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1.
Med Phys ; 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33760269

RESUMO

PURPOSE: While multi-parametric Magnetic Resonance Imaging (MRI) shows great promise in assisting with prostate cancer diagnosis and localization, subtle differences in appearance between cancer and normal tissue lead to many false positive and false negative interpretations by radiologists. We sought to automatically detect aggressive cancer (Gleason pattern ≥ 4) and indolent cancer (Gleason pattern 3) on a per-pixel basis on MRI to facilitate the targeting of aggressive cancer during biopsy. METHODS: We created the Stanford Prostate Cancer Network (SPCNet), a convolutional neural network model, trained to distinguish between aggressive cancer, indolent cancer, and normal tissue on MRI. Ground truth cancer labels were obtainedby registering MRI with whole-mount digital histopathology images from patients that underwent radical prostatectomy. Before registration, these histopathology images were automatically annotated to show Gleason patterns on a per-pixel basis. The model was trained on data from 78 patients that underwent radical prostatectomy and 24 patients without prostate cancer. The model was evaluated on a pixel and lesion level in 322 patients, including: 6 patients with normal MRI and no cancer, 23 patients that underwent radical prostatectomy, and 293 patients that underwent biopsy. Moreover, we assessed the ability of our model to detect clinically significant cancer (lesions with an aggressive component) and compared it to the performance of radiologists. RESULTS: Our model detected clinically significant lesions with an Area Under the Receiver Operator Characteristics Curve of 0.75 for radical prostatectomy patients and 0.80 for biopsy patients. Moreover, the model detected up to 18% of lesions missed by radiologists, and overall had a sensitivity and specificity that approached that of radiologists in detecting clinically significant cancer. CONCLUSIONS: Our SPCNet model accurately detected aggressive prostate cancer. Its performance approached that of radiologists, and it helped identify lesions otherwise missed by radiologists. Our model has the potential to assist physicians in specifically targeting the aggressive component of prostate cancers during biopsy or focal treatment.

2.
Magn Reson Med ; 86(1): 308-319, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33608954

RESUMO

PURPOSE: Provide a direct, non-invasive diagnostic measure of microscopic tissue texture in the size scale between tens of microns and the much larger scale measurable by clinical imaging. This paper presents a method and data demonstrating the ability to measure these microscopic pathologic tissue textures (histology) in the presence of subject motion in an MR scanner. This size range is vital to diagnosing a wide range of diseases. THEORY/METHODS: MR micro-Texture (MRµT) resolves these textures by a combination of measuring a targeted set of k-values to characterize texture-as in diffraction analysis of materials, performing a selective internal excitation to isolate a volume of interest (VOI), applying a high k-value phase encode to the excited spins in the VOI, and acquiring each individual k-value data point in a single excitation-providing motion immunity and extended acquisition time for maximizing signal-to-noise ratio. Additional k-value measurements from the same tissue can be made to characterize the tissue texture in the VOI-there is no need for these additional measurements to be spatially coherent as there is no image to be reconstructed. This method was applied to phantoms and tissue specimens including human prostate tissue. RESULTS: Data demonstrating resolution <50 µm, motion immunity, and clearly differentiating between normal and cancerous tissue textures are presented. CONCLUSION: The data reveal textural differences not resolvable by standard MR imaging. As MRµT is a pulse sequence, it is directly translatable to MRI scanners currently in clinical practice to meet the need for further improvement in cancer imaging.

3.
Cancer Res ; 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637565

RESUMO

Prostate cancer is one of the most common malignancies worldwide, yet limited tools exist for prognostic risk stratification of the disease. Identification of new biomarkers representing intrinsic features of malignant transformation and development of prognostic imaging technologies are critical for improving treatment decisions and patient survival. In this study, we analyzed radical prostatectomy specimens from 422 patients with localized disease to define the expression pattern of methionine aminopeptidase II (MetAP2), a cytosolic metalloprotease that has been identified as a druggable target in cancer. MetAP2 was highly expressed in 54% of low-grade and 59% of high-grade cancer. Elevated levels of MetAP2 at diagnosis were associated with shorter time to recurrence. Controlled self-assembly of a synthetic small molecule enabled design of the first MetAP2-activated positron emission tomography (PET) imaging tracer for monitoring MetAP2 activity in vivo. The nanoparticles assembled upon MetAP2 activation were imaged in single prostate cancer cells with post-click fluorescent labeling. The fluorine-18 labeled tracers successfully differentiated MetAP2 activity in both MetAP2 knockdown and inhibitor-treated human prostate cancer xenografts by micro-PET/CT scanning. This highly sensitive imaging technology may provide a new tool for non-invasive early risk stratification of prostate cancer and monitoring the therapeutic effect of MetAP2 inhibitors as anti-cancer drugs.

