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1.
Hum Mutat ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33169439

RESUMO

PALB2 has been identified as a breast and pancreatic cancer susceptibility gene. Utilizing a targeted sequencing approach, we discovered two novel germline missense PALB2 variants c.191C>T and c.311C>T, encoding p.Ser64Leu and p.Pro104Leu, respectively, in individuals in a pancreatic cancer registry. No missense PALB2 variants from familial pancreatic cancer patients, and few PALB2 variants overall, have been functionally characterized. Given the known role of PALB2, we tested the impact of p.Ser64Leu and p.Pro104Leu variants on DNA damage responses. Neither p.Ser64Leu nor p.Pro104Leu had clear effects on interactions with BRCA1 and KEAP1, which are mediated by adjacent motifs in PALB2. However, both variants are associated with defective recruitment of PALB2, and the RAD51 recombinase downstream, to DNA damage foci. Further, p.Ser64Leu and p.Pro104Leu both largely compromise DNA double-strand break-initiated homologous recombination, and confer increased cellular sensitivity to ionizing radiation (IR) and the poly (ADP-ribose) polymerase (PARP) inhibitor Olaparib. Taken together, our results represent the first demonstration of functionally deleterious PALB2 missense variants associated with familial pancreatic cancer and of deleterious variants in the N-terminus outside of the coiled-coil domain. Further, our results suggest the possibility of personalized treatments, using IR or PARP inhibitor, of pancreatic and other cancers that carry a deleterious PALB2 variant. This article is protected by copyright. All rights reserved.

2.
Cancer Res ; 80(20): 4578-4590, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32816852

RESUMO

Protective associations of fruits, vegetables, and fiber intake with colorectal cancer risk have been shown in many, but not all epidemiologic studies. One possible reason for study heterogeneity is that dietary factors may have distinct effects by colorectal cancer molecular subtypes. Here, we investigate the association of fruit, vegetables, and fiber intake with four well-established colorectal cancer molecular subtypes separately and in combination. Nine observational studies including 9,592 cases with molecular subtypes for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS genes, and 7,869 controls were analyzed. Both case-only logistic regression analyses and polytomous logistic regression analyses (with one control set and multiple case groups) were used. Higher fruit intake was associated with a trend toward decreased risk of BRAF-mutated tumors [OR 4th vs. 1st quartile = 0.82 (95% confidence interval, 0.65-1.04)] but not BRAF-wildtype tumors [1.09 (0.97-1.22); P difference as shown in case-only analysis = 0.02]. This difference was observed in case-control studies and not in cohort studies. Compared with controls, higher fiber intake showed negative association with colorectal cancer risk for cases with microsatellite stable/MSI-low, CIMP-negative, BRAF-wildtype, and KRAS-wildtype tumors (P trend range from 0.03 to 3.4e-03), which is consistent with the traditional adenoma-colorectal cancer pathway. These negative associations were stronger compared with MSI-high, CIMP-positive, BRAF-mutated, or KRAS-mutated tumors, but the differences were not statistically significant. These inverse associations for fruit and fiber intake may explain, in part, inconsistent findings between fruit or fiber intake and colorectal cancer risk that have previously been reported. SIGNIFICANCE: These analyses by colorectal cancer molecular subtypes potentially explain the inconsistent findings between dietary fruit or fiber intake and overall colorectal cancer risk that have previously been reported.

3.
J Clin Oncol ; 38(24): 2798-2811, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32516092

RESUMO

PURPOSE: Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS: A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS: Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing-initial testing of priority genes followed by expanded testing-was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION: This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

