Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 60
Filtrar
Más filtros










Base de datos
Intervalo de año de publicación
1.
J Mol Diagn ; 2020 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-32036084

RESUMEN

A common rationale in molecular diagnostic laboratories is that implementation of next-generation sequencing (NGS) enables simultaneous multi-gene testing, allowing increased information benefit as compared to non-NGS assays. However, minimal published data exist to support this justification. In this study, we compared clinical diagnostic yield of TruSight Tumor 26 Sequencing Panel (TST26) in melanoma, colorectal (CRC) and gastro-intestinal stromal (GIST) tumors to non-NGS assays. 1041 formalin-fixed, paraffin embedded (FFPE) tumors, of melanoma, CRC and GIST were profiled. NGS results were compared to non-NGS single-gene or single-variant assays with respect to variant output and diagnostic yield. 79% melanoma and 94% CRC tumors were variant-positive by panel testing. TST26 panel improved BRAF variant detection in melanoma as compared to single-variant BRAF V600E/K routine tests by 24% and also detected variants in genes other than BRAF, NRAS and KIT which could impact patient management in 20% additional cases. NGS enhanced diagnostic yield in CRC by 36% when compared to routine single gene assays. In contrast, no added benefit of NGS based testing for GIST tumors was observed.TST26 panel either missed or inaccurately called complex insertion/deletion variants in KIT exon 11, which were accurately identified by non-NGS methods. Our findings demonstrate the differential impact of cancer site and variant type on diagnostic test information yield from NGS assays.

2.
Haematologica ; 2020 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-31896684

RESUMEN

Core-binding factor acute myeloid leukemia is characterized by t(8;21) or inv(16) and the fusion proteins RUNX1-RUNX1T1 and CBFB-MYH11. International guidelines recommend monitoring for measurable residual disease every 3 months for 2 years after treatment. However, it is unknown if serial molecular monitoring can predict and prevent morphologic relapse. We conducted a retrospective single-center study of 114 patients in complete remission who underwent molecular monitoring with RT-qPCR of RUNX1-RUNX1T1 or CBFB-MYH11 transcripts every 3 months. Morphologic relapse was defined as re-emergence of >5% blasts and molecular relapse as ≥1 log increase in transcript level between 2 samples. Over a median follow-up time of 3.7 years (range 0.2-14.3), remission persisted in 71 (62.3%) patients but 43 (37.7%) developed molecular or morphologic relapse. Patients who achieved <3 log reduction in RUNX1-RUNX1T1 or CBFB-MYH11 transcripts at end of chemotherapy had a significantly higher risk of relapse compared to patients who achieved ≥3 log reduction (61.1% vs. 33.7%, p=0.004). The majority of relapses (74.4%, n=32) were not predicted by molecular monitoring and occurred rapidly with <100 days from molecular to morphologic relapse. Molecular monitoring enabled the detection of impending relapse and permitted pre-emptive intervention prior to morphologic relapse in only 11 (25.6%) patients. The current practice of molecular monitoring every 3 months provided insufficient lead-time to identify molecular relapses and prevent morphologic relapse in the majority of patients with core-binding factor acute myeloid leukemia treated at our institution. Further research is necessary to determine the optimal monitoring strategies for these patients.

3.
Genome Med ; 12(1): 8, 2020 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-31937368

RESUMEN

The number of druggable tumor-specific molecular aberrations has grown substantially in the past decade, with a significant survival benefit obtained from biomarker matching therapies in several cancer types. Molecular pathology has therefore become fundamental not only to inform on tumor diagnosis and prognosis but also to drive therapeutic decisions in daily practice. The introduction of next-generation sequencing technologies and the rising number of large-scale tumor molecular profiling programs across institutions worldwide have revolutionized the field of precision oncology. As comprehensive genomic analyses become increasingly available in both clinical and research settings, healthcare professionals are faced with the complex tasks of result interpretation and translation. This review summarizes the current and upcoming approaches to implement precision cancer medicine, highlighting the challenges and potential solutions to facilitate the interpretation and to maximize the clinical utility of molecular profiling results. We describe novel molecular characterization strategies beyond tumor DNA sequencing, such as transcriptomics, immunophenotyping, epigenetic profiling, and single-cell analyses. We also review current and potential applications of liquid biopsies to evaluate blood-based biomarkers, such as circulating tumor cells and circulating nucleic acids. Last, lessons learned from the existing limitations of genotype-derived therapies provide insights into ways to expand precision medicine beyond genomics.