4.
Arch Pathol Lab Med ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33571361

RESUMO

CONTEXT.­: Mutational signatures have been described in the literature and a few centers have implemented pipelines for clinical reporting. OBJECTIVE.­: To describe the performance of a mutational signature caller with clinical samples sequenced on a targeted next-generation sequencing panel with a small genomic footprint. DESIGN.­: One thousand six hundred eighty-two (n = 1682) clinical samples were analyzed for the presence of mutational signatures using deconstructSigs on variant calls with at least 20 variant reads. RESULTS.­: Signature 10 (associated with POLe mutation) achieved separation of cases and controls in hypermutated samples. Signatures 4 (associated with tobacco smoking) and 7 (associated with ultraviolet radiation) as an indicator of pulmonary or cutaneous primary sites showed moderate sensitivity and high specificity at optimal cutpoints. Mutational signatures in malignancies with unknown primaries were somewhat consistent with the clinically suspected primary site, with an apparent dose-response relationship between the number of variants analyzed and the ability of mutational signature analysis to correctly suggest a primary site. CONCLUSIONS.­: Mutational signatures represent an opportunity for orthogonal testing of primary site, which may be particularly useful in supporting cutaneous or pulmonary sites in poorly differentiated neoplasms. Tobacco smoking, ultraviolet radiation, and POLe mutational signatures are the most appropriate signatures for implementation. Even relatively small numbers of variants appear capable of supporting a clinically suspected primary.

5.
Cancer Discov ; 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608386

RESUMO

Cancer genotyping has identified a large number of putative tumor suppressor genes. Carcinogenesis is a multi-step process, however the importance and specific roles of many of these genes during tumor initiation, growth and progression remain unknown. Here we use a multiplexed mouse model of oncogenic KRAS-driven lung cancer to quantify the impact of forty-eight known and putative tumor suppressor genes on diverse aspects of carcinogenesis at an unprecedented scale and resolution. We uncover many previously understudied functional tumor suppressors that constrain cancer in vivo. Inactivation of some genes substantially increased growth, while the inactivation of others increases tumor initiation and/or the emergence of exceptionally large tumors. These functional in vivo analyses revealed an unexpectedly complex landscape of tumor suppression that has implications for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches to limit tumor initiation and progression.

6.
Med Image Anal ; 68: 101919, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33385701

RESUMO

Magnetic resonance imaging (MRI) is an increasingly important tool for the diagnosis and treatment of prostate cancer. However, interpretation of MRI suffers from high inter-observer variability across radiologists, thereby contributing to missed clinically significant cancers, overdiagnosed low-risk cancers, and frequent false positives. Interpretation of MRI could be greatly improved by providing radiologists with an answer key that clearly shows cancer locations on MRI. Registration of histopathology images from patients who had radical prostatectomy to pre-operative MRI allows such mapping of ground truth cancer labels onto MRI. However, traditional MRI-histopathology registration approaches are computationally expensive and require careful choices of the cost function and registration hyperparameters. This paper presents ProsRegNet, a deep learning-based pipeline to accelerate and simplify MRI-histopathology image registration in prostate cancer. Our pipeline consists of image preprocessing, estimation of affine and deformable transformations by deep neural networks, and mapping cancer labels from histopathology images onto MRI using estimated transformations. We trained our neural network using MR and histopathology images of 99 patients from our internal cohort (Cohort 1) and evaluated its performance using 53 patients from three different cohorts (an additional 12 from Cohort 1 and 41 from two public cohorts). Results show that our deep learning pipeline has achieved more accurate registration results and is at least 20 times faster than a state-of-the-art registration algorithm. This important advance will provide radiologists with highly accurate prostate MRI answer keys, thereby facilitating improvements in the detection of prostate cancer on MRI. Our code is freely available at https://github.com/pimed//ProsRegNet.

