencing of FLG loss-of-function (LoF) variants in children of African and European ancestry and the association of these variants with onset and persistence of AD. Design, Setting, and Participants: This prospective US cohort study assessed the genetic subcohort of the Pediatric Eczema Elective Registry (PEER). Children with mild to moderate AD were included in the analysis. Massively parallel sequencing (MPS) was used to focus on FLG LoF variation in white and African American children. Patients were enrolled from June 2005 through July 2017. Data were analyzed from January 25 through May 10, 2019. Main Outcomes and Measures: Associations of FLG LoF variation with white and African American ancestry and with the risk and persistence of AD. Results: A total of 741 children were included in the analysis (394 [53.2%] female and 347 [46.8%] male; mean [SD] age at onset, 1.97 [2.72] years); of these, 394 (53.2%) were white, 326 (44.0%) were African American, and 21 (2.8%) were of other ancestries. Using MPS technology, 23 FLG LoF variants were found in children with AD. The prevalence of FLG LoF variants was 177 participants (23.9%) in the full cohort, 124 white participants (31.5%), and 50 African American participants (15.3%). The odds ratio for carrying any FLG LoF variant in a white child compared with an African American child with AD was 2.44 (95% CI, 1.76-3.39). Some FLG LoF variants are only found in children of a specific ancestry (eg, p.S3316* and p.R826* were not seen in white patients). Children with an FLG LoF were more likely to have persistent AD (odds ratio, 0.67; 95% CI, 0.56-0.80). Conclusions and Relevance: The FLG LoF variants in a US cohort of children with mild to moderate AD differ significantly by race and their association with the persistence of AD. Conventional testing of the 4 frequently evaluated variants is inadequate. Any planned genetic diagnostic test for AD based on FLG LoF variants must be inclusive and not rely on the most frequently studied variants.

6.
Mol Cancer Ther ; 18(9): 1637-1648, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31270153

RESUMO

Combined BRAF and MEK inhibition is a standard of care in patients with advanced BRAF-mutant melanoma, but acquired resistance remains a challenge that limits response durability. Here, we quantitated in vivo ERK1/2 activity and tumor response associated with resistance to combined BRAF and MEK inhibition in mutant BRAF xenografts. We found that ERK1/2 pathway reactivation preceded the growth of resistant tumors. Moreover, we detected a subset of cells that not only persisted throughout long-term treatment but restored ERK1/2 signaling and grew upon drug removal. Cell lines derived from combination-resistant tumors (CRT) exhibited elevated ERK1/2 phosphorylation, which were sensitive to ERK1/2 inhibition. In some CRTs, we detected a tandem duplication of the BRAF kinase domain. Monitoring ERK1/2 activity in vivo was efficacious in predicting tumor response during intermittent treatment. We observed maintained expression of the mitotic regulator, polo-like kinase 1 (Plk1), in melanoma resistant to BRAF and MEK inhibitors. Plk1 inhibition induced apoptosis in CRTs, leading to slowed growth of BRAF and MEK inhibitor-resistant tumors in vivo These data demonstrate the utility of in vivo ERK1/2 pathway reporting as a tool to optimize clinical dosing schemes and establish suppression of Plk1 as potential salvage therapy for BRAF inhibitor and MEK inhibitor-resistant melanoma.

7.
Biotechniques ; 67(3): 118-122, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31267764

RESUMO

We have previously reported Hi-Plex, a multiplex PCR methodology for building targeted DNA sequencing libraries that offers a low-cost protocol compatible with high-throughput processing. Here, we detail an improved protocol, Hi-Plex2, that more effectively enables the robust construction of small-to-medium panel-size libraries while maintaining low cost, simplicity and accuracy benefits of the Hi-Plex platform. Hi-Plex2 was applied to three panels, comprising 291, 740 and 1193 amplicons, targeting genes associated with risk for breast and/or colon cancer. We show substantial reduction of off-target amplification to enable library construction for small-to-medium-sized design panels not possible using the previous Hi-Plex chemistry.

8.
Hum Mutat ; 40(10): 1781-1796, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31112363

RESUMO

BRCA1 and BRCA2 (BRCA1/2) pathogenic sequence variants (PSVs) confer elevated risks of multiple cancers. However, most BRCA1/2 PSVs reports focus on European ancestry individuals. Knowledge of the PSV distribution in African descent individuals is poorly understood. We undertook a systematic review of the published literature and publicly available databases reporting BRCA1/2 PSVs also accessed the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) database to identify African or African descent individuals. Using these data, we inferred which of the BRCA PSVs were likely to be of African continental origin. Of the 43,817 BRCA1/2 PSV carriers in the CIMBA database, 469 (1%) were of African descent. Additional African descent individuals were identified in public databases (n = 291) and the literature (n = 601). We identified 164 unique BRCA1 and 173 unique BRCA2 PSVs in individuals of African ancestry. Of these, 83 BRCA1 and 91 BRCA2 PSVs are of likely or possible African origin. We observed numerous differences in the distribution of PSV type and function in African origin versus non-African origin PSVs. Research in populations of African ancestry with BRCA1/2 PSVs is needed to provide the information needed for clinical management and decision-making in African descent individuals worldwide.