5.
BMC Cancer ; 20(1): 389, 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32375690

RESUMO

BACKGROUND: To assess metastatic breast cancer (MBC) patient psychological factors, perceptions, and comprehension of tumor genomic testing. METHODS: In a prospective, single institution, single-arm trial, patients with MBC underwent next-generation sequencing at study entry with sequencing results released at progression. Patients who completed surveys before undergoing sequencing were included in the present secondary analysis (n = 58). We administered four validated psychosocial measures: Center for Epidemiologic Studies Depression Scale, Beck Anxiety Inventory, Trust in Physician Scale, and Communication and Attitudinal Self-Efficacy scale for Cancer. Genetic comprehension was assessed using 7-question objective and 6-question subjective measures. Longitudinal data were assessed (n = 40) using paired Wilcoxon signed rank and McNemar's test of agreement. RESULTS: There were no significant differences between the beginning and end of study in depression, anxiety, physician trust, or self-efficacy (median time on study: 7.6 months). Depression and anxiety were positively associated with each other and both negatively associated with self-efficacy. Self-efficacy decreased from pre- to post-genomic testing (p = 0.05). Objective genetics comprehension did not significantly change from pre- to post-genomic testing, but patients expressed increased confidence in their ability to teach others about genetics (p = 0.04). Objective comprehension was significantly lower in non-white patients (p = 0.02) and patients with lower income (p = 0.04). CONCLUSIONS: This is the only study, to our knowledge, to longitudinally evaluate multiple psychological metrics in MBC as patients undergo tumor genomic testing. Overall, psychological dimensions remained stable over the duration of tumor genomic testing. Among patients with MBC, depression and anxiety metrics were negatively correlated with patient self-efficacy. Patients undergoing somatic genomic testing had limited genomic knowledge, which varied by demographic groups and may warrant additional educational intervention. CLINICAL TRIAL INFORMATION: NCT01987726, registered November 13, 2013.

6.
Otolaryngol Head Neck Surg ; 163(3): 538-545, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32423289

RESUMO

OBJECTIVE: To examine the microRNA (miRNA) expression profile of cutaneous squamous cell carcinoma (cSCC) tumors from aggressive head and neck locations compared with nonaggressive anatomic sites and normal controls. STUDY DESIGN: Retrospective analysis of miRNA expression. SETTING: Tertiary care center. SUBJECTS AND METHODS: Tissue samples were collected from 3 anatomic regions: aggressive head and neck sites (ie, ears/lip), nonaggressive locations (ie, extremities/trunk), and adjacent normal skin. RNA was isolated from tissue cores of 45 samples (18 aggressive sites, 15 nonaggressive sites, and 12 normal-adjacent skin). miRNA expression analysis was completed for approximately 800 miRNAs using the NanoString nCounter panel. Five candidate miRNAs were selected for validation. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed on the original samples plus 30 additional tissue samples (7 aggressive sites, 14 nonaggressive sites, and 9 normal-adjacent skin). RESULTS: Five candidate miRNAs with significant differences in miRNA expression (P < 0 ≤ .001) from discovery samples were selected: miR-21, miR-31, let-7g, miR-93, and miR-22. Relative expression for these miRNAs using qRT-PCR in the new sample set did not reveal any significant differences using 1-way analysis of variance. When sets were combined, miR-21 showed increased expression in aggressive tumors relative to nonaggressive tumors (P = .009), but no others reached statistical significance. CONCLUSION: cSCC behaves more aggressively when originating from specific anatomical subsites of the head and neck. Of 5 miRNAs evaluated, only miR-21 showed significantly higher expression in tumors from aggressive sites relative to nonaggressive sites. Larger sample sizes are needed to evaluate other miRNAs.

7.
Paediatr Perinat Epidemiol ; 34(6): 629-636, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32150298

RESUMO

BACKGROUND: While most known causes of infertility relate to the health of the woman and/or her partner, questions have been raised regarding the possible contributions of transgenerational or epigenetic factors. OBJECTIVE: The goal of this hypothesis-generating work was to examine whether Generation 1's (G1's) age at the delivery of G2 (Generation 2) was associated with G2's fertility in later life. METHODS: We conducted a retrospective cohort study of women (G2s) recruited online in 2016. A questionnaire queried G2s regarding demographics and fertility. The primary exposure was G1's age at G2's birth. Outcome measures included the following: 12-month infertility, time to pregnancy, and childlessness. The adjusted relative risk (RR) of G2 infertility and childlessness by G1 age at G2's birth was estimated through a modified Poisson regression approach. The fecundity odds ratio (FOR) for the association between G1's age at G2 birth and time to pregnancy for G2 was estimated by discrete-time survival models, with complementary log-log link. RESULTS: A total of 2,854 women enrolled. We found no association between G1 age at G2's birth and G2 infertility. Being born to a G1 aged 15-19 years was associated with a longer time to pregnancy for G2 (FOR 0.84, 95% confidence interval 0.72, 0.99), relative to being born to a G1 aged 20-24 years. We observed the suggestion of a possible increased risk of childlessness among G2s born to older G1s, but the estimate was imprecise. CONCLUSIONS: While being born to a G1 who was 15-19 years old was associated with an increase in G2 time to pregnancy, we found no association between G1 age at G2's birth and infertility and only the suggestion of a modest association with childlessness. These data suggest a possible subtle effect of G1 age at G2's birth on G2 fertility, which warrants further study.