7.
Am J Surg Pathol ; 45(5): 638-652, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33481389

RESUMO

Uterine sarcomas with variable CD34 and S100 expression represent an emerging class of tumor in the female genital tract which commonly presents in the endocervix of premenopausal women. Initial molecular characterization identified NTRK1 and NTRK3 gene fusions as oncogenic drivers in these tumors; however, the repertoire of genetic alterations is likely more diverse given the recent discovery of PDGFB and RET gene fusions in similarly described tumors. Importantly, these fusion events lead to the aberrant activation of kinases that are potentially therapeutically targetable; therefore, recognizing this class of tumor becomes critical for initiating the molecular testing required for an accurate diagnosis and identification of clinically actionable fusions. Here, we report our institutional experience with 12 cases of uterine spindle cell sarcomas harboring kinase-related fusions. Patients ranged from 21 to 80 years old (median, 38 y) and presented either asymptomatically or with pelvic pain and/or uterine bleeding. Eleven (92%; 11/12) tumors were localized to the cervix and 1 (8%; 1/12) tumor was localized in the anterior fundus of the uterine corpus. Tumors ranged in size from 1.5 to 15.0 cm (median, 6.0 cm) and were histologically characterized by a moderately cellular, infiltrative proliferation of spindle cells with features of benign gland entrapment, stromal collagen deposition, perivascular hyalinization, occasionally myxoid stroma, a lymphocytic infiltrate, occasional nuclear pseudoinclusions, and a pseudophyllodes architecture. RNA-sequencing identified NTRK1 (8/12), NTRK3 (1/12), and PDGFB (2/12) gene fusions, which have been previously implicated in this tumor class, as well as a novel FGFR1-TACC1 (1/12) fusion. All tumors in this cohort showed coexpression of CD34 and S100 by immunohistochemistry except for those tumors with PDGFB fusions which showed solely CD34 expression. Of the 10 surgically resected tumors with follow-up, outcomes best correlated with the stage of disease. One of 4 patients with stage IA tumors (1/4) had recurrences, half of the stage IB (2/4) tumors had recurrences and all of the stage IIB tumors (2/2) had recurrences and died of disease. Future studies are still required to better understand the spectrum of genetic alterations as well as evaluate the efficacy of targeted kinase inhibitors in this class of tumor.

8.
Diagn Pathol ; 15(1): 122, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32988392

RESUMO

BACKGROUND: Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of extranodal non-Hodgkin lymphomas for which diagnosis can be challenging given the potential for overlap with inflammatory dermatoses. Current diagnostic criteria for CTCL incorporate clinical and histopathologic findings as well as results of T-cell receptor (TCR) gene sequencing. Molecular interrogation of TCR genes, TRG and TRB, has proven to be a critical tool for confirming diagnoses of CTCL and for disease tracking after initiation of therapy or after stem cell transplant. Methods for confirming a diagnosis of lymphoma in the absence of TCR gene clonality are lacking. We present two patients with CTCL with pathogenic somatic mutations in the absence of TRG and TRB clonality. CASE PRESENTATIONS: Case 1: A 38-year-old male had a 19-year history of a diffuse skin rash with papulosquamous, granulomatous, and verrucous features and progressive ulcerated plaques and tumors demonstrating an atypical CD4+ T-cell infiltrate with expression of cytotoxic markers CD56, TIA-1, granzyme, and perforin on histopathology. No definitive evidence for T-cell clonality was detected by conventional PCR of 6 biopsies or by next-generation sequencing (NGS) of 14 biopsies. Somatic mutational profiling of a skin biopsy revealed pathogenic mutations in PIKC3D and TERT promoter hotspots, confirming the presence of a clonal process. Case 2: A 69-year-old male with a 13-year history of progressive, diffuse hypertrophic and eroded plaques showed an atypical CD4+ T-cell infiltrate with subset expression of TIA-1 and granzyme on histopathology. No TCR clonality was detected by TCR-NGS of 6 biopsies. Somatic mutational profiling of a skin biopsy detected a pathogenic mutation in TP53, confirming the presence of a clonal process. CONCLUSIONS: These cases highlight how detection of pathogenic somatic mutations can confirm a diagnosis of lymphoma in a clinically and histopathologically suspicious cutaneous lymphoid proliferation without detectable TCR clonality.