9.
Clin Cancer Res ; 25(14): 4363-4374, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30914433

RESUMO

PURPOSE: Breast cancers with BRCA1/2 alterations have a relatively high mutational load, suggesting that immune checkpoint blockade may be a potential treatment option. However, the degree of immune cell infiltration varies widely, and molecular features contributing to this variability remain unknown. EXPERIMENTAL DESIGN: We hypothesized that genomic signatures might predict immunogenicity in BRCA1/2 breast cancers. Using The Cancer Genome Atlas (TCGA) genomic data, we compared breast cancers with (89) and without (770) either germline or somatic BRCA1/2 alterations. We also studied 35 breast cancers with germline BRCA1/2 mutations from Penn using WES and IHC. RESULTS: We found that homologous recombination deficiency (HRD) scores were negatively associated with expression-based immune indices [cytolytic index (P = 0.04), immune ESTIMATE (P = 0.002), type II IFN signaling (P = 0.002)] despite being associated with a higher mutational/neoantigen burden, in BRCA1/2 mutant breast cancers. Further, absence of allele-specific loss of heterozygosity (LOH negative; P = 0.01) or subclonality (P = 0.003) of germline and somatic BRCA1/2 mutations, respectively, predicted for heightened cytolytic activity. Gene set analysis found that multiple innate and adaptive immune pathways that converge on NF-κB may contribute to this heightened immunogenicity. IHC of Penn breast cancers demonstrated increased CD45+ (P = 0.039) and CD8+ infiltrates (P = 0.037) and increased PDL1 expression (P = 0.012) in HRD-low or LOH-negative cancers. Triple-negative cancers with low HRD had far greater CD8+ T cells (P = 0.0011) and Perforin 1 expression (P = 0.014) compared with hormone receptor-positive HRD-high cancers. CONCLUSIONS: HRD scores and hormone receptor subtype are predictive of immunogenicity in BRCA1/2 breast cancers and may inform the design of optimal immune therapeutic strategies.

10.
Nat Med ; 25(3): 454-461, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804515

RESUMO

Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma. We hypothesized that immune reinvigoration in the tumor would be detectable at 3 weeks and that this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8 of 27 patients experiencing a complete or major pathological response after a single dose of anti-PD-1, all of whom remain disease free. These rapid pathologic and clinical responses were associated with accumulation of exhausted CD8 T cells in the tumor at 3 weeks, with reinvigoration in the blood observed as early as 1 week. Transcriptional analysis demonstrated a pretreatment immune signature (neoadjuvant response signature) that was associated with clinical benefit. In contrast, patients with disease recurrence displayed mechanisms of resistance including immune suppression, mutational escape, and/or tumor evolution. Neoadjuvant anti-PD-1 treatment is effective in high-risk resectable stage III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to predict clinical outcome and to dissect underlying mechanisms in checkpoint blockade.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Procedimentos Cirúrgicos Dermatológicos , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos , Quimioterapia Adjuvante , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Neoplasias Cutâneas/patologia , Transcriptoma , Evasão Tumoral
11.
JAMA Oncol ; 5(4): 514-522, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30676620