5.
Clin Genet ; 96(5): 461-467, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31368132

RESUMEN

Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data. As an initial trial, information from 86 VHL patients from the University Health Network/Hospital for Sick Children was populated into the database. Analysis of this cohort showed missense variants occurring with the greatest frequency, with all variants localizing to the α- or ß-domains of VHL. The most prevalent manifestations were central nervous system (CNS), renal, and retinal neoplasms, which were associated with frameshift variants and large deletions. We observed greater age-related penetrance for CNS hemangioblastomas with truncating variants compared to missense, while the reverse was true for pheochromocytomas. We demonstrate the utility of a comprehensive VHL database, which supports the standardized collection of clinical and genetic data specific to this patient population. Importantly, we expect that its web-based design will facilitate broader international collaboration and lead to a better understanding of VHL.

6.
J Med Genet ; 56(12): 792-800, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31300550

RESUMEN

PurposeThe purpose of this document is to provide guidance for the use of next-generation sequencing (NGS, also known as massively parallel sequencing or MPS) in Canadian clinical genetic laboratories for detection of genetic variants in genomic DNA and mitochondrial DNA for inherited disorders, as well as somatic variants in tumour DNA for acquired cancers. They are intended for Canadian clinical laboratories engaged in developing, validating and using NGS methods. METHODS OF STATEMENT DEVELOPMENT: The document was drafted by the Canadian College of Medical Geneticists (CCMG) Ad Hoc Working Group on NGS Guidelines to make recommendations relevant to NGS. The statement was circulated for comment to the CCMG Laboratory Practice and Clinical Practice committees, and to the CCMG membership. Following incorporation of feedback, the document was approved by the CCMG Board of Directors. DISCLAIMER: The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. The current CCMG Practice Guidelines were developed as a resource for clinical laboratories in Canada and should not be considered to be inclusive of all information laboratories should consider in the validation and use of NGS for a clinical laboratory service.

7.
Mod Pathol ; 32(12): 1823-1833, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31308508

RESUMEN

Gastric-type endocervical adenocarcinoma is an uncommon aggressive type of endocervical adenocarcinoma that is not associated with human papillomavirus (HPV). At present, this tumor is classified under the spectrum of mucinous carcinoma of the uterine cervix. The clinical stage of gastric-type endocervical adenocarcinoma at the time of diagnosis is usually more advanced compared to the HPV-associated endocervical adenocarcinoma. Widespread dissemination to unusual sites, such as omentum, peritoneum, and distant organs, can be present. Owing to its rare incidence, diagnostic dilemmas, and aggressive behavior, clinical management can be challenging. In this study, we aimed to elucidate the molecular characteristics of these tumors by using next-generation sequencing (NGS) to assess 161 unique cancer-driver genes for single-nucleotide and copy-number variations, gene fusions, and insertions/deletions within gastric-type endocervical adenocarcinoma tumors. In total, 92 variants were detected across the 14 samples tested (7 variants on average per tumor). TP53 was the most recurrently mutated gene followed by MSH6, CDKN2A/B, POLE, SLX4, ARID1A, STK11, BRCA2, and MSH2. Abnormal p53 expression was observed in nine cases by immunohistochemistry, of which TP53 variants were present in four cases. MDM2 gene amplification in 12q15 (69202190-69233452) locus was seen in two cases that express normal p53 levels by immunohistochemistry. Four cases had STK11 null (frameshift/nonsense) variants, three of which were previously reported in Peutz-Jeghers syndrome. Overall, genes that are implicated in DNA damage, repair, cell cycle, Fanconi anemia pathway, and the PI3K-AKT signaling pathways were found to be mutated. Of note, genes known to have acquired and/or inherited variants in endometrial tumors were enriched within our cohort. In conclusion, our study shows the genetic heterogeneity of gastric-type endocervical adenocarcinoma with some potentially actionable molecular alterations, which highlights the importance of further molecular characterization for better identification of this rare entity, and hence better clinical management.