9.
Hum Pathol ; 106: 62-73, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32971128

RESUMO

Inflammatory myofibroblastic tumors (IMTs) of the uterus are often associated with pregnancy and are delivered with the placenta. We describe the clinical, pathologic, and molecular findings in nine cases of placenta-associated IMT (PaIMT). All the lesions were incidentally discovered at delivery or on placental pathological examination. The maternal age ranged from 21 to 41 (mean = 30.6) years. Eight patients had high-risk pregnancies, and when known, all patients were multigravida. Macroscopically, eight tumors were well defined, ranging in size from 2 to 6 cm present at the maternal surface of the placenta (n = 3) and membranes (n = 4) or separately delivered with the placenta (n = 2). All nine lesions revealed classical IMT morphology with spindle cells associated with a lymphoplasmacytic infiltrate and thin elongated vessels. Five showed decidualization, and five showed coagulative necrosis. All tumors expressed CD10. Of the seven tumors that were anaplastic lymphoma kinase (ALK) positive, six were confirmed to have an ALK rearrangement by fluorescence in situ hybridization (FISH), whereas one failed FISH testing. Fusions included TIMP3-ALK (n = 3), THBS1-ALK (n = 2), and a novel SYN3-ALK fusion (n = 1). Clinical follow-up was available in three patients, with no recurrence reported. There appears to be an increased frequency of uterine IMTs in pregnancy and associated with the placenta. No PaIMT has behaved aggressively, although follow-up has been quite limited. This may speak to a specific behavior of these tumors when associated with pregnancy.

10.
J Thorac Dis ; 12(5): 2161-2171, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32642121

RESUMO

Background: Asian and Caucasian patients with lung cancer have been compared in several database studies, with conflicting findings regarding survival. However, these studies did not include proportion of ground-glass opacity or mutational status in their analyses. Asian patients commonly develop sub-solid lung adenocarcinomas that harbor EGFR mutations, which have a better prognosis. We hypothesized that among patients undergoing surgery for sub-solid lung adenocarcinomas, Asian patients have better survival compared to Caucasian patients. Methods: We identified Asian and Caucasian patients who underwent surgical resection for a sub-solid lung adenocarcinoma from 2002 to 2015 at our institution. Sub-solid was defined as ≥10% ground-glass opacity on preoperative CT scan or ≥10% lepidic component on surgical pathology. Time-to-event multivariable analysis was performed to determine which characteristics were associated with recurrence and survival. Results: Two hundred twenty-four patients were included with median follow up 48 months. Asian patients were more likely to be never smokers (76.3% vs. 29.0%, P<0.01) and have an EGFR mutation (69.4% vs. 25.6% of those tested, P<0.01), while Caucasian patients were more likely to have a KRAS mutation (23.5% vs. 4.9% of those tested, P<0.01). There was a trend towards Asian patients having a higher proportion of ground-glass opacity (38.8% vs. 30.5%, P=0.11). Time-to-event multivariable analysis showed that higher proportion of ground-glass opacity was significantly associated with better recurrence-free survival (HR 0.76 per 20% increase, P=0.02). However, mutational status and race did not have a significant impact on recurrence-free or overall survival. Conclusions: Asian and Caucasian patients with sub-solid lung adenocarcinoma have different tumor biology, but recurrence-free and overall survival after surgical resection is similar.

11.
Pract Lab Med ; 21: e00164, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32490123

RESUMO

Objectives: To identify oncogenic driver mutations in congenital mesoblastic nephroma (CMN) cases lacking ETV6-NTRK3 fusion and discuss their diagnostic value. Design: The institutional pathology database was queried for cases with a morphologic diagnosis of CMN. Cases positive for ETV6 rearrangement or with unavailable blocks were excluded. Four cases met the inclusion criteria and were sequenced by next-generation sequencing. Three additional cases were contributed by our collaborators. Results: Three of four internal cases harbor an EGFR kinase domain duplication (KDD), which is known to be oncogenic yet exceedingly rare in other histologies. All three outside cases are positive for EGFR alterations, including KDD in two and a splicing site mutation in one. The splicing site mutation is predicted to be EGFR activating. One of the outside cases was a retroperitoneal mass without a clear site of origin. A diagnosis of CMN is suggested based on exclusion of differential diagnoses by expert consultation and detection of EGFR KDD. Conclusions: EGFR activation, predominantly via EGFR KDD, is a common recurrent genetic alteration in CMN lacking NTRK3 fusions. CMN can be molecularly classified into NTRK3 fusion type, EGFR activation type and others.