8.
Nat Commun ; 11(1): 820, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32041948

RESUMO

Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers in the United States. Previous genome-wide association studies (GWAS) have identified 14 single nucleotide polymorphisms (SNPs) associated with cutaneous SCC. Here, we report the largest cutaneous SCC meta-analysis to date, representing six international cohorts and totaling 19,149 SCC cases and 680,049 controls. We discover eight novel loci associated with SCC, confirm all previously associated loci, and perform fine mapping of causal variants. The novel SNPs occur within skin-specific regulatory elements and implicate loci involved in cancer development, immune regulation, and keratinocyte differentiation in SCC susceptibility.


Assuntos
Carcinoma de Células Escamosas/genética , Predisposição Genética para Doença/genética , Expressão Gênica , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Anotação de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Neoplasias Cutâneas/genética
9.
J Health Commun ; 24(4): 377-384, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31060454

RESUMO

Refined estimates of risk based on genetic risk modifiers could assist BRCA mutation carriers in understanding their risk, but it is not clear whether carriers are interested in receiving these estimates or how they might benefit from them. Using qualitative interviews, we investigated female BRCA1 and BRCA2 mutation carriers' (N = 20) reactions to numerical and verbal presentations of breast cancer risk based on risk modifiers and assessed women's preferences regarding visual formats for communicating risk. Our results show carriers are interested in receiving refined risk estimates and suggest the estimates may influence decision-making regarding cancer prevention, depending on the nature of the risk assessment. Although accurate and precise estimates of breast cancer risk are most important to women, they preferred quantitative risk estimates expressed as a proportion with or without a population comparison; however, women noted that comparisons to other BRCA mutation carriers were less useful given their high risk. Participants also preferred communication of a risk as a specific percentage versus a range of risk, but a clear preference regarding visual displays was not expressed. Results support many existing recommendations for genetic risk communication and provide guidance for the development of tools incorporating genetic risk modifiers.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/psicologia , Comunicação , Tomada de Decisões , Predisposição Genética para Doença , Medição de Risco/métodos , Adulto , Proteína BRCA1 , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Entrevistas como Assunto , Pessoa de Meia-Idade
10.
Hum Mutat ; 40(10): 1781-1796, 2019 10.
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.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Predisposição Genética para Doença , Variação Genética , Alelos , Feminino , Estudos de Associação Genética , Humanos , Mutação , Vigilância da População
11.
J Nutr ; 149(3): 381-397, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30801647

RESUMO

BACKGROUND: Human plasma and tissue lycopene concentrations are heterogeneous even when consuming controlled amounts of tomato or lycopene. OBJECTIVES: Our objective is to determine whether single nucleotide polymorphisms (SNPs) in or near known or putative carotenoid metabolism genes [ß-carotene 15,15' monooxygenase 1 (BCO1), scavenger receptor class B type 1 (SCARB1), ATP-binding cassette transporter subfamily A member 1 (ABCA1), microsomal triglyceride transfer protein (MTTP), apolipoprotein B-48, elongation of very long chain fatty acids protein 2 (ELOVL2), and ATP-binding cassette subfamily B member 1 (ABCB1), and an intergenic superoxide dismutase 2, mitochondrial-associated SNP] are predictive of plasma lycopene responses to steady state tomato juice consumption. METHODS: Secondary linear regression analyses of data from a dose-escalation study of prostate cancer patients [n = 47; mean ± SEM age: 60 ± 1 y; BMI (in kg/m2): 32 ± 1] consuming 0, 1, or 2 cans of tomato-soy juice/d (163 mL/can; 20.6 mg lycopene 1.2 mg ß-carotene/can) for 24 ± 0.7 d before prostatectomy were conducted to explore 11 SNP genotype effects on the change in plasma lycopene and plasma and prostate tissue concentrations of lycopene, ß-carotene, phytoene, and phytofluene. RESULTS: Two BCO1 SNP genotypes were significant predictors of the change in plasma lycopene, with SNP effects differing in magnitude and direction, depending on the level of juice intake (rs12934922 × diet group P = 0.02; rs6564851 × diet group P = 0.046). Further analyses suggested that plasma ß-carotene changes were predicted by BCO1 rs12934922 (P < 0.01), prostate lycopene by trending interaction and main effects of BCO1 SNPs (rs12934922 × diet group P = 0.09; rs12934922 P = 0.02; rs6564851 P = 0.053), and prostate ß-carotene by BCO1 SNP interaction and main effects (rs12934922 × diet group P = 0.01; rs12934922 P < 0.01; rs7501331 P = 0.02). CONCLUSIONS: In conclusion, SNPs in BCO1 and other genes may modulate human plasma and prostate tissue responses to dietary lycopene intake and warrant validation in larger, human controlled feeding intervention and cohort studies. Genetic variants related to carotenoid metabolism may partially explain heterogeneous human blood and tissue responses and may be critical covariates for population studies and clinical trials. This trial was registered at clinicaltrials.gov as NCT01009736.