8.
Lung Cancer ; 131: 86-89, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31027703

RESUMEN

BACKGROUND: Peripheral blood sampling for detection of EGFR T790M in cell-free circulating tumour (ct) DNA in TKI-resistant EGFR mutant (EGFRm) lung cancer is now standard. The value of more comprehensive sequencing is unknown. METHODS: Prospective ctDNA analysis in patients with EGFRm NSCLC was performed using a next generation sequencing (NGS) panel of regions of 11 genes detecting single nucleotide variants and small insertions/deletions at ≥0.1% variant allele frequency (VAF) was performed. Patients were grouped according to treatment phase, including: (A) pre EGFR-TKI, (B) stable or responding to EGFR-TKI, (C) radiographic progression during EGFR-TKI, and (D) during chemotherapy treatment. RESULTS: Seventy-two patients with stage IV EGFRm NSCLC were enrolled and first blood samples were analysed. Primary sensitizing mutations in del19 or L858R were present in 66 (92%) and uncommon EGFRm in 6 (8%). Mutations in ctDNA were found in 53 samples (74%). T790M was detected in 3 of 4 patients with T790M-negative tissue. Other co-occurring EGFRm were found in 10 patients (7%) including K745R during first-line osimertinib. TP53 (n = 10), KRAS (n = 1), PI3KCA (n = 1) and ALK (n = 3) gene mutations also were detected. The presence of an EGFRm (excluding T790M) was associated with untreated or progressive disease, p = 0.04. In TKI-treated patients without radiologic progression, median progression free survival (PFS) was 10 months versus 2.1 months (HR 2.22, 95% CI: 0.89-5.54, p = 0.08) if an EGFRm in ctDNA was detected. If T790M was present in ctDNA, median PFS was 3.0 months versus 9.7 months (HR 4.59, 95% CI: 1.43-14.73, p = 0.005). High % VAF of both EGFRm and T790M correlated with inferior PFS (p = 0.01 and p = 0.03 respectively). CONCLUSION: In addition to the emergence of resistance mutations, the presence of the primary or co-occurring EGFRm in patients receiving EGFR-TKIs may associate with shorter PFS and may be useful in longitudinal analyses of ctDNA to direct therapy.

9.
Clin Lung Cancer ; 20(3): e338-e345, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30770327

RESUMEN

BACKGROUND: KRAS and TP53 are common mutations in non-small-cell lung cancer (NSCLC). The Lung Adjuvant Cisplatin Evaluation Biological Program group found adjuvant chemotherapy to be deleterious in patients with coexisting KRAS/TP53 mutations. PATIENTS AND METHODS: To validate these results, patients with NSCLC tested for KRAS and TP53 mutations and receiving chemotherapy for any stage NSCLC were selected. Mutation status was analyzed using next generation sequencing (Illumina) or multiplex recurrent mutation detection (MassARRAY, Agena Biosciences) assays, and was correlated with clinical and demographic data. Disease-free (DFS) or progression-free survival (PFS) was the main endpoint, and overall survival (OS) was the secondary endpoint. RESULTS: Among 218 patients, 28 had coexisting KRAS/TP53 mutations, 77 TP53, 37 KRAS, 76 had neither KRAS nor TP53 mutation (WT/WT). There was no DFS/PFS difference for the KRAS/TP53 group versus all others among 99 patients who received adjuvant chemotherapy (hazard ratio [HR], 1.22; 95% confidence interval [CI], 0.61-2.44; P = .57), 27 stage III patients who received chemo-radiation (HR, 0.87; 95% CI, 0.32-2.38; P = .8), and 63 patients who received palliative chemotherapy (HR, 0.68; 95% CI, 0.31-1.48; P = .33). OS was longer in the WT/WT group compared with any other group (KRAS: HR, 1.87; 95% CI, 1.02-3.43; P = .043; TP53: HR, 2.17; 95% CI, 1.3-3.61; P = .0028; KRAS/TP53: HR, 2.06; 95% CI, 1.09-3.88; P = .026). No OS difference was seen for KRAS/TP53 compared with the other groups (HR, 1.26; 95% CI, 0.75-2.13; P = .38). CONCLUSIONS: There was no significant difference in DFS/PFS between the 4 groups. However, OS was longer for patients with TP53 and KRAS wild-type NSCLC who received chemotherapy for any stage compared with patients with KRAS, TP53 mutation, or double mutant tumors.