12.
Med Phys ; 47(9): 4177-4188, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32564359

RESUMO

PURPOSE: Magnetic resonance imaging (MRI) has great potential to improve prostate cancer diagnosis; however, subtle differences between cancer and confounding conditions render prostate MRI interpretation challenging. The tissue collected from patients who undergo radical prostatectomy provides a unique opportunity to correlate histopathology images of the prostate with preoperative MRI to accurately map the extent of cancer from histopathology images onto MRI. We seek to develop an open-source, easy-to-use platform to align presurgical MRI and histopathology images of resected prostates in patients who underwent radical prostatectomy to create accurate cancer labels on MRI. METHODS: Here, we introduce RAdiology Pathology Spatial Open-Source multi-Dimensional Integration (RAPSODI), the first open-source framework for the registration of radiology and pathology images. RAPSODI relies on three steps. First, it creates a three-dimensional (3D) reconstruction of the histopathology specimen as a digital representation of the tissue before gross sectioning. Second, RAPSODI registers corresponding histopathology and MRI slices. Third, the optimized transforms are applied to the cancer regions outlined on the histopathology images to project those labels onto the preoperative MRI. RESULTS: We tested RAPSODI in a phantom study where we simulated various conditions, for example, tissue shrinkage during fixation. Our experiments showed that RAPSODI can reliably correct multiple artifacts. We also evaluated RAPSODI in 157 patients from three institutions that underwent radical prostatectomy and have very different pathology processing and scanning. RAPSODI was evaluated in 907 corresponding histpathology-MRI slices and achieved a Dice coefficient of 0.97 ± 0.01 for the prostate, a Hausdorff distance of 1.99 ± 0.70 mm for the prostate boundary, a urethra deviation of 3.09 ± 1.45 mm, and a landmark deviation of 2.80 ± 0.59 mm between registered histopathology images and MRI. CONCLUSION: Our robust framework successfully mapped the extent of cancer from histopathology slices onto MRI providing labels from training machine learning methods to detect cancer on MRI.

13.
J Cutan Pathol ; 47(9): 860-864, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32358805

RESUMO

Primary cutaneous signet-ring cell/histiocytoid carcinoma of the eyelid is a rare and aggressive neoplasm. Fewer than 50 cases have been reported in the literature, and the genetic driving mutations are unknown. Herein, we present a case of this rare disease along with the results of molecular profiling via targeted next-generation sequencing. The patient is an 85-year-old man who presented with left eyelid swelling initially thought to be a chalazion. After no response to incision and drainage and antibiotics, an incisional biopsy was performed. Histopathologic sections revealed a proliferation of cells with signet-ring and histiocytoid morphology arranged singly and in cords infiltrating the dermis, subcutaneous tissue, and muscle. The lesional cells strongly expressed cytoplasmic cytokeratin 7 and nuclear androgen receptor. Next-generation sequencing revealed a CDH1 mutation, which is known to confer signet-ring morphology in other carcinomas. Pathogenic mutations in NTRK3, CDKN1B, and PIK3CA were also detected. To our knowledge, this is the first documented genetic analysis of this rare disease with findings that offer insights into disease pathogenesis and potential therapeutic targets.

14.
Am J Clin Pathol ; 154(3): 369-380, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32445471

RESUMO

OBJECTIVES: The possibility of a so-called primary lymph node neuroendocrine carcinoma has been described in the literature. Here we evaluate cases fitting such a diagnosis and find that the cases demonstrate a convincing and pervasive pattern consistent with metastatic Merkel cell carcinoma. METHODS: Six cases of primary lymph node Merkel cell carcinoma and one case of metastatic neuroendocrine carcinoma at a bony site, all with unknown primary, were sequenced using a combination of whole-exome and targeted panel methods. Sequencing results were analyzed for the presence of an ultraviolet (UV) mutational signature or off-target detection of Merkel cell polyomavirus (MCPyV). RESULTS: Four of six primary lymph node cases were positive for a UV mutational signature, with the remaining two cases positive for off-target alignment of MCPyV. One case of neuroendocrine carcinoma occurring at a bony site was also positive for a UV mutational signature. CONCLUSIONS: We find no evidence to corroborate the existence of so-called primary Merkel cell carcinoma of lymph node.