Assuntos
Licopeno/sangue , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/dietoterapia , Proteínas de Soja , beta-Caroteno 15,15'-Mono-Oxigenase/genética , Bebidas/análise , Carotenoides/sangue , Genótipo , Humanos , Desequilíbrio de Ligação , Licopeno/metabolismo , Lycopersicon esculentum/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/enzimologia , beta Caroteno/sangue , beta-Caroteno 15,15'-Mono-Oxigenase/metabolismo
13.
Oncologist ; 24(7): 973-979, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30541756

RESUMO

BACKGROUND: Soft-tissue sarcomas (STS) describe a heterogeneous group of mesenchymal tumors with limited treatment options. Targeted therapies exist for BRCA1/2 gene alterations, but their prevalence and role have not been fully described in STS. Here, we present the largest effort to characterize the frequency of homologous recombination (HR) DNA repair pathway alterations in STS subtypes and highlight the unique nature of leiomyosarcoma (LMS). MATERIALS AND METHODS: DNA sequencing data were analyzed for HR pathway alterations for 1,236 patients with STS. DNA sequencing data from an additional 1,312 patients were used to confirm the prevalence of HR pathway alterations in LMS. Four uterine LMS (uLMS) patients with functional BRCA2 loss were evaluated for response to poly (ADP-ribose) polymerase (PARP) inhibition. RESULTS: In an unselected STS study population, BRCA2 alterations were identified in 15 (1%) patients, and homozygous BRCA2 loss was detected in 9 (<1%). However, subset analysis revealed that these BRCA2 alterations were concentrated in uLMS as compared with any other STS subtype. Notably, 10% of uLMS tumors had a BRCA2 alteration. We further report that PARP inhibitors had demonstrated durable clinical benefit in four uLMS patients with BRCA2 loss. CONCLUSION: HR pathway alterations are rare in most STS. However, we identify uLMS to be enriched for BRCA2 loss and report the positive outcomes of a series of patients treated with PARP inhibitors. Our data suggest that patients with uLMS should be considered for somatic BRCA2 profiling. Prospective trials are necessary to confirm the efficacy of PARP inhibition in uLMS. IMPLICATIONS FOR PRACTICE: Soft-tissue sarcomas are a highly morbid, diverse set of tumors with limited treatment options. This study identifies an increased prevalence of functional BRCA1/2 loss in patients with uterine leiomyosarcoma (uLMS). It also presents four patients with uLMS and BRCA2 loss who achieved durable clinical benefit from poly (ADP-ribose) polymerase inhibition. These data suggest that patients with uLMS in particular should be screened for BRCA1/2 alterations and may benefit from treatment targeted to these alterations.