RESUMO

Importance: Approximately 50% of the risk for the development of testicular germ cell tumors (TGCTs) is estimated to be heritable, but no mendelian TGCT predisposition genes have yet been identified. It is hypothesized that inherited pathogenic DNA repair gene (DRG) alterations may drive susceptibility to TGCTs. Objective: To systematically evaluate the enrichment of germline pathogenic variants in the mendelian cancer predisposition DRGs in patients with TGCTs vs healthy controls. Design, Setting, and Participants: A case-control enrichment analysis was performed from January 2016 to May 2018 to screen for 48 DRGs in 205 unselected men with TGCT and 27 173 ancestry-matched cancer-free individuals from the Exome Aggregation Consortium cohort in the discovery stage. Significant findings were selectively replicated in independent cohorts of 448 unselected men with TGCTs and 442 population-matched controls, as well as 231 high-risk men with TGCTs and 3090 ancestry-matched controls. Statistical analysis took place from January to May 2018. Main Outcomes and Measures: Gene-level enrichment analysis of germline pathogenic variants in individuals with TGCTs relative to cancer-free controls. Results: Among 205 unselected men with TGCTs (mean [SD] age, 33.04 [9.67] years), 22 pathogenic germline DRG variants, one-third of which were in CHEK2 (OMIM 604373), were identified in 20 men (9.8%; 95% CI, 6.1%-14.7%). Unselected men with TGCTs were approximately 4 times more likely to carry germline loss-of-function CHEK2 variants compared with cancer-free individuals from the Exome Aggregation Consortium cohort (odds ratio [OR], 3.87; 95% CI, 1.65-8.86; nominal P = .006; q = 0.018). Similar enrichment was also seen in an independent cohort of 448 unselected Croatian men with TGCTs (mean [SD] age, 31.98 [8.11] years) vs 442 unselected Croatian men without TGCTs (at least 50 years of age at time of sample collection) (OR, >1.4; P = .03) and 231 high-risk men with TGCTs (mean [SD] age, 31.54 [9.24] years) vs 3090 men (all older than 50 years) from the Penn Medicine Biobank (OR, 6.30; 95% CI, 2.34-17.31; P = .001). The low-penetrance CHEK2 variant (p.Ile157Thr) was found to be a Croatian founder TGCT risk variant (OR, 3.93; 95% CI, 1.53-9.95; P = .002). Individuals with the pathogenic CHEK2 loss-of-function variants developed TGCTs 6 years earlier than individuals with CHEK2 wild-type alleles (5.95 years; 95% CI, 1.48-10.42; P = .009). Conclusions and Relevance: This multicenter case-control analysis of men with or without TGCTs provides evidence for CHEK2 as a novel moderate-penetrance TGCT susceptibility gene, with potential clinical utility. In addition to highlighting DNA-repair deficiency as a potential mechanism driving TGCT susceptibility, this analysis also provides new avenues to explore management strategies and biological investigations for high-risk individuals.

12.
J Cutan Pathol ; 46(3): 190-194, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30552700

RESUMO

BACKGROUND: BRAF inhibition has improved overall survival in patients with BRAF mutant melanoma, but this is associated with a range of known and predictable cutaneous side effects, including squamous cell carcinomas associated with RAS mutations. METHODS: We identified three severely dysplastic nevi, one atypical intraepidermal melanocytic proliferation, and four melanoma in situ lesions, newly arising in four patients undergoing treatment with vemurafenib. To characterize mutations in these atypical melanocytic lesions, we used a custom iPlex panel detecting 74 mutations in 13 genes known to play a role in melanoma pathogenesis. RESULTS: We identified an NRAS mutation at codon 61 (Q61R) and a rare BRAF exon 11 mutation (G466A) in atypical melanocytic lesions that arose in patients treated with vemurafenib. CONCLUSION: There appears to be development or accelerated growth of atypical melanocytic lesions in the setting of BRAF inhibition. Our results underscore the need for careful surveillance for melanocytic lesions in patients on BRAF inhibitor therapy and shed light on potential mechanisms for melanoma pathogenesis in the context of BRAF pathway blockade. Further studies are warranted to show a causal relationship.


Assuntos
Antineoplásicos/efeitos adversos , GTP Fosfo-Hidrolases/genética , Melanoma/tratamento farmacológico , Proteínas de Membrana/genética , Segunda Neoplasia Primária/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Vemurafenib/efeitos adversos , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Mutação , Segunda Neoplasia Primária/induzido quimicamente , Estudos Retrospectivos , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/genética
13.
Artigo em Inglês | MEDLINE | ID: mdl-30507552

RESUMO

Genome-wide association studies (GWAS) are susceptible to bias due to population stratification (PS). The most widely used method to correct bias due to PS is principal components (PCs) analysis (PCA), but there is no objective method to guide which PCs to include as covariates. Often, the ten PCs with the highest eigenvalues are included to adjust for PS. This selection is arbitrary, and patterns of local linkage disequilibrium may affect PCA corrections. To address these limitations, we estimate genomic propensity scores based on all statistically significant PCs selected by the Tracy-Widom (TW) statistic. We compare a principal components and propensity scores (PCAPS) approach to PCA and EMMAX using simulated GWAS data under no, moderate, and severe PS. PCAPS reduced spurious genetic associations regardless of the degree of PS, resulting in odds ratio (OR) estimates closer to the true OR. We illustrate our PCAPS method using GWAS data from a study of testicular germ cell tumors. PCAPS provided a more conservative adjustment than PCA. Advantages of the PCAPS approach include reduction of bias compared to PCA, consistent selection of propensity scores to adjust for PS, the potential ability to handle outliers, and ease of implementation using existing software packages.