Assuntos
Carcinoma de Célula de Merkel/patologia , Carcinoma Neuroendócrino/patologia , Linfonodos/patologia , Metástase Linfática/patologia , Neoplasias Cutâneas/patologia , Carcinoma de Célula de Merkel/virologia , Carcinoma Neuroendócrino/virologia , Humanos , Linfonodos/virologia , Poliomavírus das Células de Merkel , Neoplasias Cutâneas/virologia , Infecções Tumorais por Vírus/patologia , Infecções Tumorais por Vírus/virologia
15.
Am J Surg Pathol ; 44(7): 970-981, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32271187

RESUMO

As inflammatory myofibroblastic tumors (IMTs) have become more widely recognized in the female genital tract, an intriguing subset of uterine tumors associated with pregnancy has emerged. Whether uterine IMTs occurring in the setting of pregnancy are clinically or biologically distinct from other uterine IMTs is unknown. Furthermore, little is known about the perinatal factors that may influence the development of these tumors. Here, we report the largest case series of 8 pregnancy-associated IMTs. All pregnancy-associated IMTs in this series occurred in association with pregnancy complications, including abnormal implantation (n=1), gestational diabetes (n=2), preeclampsia and/or HELLP syndrome (n=2), antiphospholipid syndrome (n=1), premature rupture of membranes (n=1), and hepatitis B (n=1). Notably, all IMTs were expelled at the time of delivery or immediately postpartum and were either adherent to the placenta or presented as separate, detached tissue. Tumors ranged from 2.0 to 6.0 cm (median, 3.9 cm), were well-circumscribed and showed classic histologic features of IMTs, including myxoid stroma and a lymphoplasmacytic infiltrate. Seven of 8 cases were positive by ALK immunohistochemistry and confirmed to have an ALK gene rearrangement by fluorescent in situ hybridization and RNA sequencing. The ALK-rearranged IMTs were found to be particularly enriched for TIMP3-ALK (n=5) and THBS1-ALK (n=2) fusions. The single case that was negative for an ALK rearrangement exhibited the classic morphology of an IMT. None of the 4 cases with available clinical follow-up recurred. The clinicopathologic features of pregnancy-associated IMTs in this series in conjunction with those reported in the literature suggests that these may be transient tumors that develop during pregnancy and shed at parturition; they appear to have a relatively indolent clinical course and favorable outcome, although studies with a longer duration of follow-up are still required.


Assuntos
Quinase do Linfoma Anaplásico/genética , Neoplasias de Tecido Muscular/diagnóstico , Proteínas de Fusão Oncogênica/genética , Complicações Neoplásicas na Gravidez/diagnóstico , Trombospondina 1/genética , Inibidor Tecidual de Metaloproteinase-3/genética , Neoplasias Uterinas/diagnóstico , Adulto , Quinase do Linfoma Anaplásico/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias de Tecido Muscular/genética , Neoplasias de Tecido Muscular/patologia , Fusão Oncogênica , Proteínas de Fusão Oncogênica/metabolismo , Gravidez , Complicações Neoplásicas na Gravidez/genética , Complicações Neoplásicas na Gravidez/patologia , Análise de Sequência de RNA , Trombospondina 1/metabolismo , Inibidor Tecidual de Metaloproteinase-3/metabolismo , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia
16.
Nature ; 580(7802): 245-251, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32269342

RESUMO

Radiologic screening of high-risk adults reduces lung-cancer-related mortality1,2; however, a small minority of eligible individuals undergo such screening in the United States3,4. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)5, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.