Assuntos
Antineoplásicos/uso terapêutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/genética , Leiomiossarcoma/genética , Leiomiossarcoma/patologia , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Leiomiossarcoma/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Prognóstico , Estudos Retrospectivos
14.
J Pers Med ; 8(3)2018 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-30046027

RESUMO

Information on patients' preferences is essential to guide the development of more efficient genomic counseling service delivery models. We examined patient preferences in the context of use of a post-test genomic counseling framework on patients (n = 44) with chronic disease receiving online test reports for eight different diseases and one drug-response result. We also explored patients' disease risk awareness, recall of test report information, and confidence in knowing what to do with their test results. Prior to the post-test genomic counseling session, all participants viewed at least one test report; 81.6% of available test reports were reviewed in total. Participants requested more phone (36) than in-person counseling sessions (8), and phone sessions were shorter (mean 29.1 min; range 12⁻75 min) than in-person sessions (mean 52.8 min; range 23⁻85 min). A total of 182 test reports were discussed over the course of 44 counseling sessions (mean 4.13, range 1⁻9). Thirty-six (81.8%) participants requested assessment for additional medical/family history concerns. In exploring patient experiences of disease risk awareness and recall, no significant differences were identified in comparison to those of participants (n = 199) that had received in-person post-test genomic counseling in a parent study randomized controlled trial (RCT). In summary, a novel post-test genomic counseling framework allowed for a tailored approach to counseling based on the participants' predetermined choices.

15.
J Genet Couns ; 27(5): 1111-1129, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29460110

RESUMO

With the advent of widespread genomic testing for diagnostic indications and disease risk assessment, there is increased need to optimize genetic counseling services to support the scalable delivery of precision medicine. Here, we describe how we operationalized the reciprocal engagement model of genetic counseling practice to develop a framework of counseling components and strategies for the delivery of genomic results. This framework was constructed based upon qualitative research with patients receiving genomic counseling following online receipt of potentially actionable complex disease and pharmacogenomics reports. Consultation with a transdisciplinary group of investigators, including practicing genetic counselors, was sought to ensure broad scope and applicability of these strategies for use with any large-scale genomic testing effort. We preserve the provision of pre-test education and informed consent as established in Mendelian/single-gene disease genetic counseling practice. Following receipt of genomic results, patients are afforded the opportunity to tailor the counseling agenda by selecting the specific test results they wish to discuss, specifying questions for discussion, and indicating their preference for counseling modality. The genetic counselor uses these patient preferences to set the genomic counseling session and to personalize result communication and risk reduction recommendations. Tailored visual aids and result summary reports divide areas of risk (genetic variant, family history, lifestyle) for each disease to facilitate discussion of multiple disease risks. Post-counseling, session summary reports are actively routed to both the patient and their physician team to encourage review and follow-up. Given the breadth of genomic information potentially resulting from genomic testing, this framework is put forth as a starting point to meet the need for scalable genetic counseling services in the delivery of precision medicine.


Assuntos
Aconselhamento Genético/organização & administração , Testes Genéticos , Genômica , Comunicação , Conselheiros , Humanos , Farmacogenética , Médicos , Medicina de Precisão , Pesquisa Qualitativa , Projetos de Pesquisa
16.
Appl Immunohistochem Mol Morphol ; 25(8): 559-565, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-26894649

RESUMO

Desmoid fibromatosis is a locally aggressive clonal fibroblastic proliferation with high recurrence rates and no metastatic potential. Implicated molecular aberrations occur within the Wnt/ß-catenin pathway (APC and ß-catenin gene mutations). Transforming growth factor-ß (TGF-ß) and connective tissue growth factor (CTGF) are profibrotic growth factors, downstream from nuclear translocation of ß-catenin, that lead to increased fibrogenesis. CTGF (a downstream effector of TGF-ß) is a matricellular protein that modulates the activity of growth factors, adhesion molecules, integrins, and extracellular matrix thus playing a central role in tissue remodeling and fibrosis. Recently there has been growing interest in use of extracellular matrix inhibitors for treatment of various fibrogenic diseases. Desmoid fibromatosis samples (n=15) were evaluated for expression of ß-catenin, TGF-ß, and CTGF using immunohistochemistry on formalin paraffin-embedded material. A control group comprising scar tissue and adjacent normal skin (n=10) were simultaneously immunostained with above mentioned markers. Real-time polymerase chain reaction was performed on frozen specimens of desmoid fibromatosis (n=6) and normal skin (n=2). All 15 desmoid tumors were positive for ß-catenin (surrogate marker of Wnt/ß-catenin pathway dysregulation) which was negative in control normal skin and scar samples. TGF-ß and CTGF were negative in 9 of 10 normal skin controls. TGF-ß and CTGF were positive in all cases of scar tissue. All 15 cases of desmoid tumors were positive for TGF-ß and CTGF. The real-time polymerase chain reaction showed higher expression levels of TGF-ß and CTGF in desmoid fibromatosis compared with normal skin. The high constitutive expression of ß-catenin downstream effectors; TGF-ß, CTGF has the potential for enabling targeted therapy.