14.
Genome Biol ; 19(1): 202, 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30477554

RESUMO

High-throughput DNA sequencing enables detection of copy number variations (CNVs) on the genome-wide scale with finer resolution compared to array-based methods but suffers from biases and artifacts that lead to false discoveries and low sensitivity. We describe CODEX2, as a statistical framework for full-spectrum CNV profiling that is sensitive for variants with both common and rare population frequencies and that is applicable to study designs with and without negative control samples. We demonstrate and evaluate CODEX2 on whole-exome and targeted sequencing data, where biases are the most prominent. CODEX2 outperforms existing methods and, in particular, significantly improves sensitivity for common CNVs.

18.
Genet Med ; 20(7): 671-682, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30006586

RESUMO

DISCLAIMER: This practice resource is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this practice resource is completely voluntary and does not necessarily assure a successful medical outcome. This practice resource should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this practice resource. Clinicians also are advised to take notice of the date this practice resource was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. PURPOSE: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that is caused by a heterozygous loss-of-function variant in the tumor suppressor gene NF1; it affects ~1/1,900-1/3,500 people worldwide. The disorder is associated with an 8-15-year reduction in average life expectancy in both men and women, primarily due to malignant neoplasms and cardiovascular causes. METHODS: A work group of experts sought to determine the prevalence, morbidity and mortality, and available treatments of common and emerging NF1-related clinical problems in adults. Work-group members identified peer-reviewed publications from PubMed. Publications derived from populations and multi-institution cohorts were prioritized. Recommendations for management arose by consensus from this literature and the collective expertise of the authors. RESULTS: Malignant peripheral nerve sheath tumor (MPNST), breast cancer, cutaneous neurofibromas, and significant psychiatric and neurologic diagnoses are common problems in patients with NF1. CONCLUSION: Patient education and sensitization to worrisome signs and symptoms such as progressive severe pain (MPNST), changes in tumor volume (MPNST), new, unexplained neurologic symptoms (MPNST, brain tumors), and diaphoresis/palpitations (pheochromocytoma) are important. Although many issues in adults with NF1 can be managed by an internist or family physician, we strongly encourage evaluation by, and care coordination with, a specialized NF1 clinic.

19.
Cell Rep ; 23(11): 3392-3406, 2018 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-29898407

RESUMO

We studied 137 primary testicular germ cell tumors (TGCTs) using high-dimensional assays of genomic, epigenomic, transcriptomic, and proteomic features. These tumors exhibited high aneuploidy and a paucity of somatic mutations. Somatic mutation of only three genes achieved significance-KIT, KRAS, and NRAS-exclusively in samples with seminoma components. Integrated analyses identified distinct molecular patterns that characterized the major recognized histologic subtypes of TGCT: seminoma, embryonal carcinoma, yolk sac tumor, and teratoma. Striking differences in global DNA methylation and microRNA expression between histology subtypes highlight a likely role of epigenomic processes in determining histologic fates in TGCTs. We also identified a subset of pure seminomas defined by KIT mutations, increased immune infiltration, globally demethylated DNA, and decreased KRAS copy number. We report potential biomarkers for risk stratification, such as miRNA specifically expressed in teratoma, and others with molecular diagnostic potential, such as CpH (CpA/CpC/CpT) methylation identifying embryonal carcinomas.

20.
Mol Carcinog ; 57(10): 1311-1318, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29873413

RESUMO

Gene expression changes within the Hippo pathway were found to be associated with large tumor size and metastasis in breast cancer. The combined effect of genetic variants in genes of this pathway may have a causal role in breast cancer development. We examined 7086 SNPs that were not highly correlated (r2 < 0.8) in 35 Hippo pathway genes using data from the genome-wide association study of breast cancer from the Root Consortium, which includes 3686 participants of African ancestry from Nigeria, United States of America, and Barbados: 1657 cases (403 estrogen receptor-positive [ER+], 374 ER-) and 2029 controls. Gene-level analyses were conducted using improved AdaJoint test for large-scale genetic association studies adjusting for age, study site and the first four eigenvectors from the principal component analysis. SNP-level analyses were conducted with logistic regression. The Hippo pathway was significantly associated with risk of ER+ breast cancer (pathway-level P = 0.019), with WWC1 (Padj = 0.04) being the leading gene. The pathway-level significance was lost without WWC1 (P = 0.12). rs147106204 in the WWC1 gene was the most statistically significant SNP after gene-level adjustment for multiple comparisons (OR = 0.53, 95%CI = 0.41-0.70, Padj = 0.025). We found evidence of an association between genetic variations in the Hippo pathway and ER+ breast cancer. Moreover, WWC1 was identified as the most important genetic susceptibility locus highlighting the importance of genetic epidemiology studies of breast cancer in understudied populations.

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