10.
Int J Gynecol Cancer ; 2019 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-30659026

RESUMEN

OBJECTIVE: Mutations in TP53 are found in the majority of high grade serous ovarian cancers, leading to gain of function or loss of function of its protein product, p53, involved in oncogenesis. There have been conflicting reports as to the impact of the type of these on prognosis. We aim to further elucidate this relationship in our cohort of patients. METHODS: 229 patients with high grade serous ovarian cancer underwent tumor profiling through an institutional molecular screening program with targeted next generation sequencing. TP53 mutations were classified using methods previously described in the literature. Immunohistochemistry on formalin-fixed paraffin embedded tissue was used to assess for TP53 mutation. Using divisive hierarchal clustering, we generated patient clusters with similar clinicopathologic characteristics to investigate differences in outcomes. RESULTS: Six different classification schemes of TP53 mutations were studied. These did not show an association with first platinum-free interval or overall survival. Next generation sequencing reliably predicted mutation in 80% of cases, similar to the proportion detected by immunohistochemistry. Divisive hierarchical clustering generated four main clusters, with cluster 3 having a significantly worse prognosis (p<0.0001; log-rank test). This cluster had a higher concentration of gain of function mutations and these patients were less likely to have undergone optimal debulking surgery. CONCLUSIONS: Different classifications of TP53 mutations did not show an impact on outcomes in this study. Immunohistochemistry was a good predictor for TP53 mutation. Cluster analysis showed that a subgroup of patients with gain of function mutations (cluster 3) had a worse prognosis.

11.
Gynecol Oncol ; 153(1): 108-115, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30638766

RESUMEN

OBJECTIVE: Genetic testing identifies cancer patients who may benefit from targeted treatment and allows for enhanced cancer screening and risk-reduction in their at-risk relatives. Traditional models of genetic counseling (GC) cannot meet the increasing demand and urgency for genetic testing. The objective of this study was to evaluate a new model of service delivery to improve the efficiency of pre-test GC for panel-based genetic testing. METHODS: A parallel, two-armed, randomized non-inferiority study compared traditional and modified pre-test GC models (1:2) prior to panel-based genetic testing. Participants were adult females, whose first-degree relative died of serous ovarian cancer. In the modified group, participants were emailed a 20-minute presentation prior to a scheduled pre-test GC telephone call. Psychosocial and knowledge questionnaires were provided at baseline (P1) and one week after pre-test GC (P2). RESULTS: 382 women completed pre-test GC (256 modified, 126 traditional). There were no differences in marital status, education level or household income. Pre-test GC time was shorter in the modified group (average 19 vs. 46 min, p < 0.001), with no difference in post-test GC time (average 16 min each, p = 0.78). The modified pre-test GC model was found to be non-inferior to traditional GC on measures of cancer-specific distress, depression, anxiety, decisional conflict, ovarian cancer knowledge and satisfaction. Perceived lifetime risk for ovarian cancer decreased to a lesser extent from baseline in women who received modified pre-test GC. CONCLUSIONS: A 20-minute presentation prior to pre-test telephone GC is non-inferior to traditional in-person GC on all variables tested, except for perceived ovarian cancer risk. This modified model improved GC efficiency without negatively affecting psychosocial outcomes, providing an alternative strategy to meet the growing demand for genetic testing.


Asunto(s)
Asesoramiento Genético/métodos , Neoplasias Ováricas/genética , Neoplasias Ováricas/psicología , Técnicas de Apoyo para la Decisión , Femenino , Asesoramiento Genético/psicología , Predisposición Genética a la Enfermedad/psicología , Pruebas Genéticas/métodos , Humanos , Persona de Mediana Edad , Modelos Psicológicos
12.
J Mol Diagn ; 21(2): 261-273, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30576869