Assuntos
Fator de Crescimento do Tecido Conjuntivo/metabolismo , Fibromatose Agressiva/metabolismo , Mitógenos/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Adulto , Feminino , Fibromatose Agressiva/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
J Genet Couns ; 26(4): 738-751, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27921197

RESUMO

Genomic applications raise multiple challenges including the optimization of genomic counseling (GC) services as part of the results delivery process. More information on patients' motivations, preferences, and informational needs are essential to guide the development of new, more efficient practice delivery models that capitalize on the existing strengths of a limited genetic counseling workforce. Semi-structured telephone interviews were conducted with a subset of counselees from the Coriell Personalized Medicine Collaborative following online receipt of multiple personalized genomic test reports. Participants previously had either in-person GC (chronic disease cohort, n = 20; mean age 60 years) or telephone GC (community cohort, n = 31; mean age 46.8 years). Transcripts were analyzed using a Grounded Theory framework. Major themes that emerged from the interviews include 1) primary reasons for seeking GC were to clarify results, put results into perspective relative to other health-related concerns, and to receive personalized recommendations; 2) there is need for a more participant driven approach in terms of mode of GC communication (in-person, phone, video), and refining the counseling agenda pre-session; and 3) there was strong interest in the option of follow up GC. By clarifying counselees' expectations, views and desired outcomes, we have uncovered a need for a more participant-driven GC model when potentially actionable genomic results are received online.


Assuntos
Aconselhamento Genético/psicologia , Internet , Aceitação pelo Paciente de Cuidados de Saúde , Satisfação do Paciente , Farmacogenética , Medicina de Precisão , Relações Profissional-Paciente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa
19.
Artigo em Inglês | MEDLINE | ID: mdl-29204558

RESUMO

The majority of patients with head and neck cutaneous squamous cell carcinoma (cSCC) are successfully treated with surgical treatment of the primary site. While only a minority of patients is at risk for regional metastasis, these patients have significantly worse outcomes. Tumor and patient factors that place patients at high risk for development of regional metastasis have been identified. Advancing treatment of cSCC requires identifying and escalating treatment in this high risk patient population, while avoiding overtreatment of the majority of cSCC patients that do not develop regional metastasis. Sentinel lymph node biopsy has emerged as a promising technique in cSCC to detect micrometastasis and allow early surgical treatment of regional disease. Future directions involve genomic characterization of metastatic and nonmetastatic cSCC to identify genomic alterations causing metastasis that may be used to predict disease behavior.

20.
Hum Mutat ; 36(12): 1205-14, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26350354

RESUMO

Genes associated with hereditary breast and ovarian cancer (HBOC) are often sequenced in search of mutations that are predictive of susceptibility to these cancer types, but the sequence results are frequently ambiguous because of the detection of missense substitutions for which the clinical impact is unknown. The BARD1 protein is the heterodimeric partner of BRCA1 and is included on clinical gene panels for testing for susceptibility to HBOC. Like BRCA1, it is required for homology-directed DNA repair (HDR). We measured the HDR function of 29 BARD1 missense variants, 27 culled from clinical test results and two synthetic variants. Twenty-three of the assayed variants were functional for HDR; of these, four are known neutral variants. Three variants showed intermediate function, and three others were defective in HDR. When mapped to BARD1 domains, residues crucial for HDR were located in the N- and C- termini of BARD1. In the BARD1 RING domain, critical residues mapped to the zinc-coordinating amino acids and to the BRCA1-BARD1 binding interface, highlighting the importance of interaction between BRCA1 and BARD1 for HDR activity. Based on these results, we propose that the HDR assay is a useful complement to genetic analyses to classify BARD1 variants of unknown clinical significance.


Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA , Mutação de Sentido Incorreto , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Processamento Alternativo , Proteína BRCA1/metabolismo , Linhagem Celular , Evolução Molecular , Expressão Gênica , Humanos , Modelos Moleculares , Fenótipo , Ligação Proteica , Conformação Proteica , RNA Mensageiro/genética , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/química , Ubiquitina-Proteína Ligases/metabolismo
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