Assuntos
DNA Tumoral Circulante/análise , DNA Tumoral Circulante/genética , Detecção Precoce de Câncer/métodos , Genoma Humano/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Mutação , Estudos de Coortes , Feminino , Hematopoese/genética , Humanos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
18.
Proc Natl Acad Sci U S A ; 117(4): 2032-2042, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31932422

RESUMO

Resistance to androgen deprivation therapy, or castration-resistant prostate cancer (CRPC), is often accompanied by metastasis and is currently the ultimate cause of prostate cancer-associated deaths in men. Recently, secondary hormonal therapies have led to an increase of neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. Here, we identify that high levels of cell surface receptor Trop2 are predictive of recurrence of localized prostate cancer. Moreover, Trop2 is significantly elevated in CRPC and NEPC, drives prostate cancer growth, and induces neuroendocrine phenotype. Overexpression of Trop2 induces tumor growth and metastasis while loss of Trop2 suppresses these abilities in vivo. Trop2-driven NEPC displays a significant up-regulation of PARP1, and PARP inhibitors significantly delay tumor growth and metastatic colonization and reverse neuroendocrine features in Trop2-driven NEPC. Our findings establish Trop2 as a driver and therapeutic target for metastatic prostate cancer with neuroendocrine phenotype and suggest that high Trop2 levels could identify cancers that are sensitive to Trop2-targeting therapies and PARP1 inhibition.


Assuntos
Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/secundário , Carcinoma Neuroendócrino/patologia , Moléculas de Adesão Celular/metabolismo , Regulação Neoplásica da Expressão Gênica , Poli(ADP-Ribose) Polimerase-1/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Animais , Antígenos de Neoplasias/genética , Apoptose , Biomarcadores Tumorais/genética , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/metabolismo , Moléculas de Adesão Celular/genética , Movimento Celular , Proliferação de Células , Seguimentos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica , Fenótipo , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Pac Symp Biocomput ; 25: 31-42, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31797584

RESUMO

Successful implementation of precision oncology requires both the deployment of nucleic acid sequencing panels to identify clinically actionable biomarkers, and the efficient screening of patient biomarker eligibility to on-going clinical trials and therapies. This process is typically performed manually by biocurators, geneticists, pathologists, and oncologists; however, this is a time-intensive, and inconsistent process amongst healthcare providers. We present the development of a feature matching algorithmic pipeline that identifies patients who meet eligibility criteria of precision medicine clinical trials via genetic biomarkers and apply it to patients undergoing treatment at the Stanford Cancer Center. This study demonstrates, through our patient eligibility screening algorithm that leverages clinical sequencing derived biomarkers with precision medicine clinical trials, the successful use of an automated algorithmic pipeline as a feasible, accurate and effective alternative to the traditional manual clinical trial curation.

20.
Cancer Cytopathol ; 128(1): 43-56, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31751001

RESUMO

BACKGROUND: Liquid biopsy using cell-free DNA (cfDNA) presents new opportunities for solid tumor genotyping. While studies have demonstrated the utility of cfDNA from plasma, cfDNA from other body fluids remains underexplored. METHODS: We evaluated the molecular features and clinicopathologic correlates of cfDNA from serous body cavity fluids by performing hybrid capture-based next-generation sequencing (NGS) on cfDNA isolated from residual effusion supernatants. Twenty-one serous effusions from pleural (n = 15), peritoneal (n = 5), and pericardial (n = 1) cavity were analyzed. RESULTS: The supernatants provided a median cfDNA concentration of 10.3 ng/µL. Notably, all effusions were sequenced successfully to a median depth >1000×, revealing a broad range of genetic alterations including single nucleotide variants, small insertions and deletions, amplifications, and fusions. Specifically, pathogenic alterations were identified in all malignant fluids (13/13), all fluids suspicious for malignancy (2/2), and 1 benign fluid (1/6) from a patient with metastatic cancer. To validate our findings, we examined matching results from 11 patients who underwent additional testing using formalin-fixed, paraffin-embedded (FFPE) specimens. In 8 patients, the paired results between FFPE and supernatant testing were concordant, whereas in the remaining 3 patients, supernatant analysis identified additional variants likely associated with resistance to targeted therapies. Additional comparison between FFPE and supernatant testing showed no difference in DNA concentration (P = .5), depth of coverage (P = .6), or allele frequency of pathogenic mutations (P = .7). CONCLUSION: cfDNA isolated from serous body cavity fluids represents a promising source of genomic input for targeted NGS.


Assuntos
Biomarcadores Tumorais/análise , Líquidos Corporais/química , DNA Tumoral Circulante/análise , Técnicas de Genotipagem/métodos , Neoplasias/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Biópsia Líquida/métodos , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/patologia
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