RESUMEN

A common approach in clinical diagnostic laboratories to variant assessment from tumor molecular profiling is sequencing of genomic DNA extracted from both tumor (somatic) and normal (germline) tissue, with subsequent variant comparison to identify true somatic variants with potential impact on patient treatment or prognosis. However, challenges exist in paired tumor-normal testing, including increased cost of dual sample testing and identification of germline cancer predisposing variants. Alternatively, somatic variants can be identified by in silico tumor-only variant filtration precluding the need for matched normal testing. The barrier to tumor-only variant filtration is defining a reliable approach, with high sensitivity and specificity to identify somatic variants. In this study, we used retrospective data sets from paired tumor-normal samples tested on small (48 gene) and large (555 gene) targeted next-generation sequencing panels, to model algorithms for tumor-only variants classification. The optimal algorithm required an ordinal filtering approach using information from variant population databases (1000 Genomes Phase 3, ESP6500, ExAC), clinical mutation databases (ClinVar), and information on recurring clinically relevant somatic variants. Overall the tumor-only variant filtration strategy described in this study can define clinically relevant somatic variants from tumor-only analysis with sensitivity of 97% to 99% and specificity of 87% to 94%, and with significant potential utility for clinical laboratories implementing tumor-only molecular profiling.

13.
Head Neck Pathol ; 13(3): 516-522, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29845478

RESUMEN

Neuroendocrine carcinomas (NECs) are epithelial neoplasms showing morphologic, immunophenotypic or ultrastructural evidence of neuroendocrine differentiation. The 2017 WHO Classification of Head and Neck Tumours classifies NECs into well, moderately and poorly differentiated NECs according to light microscopic features, mitotic rate and presence of tumour necrosis. In this study, we performed next generation sequencing (NGS) using a targeted 161 cancer gene panel on a poorly differentiated NEC of the nasal cavity. The tumour was composed of large cells arranged in poorly formed glands and solid nests. The mitotic count rate was 30/10 HPFs and p53 protein was strongly expressed in all tumour cells. NGS identified a missense mutation, c.764T > G (p.Ile255Ser) in the TP53 gene with an allele frequency of 85%. This mutation results in an isoleucine to serine substitution and a non-functional protein. No other mutations were identified. These results suggest that TP53 mutations may drive oncogenesis in poorly differentiated NECs of the head and neck.


Asunto(s)
Carcinoma Neuroendocrino/genética , Cavidad Nasal/patología , Neoplasias Nasales/genética , Proteína p53 Supresora de Tumor/genética , Carcinoma Neuroendocrino/patología , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Persona de Mediana Edad , Mutación Missense , Neoplasias Nasales/patología
14.
J Pathol Clin Res ; 5(2): 115-129, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30387329

RESUMEN

Immunohistochemistry (IHC) for mismatch repair (MMR) proteins is used to identify MMR status: being diffusely positive (intact/retained nuclear staining) or showing loss of nuclear tumour staining (MMR protein deficient). Four colonic adenocarcinomas and a gastric adenocarcinoma with associated dysplasia that displayed heterogenous IHC staining patterns in at least one of the four MMR proteins were characterised by next-generation sequencing (NGS). In order to examine a potential molecular mechanism for these staining patterns, the respective areas were macrodissected, analysed for microsatellite instability (MSI) and investigated by NGS and multiplex ligation-dependent probe amplification (MLPA) analysis of MLH1, MSH2, MSH6 and PMS2 genes, including MLH1 methylation analysis. One colonic adenocarcinoma showed heterogenous MSH6 IHC staining and molecular analysis demonstrated increasing allelic burden of two MSH6 frameshift variants (c.3261delC and c.3261dupC) in areas with MSH6 protein loss compared to areas where MSH6 was retained. Two colonic adenocarcinomas with heterogenous MLH1 staining showed no differences in sequence variants. In one of these cases, however, MLH1 was hypermethylated in the area of MLH1 loss. Another colon carcinoma with heterogenous PMS2 staining (but with retained MSH6) showed both MSH6 c.3261dupC and 3260_3261dupCC where PMS2 protein was lost and only c.3261dupC where PMS2 was retained. The gastric carcinoma showed complete loss of MSH6 in dysplastic foci, while the underlying invasive carcinoma showed retention of MSH6. Both these areas, however, were MSI-high and showed the same MSH6 variant: c.3261delC. The gastric dysplasia additionally showed MSH6 c.3261dupC. In four of the five cases where MMR protein was lost, these areas were MSI-high. Heterogenous MMR IHC (focal and/or zonal within the same tumour or between invasive and dysplastic preinvasive areas) is not always due to artefact and is invariably related to MSI-high status in the areas of loss. An interesting aspect to this study is the presence of MSH6 somatic mutations irrespective of whether MSH6 IHC staining was intact or lost.

15.
Blood Adv ; 2(20): 2658-2671, 2018 10 23.
Artículo en Inglés | MEDLINE | ID: mdl-30327374

RESUMEN

There is a paucity of data regarding the impact of mutations on outcomes in accelerated-phase (AP) and blast-phase (BP) myeloproliferative neoplasms (MPNs). Moreover, it is unknown whether mutational status affects survival, as seen in chronic-phase MPNs. Therefore, we performed a retrospective analysis of all patients treated at our institution with AP/BP MPNs (N = 122; AP = 14; BP = 108) to comprehensively describe the mutational profile and correlate with clinical outcomes. Targeted sequencing with a 54-gene panel was performed. Forty-four patients were treated with intensive therapy, 27 with nonintensive therapy, and 51 with best supportive care (BSC). The most common mutation was JAK2V617F, occurring in 55% of subjects; CALR was found in 13% of patients and MPL in 6%. Thirty-two (26%) patients were triple negative. Other frequently mutated genes were ASXL1 (30%), TET2 (25%), SRSF2 (22%), RUNX1 (20%), and TP53 (17%). Mutations in 1, 2, 3, and ≥4 genes were seen in 15%, 13%, 25%, and 46% of patients, respectively. There was no difference in survival between patients treated with intensive vs nonintensive therapy, and the benefit of intensive therapy was limited to patients who were able to undergo transplantation. TP53 was the only individual mutation to correlate with shorter overall survival (hazard ratio, 1.89; P = .03). In the multivariate analysis, mutated TP53, ≥4 mutations, low albumin, increased peripheral blood blasts, ≥3 cytogenetic abnormalities, and BSC were associated with shorter survival. In conclusion, mutational data enhance the understanding of patients with AP/BP MPN who are likely to benefit from current therapeutic options.


Asunto(s)
Crisis Blástica/metabolismo , Trastornos Mieloproliferativos/diagnóstico , Femenino , Humanos , Masculino , Trastornos Mieloproliferativos/patología , Resultado del Tratamiento
17.
BMC Med Genomics ; 11(1): 65, 2018 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-30092803

RESUMEN

BACKGROUND: Matched tumor-normal sequencing, applied in precision cancer medicine, can identify unidentified germline Medically Actionable Variants (gMAVS) in cancer predisposition genes. We report patient preferences for the return of additional germline results, and describe various gMAV scenarios delivered through a clinical genetics service. METHODS: Tumor profiling was offered to 1960 advanced cancer patients, of which 1556 underwent tumor-normal sequencing with multigene hotspot panels containing 20 cancer predisposition genes. All patients were provided with an IRB-approved consent for return of additional gMAVs. RESULTS: Of the whole cohort 94% of patients consented to be informed of additional germline results and 5% declined, with no statistically significant differences based on age, sex, race or prior genetic testing. Eight patients were found to have gMAVs in a cancer predisposition gene. Five had previously unidentified gMAVs: three in TP53 (only one fulfilled Chompret's Revised criteria for Li-Fraumeni Syndrome), one in SMARCB1 in the absence of schwannomatosis features and one a TP53 variant at low allele frequency suggesting an acquired event in blood. CONCLUSION: Interest in germline findings is high among patients who undergo tumor profiling. Disclosure of previously unidentified gMAVs present multiple challenges, thus supporting the involvement of a clinical genetics service in all tumor profiling programs.


Asunto(s)
Pruebas Genéticas , Mutación de Línea Germinal , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias/genética , Neoplasias/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
18.
J Med Genet ; 55(9): 571-577, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-30042185

RESUMEN

The landscape of genetic testing in ovarian cancer patients has changed dramatically in recent years. The therapeutic benefits of poly ADP-ribose polymerase (PARP) inhibitors in treatment of BRCA1/2-related ovarian cancers has resulted in an increased demand and urgency for genetic testing results, while technological developments have led to widespread use of multi-gene cancer panels and development of tumour testing protocols. Traditional genetic counselling models are no longer sustainable and must evolve to match the rapid evolution of genetic testing technologies and developments in personalized medicine. Recently, representatives from oncology, clinical genetics, molecular genetics, pathology, and patient advocacy came together to create a national multi-disciplinary Canadian consortium. By aligning stakeholder interests, the BRCA Testing to Treatment (BRCA TtoT) Community of Practice aims to develop a national strategy for tumour and germline BRCA1/2 testing and genetic counselling in women with ovarian cancer. This article serves to provide an overview of the recent evolution of genetic assessment for BRCA1/2-associated gynecologic malignancies and outline a Canadian roadmap to facilitate change, improve genetic testing rates, and ultimately improve outcomes for hereditary ovarian cancer patients and their families.


Asunto(s)
Proteína BRCA1/genética , Proteína BRCA2/genética , Asesoramiento Genético/tendencias , Pruebas Genéticas/tendencias , Mutación , Neoplasias Ováricas/genética , Canadá , Femenino , Pruebas Genéticas/métodos , Humanos , Medicina de Precisión
19.
Leuk Res ; 68: 22-28, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29518628

RESUMEN

We evaluated outcomes of 100 patients with high risk AML treated with Ida-FLAG induction as first-line therapy. 72 achieved remission with one cycle; 19 did not. High risk cytogenetics and TP53 mutations were associated with failure to achieve remission. In those reaching remission, allogeneic bone marrow transplantation was associated with better relapse-free and overall survival. Those not achieving remission with induction therapy were extremely unlikely to reach remission with further therapy and had a dismal prognosis. Exploratory molecular analysis confirmed persistence of the dominant genetic mutations identified at diagnosis. Ex vivo chemosensitivity did not demonstrate significant differences between responders and non-responders. Thus, Ida-FLAG induction has a high chance of inducing remission in patients with high risk AML. Those achieving remission require allogeneic transplantation to achieve cure; those not achieving remission rarely respond to salvage chemotherapy and have a dismal outcome. Alternatives to conventional chemotherapy must be considered in this group.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia de Inducción , Leucemia Mieloide Aguda/tratamiento farmacológico , Vidarabina/análogos & derivados , Adolescente , Adulto , Anciano , Citarabina/uso terapéutico , Femenino , Genes p53 , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Idarrubicina/uso terapéutico , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Inducción de Remisión , Estudios Retrospectivos , Resultado del Tratamiento , Vidarabina/uso terapéutico , Adulto Joven
20.
Breast Cancer Res Treat ; 168(1): 159-168, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29177603

RESUMEN

PURPOSE: Next-generation sequencing (NGS) has identified recurrent genomic alterations in metastatic breast cancer (MBC); however, the clinical utility of incorporating routine sequencing to guide treatment decisions in this setting is unclear. We examine the frequency of genomic alterations in MBC patients from academic and community hospitals and correlate with clinical outcomes. METHODS: MBC patients with good performance status were prospectively recruited at the Princess Margaret Cancer Centre (PM) in Canada. Molecular profiling on DNA extracted from FFPE archival tissues was performed on the Sequenom MassArray platform or the TruSeq Amplicon Cancer Panel (TSACP) on the MiSeq platform. Clinical trial outcomes by RECIST 1.1 and time on treatment were reviewed retrospectively. RESULTS: From January 2012 to November 2015, 483 MBC patients were enrolled and 440 were genotyped. At least one somatic mutation was identified in 46% of patients, most commonly in PIK3CA (28%) or TP53 (13%). Of 203 patients with ≥ 1 mutation(s), 15% were treated on genotype-matched and 9% on non-matched trials. There was no significant difference for median time on treatment for patients treated on matched vs. non-matched therapies (3.6 vs. 3.8 months; p = 0.89). CONCLUSIONS: This study provides real-world outcomes on hotspot genotyping and small targeted panel sequencing of MBC patients from academic and community settings. Few patients were matched to clinical trials with targeted therapies. More comprehensive profiling and improved access to clinical trials may increase therapeutic options for patients with actionable mutations. Further studies are needed to evaluate if this approach leads to improved clinical outcomes.


Asunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Técnicas de Genotipaje/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Adulto , Anciano , Anciano de 80 o más Años , Mama/patología , Mama/cirugía , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Ensayos Clínicos como Asunto , Análisis Mutacional de ADN/métodos , Femenino , Genómica/métodos , Humanos , Mastectomía , Persona de Mediana Edad , Mutación , Fosfohidrolasa PTEN/genética , Estudios Prospectivos , Criterios de Evaluación de Respuesta en Tumores Sólidos , Estudios Retrospectivos , Análisis de Supervivencia , Adulto Joven
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA