scholarly journals Metastatic adrenocortical carcinoma displays higher mutation rate and tumor heterogeneity than primary tumors

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Sudheer Kumar Gara ◽  
Justin Lack ◽  
Lisa Zhang ◽  
Emerson Harris ◽  
Margaret Cam ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Adrenocortical Carcinoma ◽  
Tumor Heterogeneity ◽  
Primary Tumors

scholarly journals Metastatic heterogeneity of the consensus molecular subtypes of colorectal cancer

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Peter W. Eide ◽  
Seyed H. Moosavi ◽  
Ina A. Eilertsen ◽  
Tuva H. Brunsell ◽  
Jonas Langerud ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Principal Components ◽  
Prognostic Value ◽  
Tumor Heterogeneity ◽  
Molecular Subtypes ◽  
R Package ◽  
Data Set ◽  
Primary Tumors ◽  
External Data

AbstractGene expression-based subtypes of colorectal cancer have clinical relevance, but the representativeness of primary tumors and the consensus molecular subtypes (CMS) for metastatic cancers is not well known. We investigated the metastatic heterogeneity of CMS. The best approach to subtype translation was delineated by comparisons of transcriptomic profiles from 317 primary tumors and 295 liver metastases, including multi-metastatic samples from 45 patients and 14 primary-metastasis sets. Associations were validated in an external data set (n = 618). Projection of metastases onto principal components of primary tumors showed that metastases were depleted of CMS1-immune/CMS3-metabolic signals, enriched for CMS4-mesenchymal/stromal signals, and heavily influenced by the microenvironment. The tailored CMS classifier (available in an updated version of the R package CMScaller) therefore implemented an approach to regress out the liver tissue background. The majority of classified metastases were either CMS2 or CMS4. Nonetheless, subtype switching and inter-metastatic CMS heterogeneity were frequent and increased with sampling intensity. Poor-prognostic value of CMS1/3 metastases was consistent in the context of intra-patient tumor heterogeneity.

scholarly journals Genetic Alterations among Korean Melanoma Patients Showing Tumor Heterogeneity: A Comparison between Primary Tumors and Corresponding Metastatic Lesions

2018 ◽  
Vol 50 (4) ◽  
pp. 1378-1387 ◽  
Author(s):  
Si-Hyung Lee ◽  
Jee Eun Kim ◽  
Hong Sun Jang ◽  
Kyu Hyun Park ◽  
Byung Ho Oh ◽  
...  
Keyword(s):  
Tumor Heterogeneity ◽  
Genetic Alterations ◽  
Primary Tumors ◽  
Metastatic Lesions ◽  
Melanoma Patients

Adrenocortical Carcinoma: Clinical, Morphologic, and Molecular Characterization

2002 ◽  
Vol 20 (4) ◽  
pp. 941-950 ◽  
Author(s):  
Alexander Stojadinovic ◽  
Ronald A. Ghossein ◽  
Axel Hoos ◽  
Aviram Nissan ◽  
David Marshall ◽  
...  
Keyword(s):  
Adrenocortical Carcinoma ◽  
Cox Regression ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Prognostic Significance ◽  
Phenotypic Expression ◽  
Patient Specific ◽  
Rank Test ◽  
Primary Tumors ◽  
Adrenal Tissue

PURPOSE: To define multimolecular phenotypes of adrenocortical carcinoma (ACC) and to correlate outcome with morphologic and molecular parameters. PATIENTS AND METHODS: Clinical data were analyzed for 124 patients, histopathologic slides for 67 primary tumors, and tissue specimens for 74 patients (38 primary and 36 metastatic tumors) with ACC and for 38 normal adrenal tissue samples. Molecular expression profiles were investigated by immunohistochemistry. The prognostic significance of 12 gross and histologic parameters in 67 primary ACCs was evaluated. Morphologic and protein expression patterns were correlated with disease-specific survival (DSS). Univariate influence of prognostic factors on DSS was analyzed by log-rank test and multivariate analysis by Cox regression. RESULTS: The median follow-up period was 4.7 years. Significant predictors of DSS included distant metastasis at time of initial presentation; venous, capsular, and adjacent organ invasion; tumor necrosis, mitotic rate, atypical mitosis, and mdm-2 overexpression. Five-year DSS by number (one to six) of adverse histologic parameters was as follows: one to two, 84%; three to four, 37%; more than four, 9% (P = .005).The phenotype Ki-67(−)p53(−)mdm-2(+)cyclinD1(−)Bcl-2(−)p21(−)p27(+) was observed in 83% of normal and 3% of malignant adrenal tissue (P = .01). Molecular phenotypic expression was more heterogeneous in malignant than in normal (10 v five phenotypes) adrenal tissue. CONCLUSION: Meticulous morphologic evaluation, mitotic count, and tumor stage are essential in determining prognosis for patients with ACC. Multimolecular phenotyping demonstrates that the molecular complexity and heterogeneity of these neoplasms are such that targeted therapy needs to be patient specific.

scholarly journals Heterogenous Profiles Between Matched Primary Tumors and Brain Metastases Reveal Tumor Evolution

2021 ◽  
Author(s):  
Yanming Chen ◽  
Xiaoxiao Dai ◽  
Ji Wang ◽  
Chuming Tao ◽  
Ye Wang ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Tumor Heterogeneity ◽  
Spatial Diversity ◽  
Immune Checkpoints ◽  
Tumor Evolution ◽  
Single Patient ◽  
Molecular Phenotype ◽  
Primary Tumors ◽  
Patient Level ◽  
Temporal And Spatial

Abstract Background: Brain metastases (BMs) are the most common central nervous system (CNS) malignant tumors, with rapid disease progression and extremely poor prognosis. The heterogeneity between primary tumors and BMs leads to the divergent efficacy of the adjuvant therapy response to primary tumors and BMs. However, the extent of heterogeneity between primary tumors and BMs, and the evolutionary process remains little known. Methods: To deeply insight the extent of inter-tumor heterogeneity at single-patient level and the process of these evolutions, we retrospectively analyzed a total of 26 tumor samples from 11 patients with matched primary tumors and BMs. One patient underwent four times brain metastatic lesion surgery with diverse locations and one operation for the primary lesion. The genomic and immune heterogeneity between primary tumors and BMs was evaluated by utilizing the whole-exome sequencing (WESeq) and immunohistochemical analysis.Results: In addition to inheriting genomic phenotype and molecular phenotype from the primary tumors, massive unique genomic phenotype and molecular phenotype were also observed in BMs, which revealed unimaginable complexity of tumor evolution and extensive heterogeneity among lesions at single-patient level. Our study also verified that the expression level of immune checkpoints-related molecule Programmed Death-Ligand 1 (PD-L1) (P = 0.0013) and the density of tumor-infiltrating lymphocytes (TILs) (P = 0.0248) in BMs were significantly lower than that in paired primary tumors. Additionally, tumor microvascular density (MVD) and tumor invasiveness were also differed between primary tumors and paired BMs, indicating that temporal and spatial diversity profoundly contributes to the evolution of BMs heterogeneity.Conclusion: We verified the significance of temporal and spatial factors to the evolution of tumor heterogeneity by multi-dimensional analysis of matched primary tumors and BMs, which also provided novel insight for formulating individualized treatment strategies of BMs.

scholarly journals Features of tumor heterogeneity in regional metastasis of breast cancer

2021 ◽  
Vol 102 (5) ◽  
pp. 716-725
Author(s):  
K K Konyshev ◽  
S V Sazonov
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Primary Tumor ◽  
Tumor Heterogeneity ◽  
Tumor Tissue ◽  
Clonal Evolution ◽  
Clinical Manifestations ◽  
Progesterone Receptors ◽  
Primary Tumors ◽  
Regional Metastases

The review looked at the issues of tumor heterogeneity in breast cancer. Tumor heterogeneity is classified according to the main feature demonstrating regional differences within a tumor (for example, heterogeneity of clinical manifestations, histological heterogeneity, heterogeneity of protein expression, etc.) and by tumor regions (differences between primary tumors and metastases, differences between cell clones within a single tumor node, etc.). Temporal heterogeneity is also distinguished, which manifests itself in the clonal evolution of tumor cells. The review covers the heterogeneity in the expression of four biomarkers from the gold standard for immunohistochemical staining of breast cancer: estrogen receptors, progesterone receptors, Her2/neu and Ki67 in primary tumor tissue and regional metastases. According to various studies, discordance in estrogen receptor status of primary tumor cells and metastases was observed with a frequency of 4 to 62%, progesterone receptors from 12 to 54%, Her2/neu from 0 to 24%, Ki67 from 4 to 39%. The results of studies of changes in the expression levels of individual markers in breast cancer metastases, as well as the heterogeneity of surrogate subtypes of tumor tissue in metastasis, are briefly described. Possible reasons for heterogeneity in the expression of key prognostic and predictive markers by primary tumor and metastatic cells, such as artificial factors at the preanalytic and analytic stages of the study, polyclonality of the primary tumor before metastasis, clonal evolution of tumor cells during metastasis, selection of tumor clones under the therapy are highlighted.

scholarly journals De novo transcriptomic subtyping of colorectal cancer liver metastases in the context of tumor heterogeneity

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Seyed H. Moosavi ◽  
Peter W. Eide ◽  
Ina A. Eilertsen ◽  
Tuva H. Brunsell ◽  
Kaja C. G. Berg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Liver Metastases ◽  
Expression Profiling ◽  
Tumor Heterogeneity ◽  
Progenitor Cell ◽  
De Novo ◽  
Primary Tumors ◽  
Malignant Liver

Abstract Background Gene expression-based subtyping has the potential to form a new paradigm for stratified treatment of colorectal cancer. However, current frameworks are based on the transcriptomic profiles of primary tumors, and metastatic heterogeneity is a challenge. Here we aimed to develop a de novo metastasis-oriented framework. Methods In total, 829 transcriptomic profiles from patients with colorectal cancer were analyzed, including primary tumors, liver metastases, and non-malignant liver samples. High-resolution microarray gene expression profiling was performed of 283 liver metastases from 171 patients treated by hepatic resection, including multiregional and/or multi-metastatic samples from each of 47 patients. A single randomly selected liver metastasis sample from each patient was used for unsupervised subtype discovery by nonnegative matrix factorization, and a random forest prediction model was trained to classify multi-metastatic samples, as well as liver metastases from two independent series of 308 additional patients. Results Initial comparisons with non-malignant liver samples and primary colorectal tumors showed a highly variable degree of influence from the liver microenvironment in metastases, which contributed to inter-metastatic transcriptomic heterogeneity, but did not define subtype distinctions. The de novo liver metastasis subtype (LMS) framework recapitulated the main distinction between epithelial-like and mesenchymal-like tumors, with a strong immune and stromal component only in the latter. We also identified biologically distinct epithelial-like subtypes originating from different progenitor cell types. LMS1 metastases had several transcriptomic features of cancer aggressiveness, including secretory progenitor cell origin, oncogenic addictions, and microsatellite instability in a microsatellite stable background, as well as frequent RAS/TP53 co-mutations. The poor-prognostic association of LMS1 metastases was independent of mutation status, clinicopathological variables, and current subtyping frameworks (consensus molecular subtypes and colorectal cancer intrinsic subtypes). LMS1 was also the least heterogeneous subtype in comparisons of multiple metastases per patient, and tumor heterogeneity did not confound the prognostic value of LMS1. Conclusions We report the first large study of multi-metastatic gene expression profiling of colorectal cancer. The new metastasis-oriented subtyping framework showed potential for clinically relevant transcriptomic classification in the context of metastatic heterogeneity, and an LMS1 mini-classifier was constructed to facilitate prognostic stratification and further clinical testing.

Tumor heterogeneity and drug resistance.

1986 ◽  
Vol 4 (2) ◽  
pp. 244-257 ◽  
Author(s):  
D L Dexter ◽  
J T Leith
Keyword(s):  
Drug Resistance ◽  
Tumor Heterogeneity ◽  
Metastatic Potential ◽  
Primary Tumors ◽  
Multiple Tumor ◽  
Underlying Basis ◽  
Human Solid Tumors ◽  
History Of ◽  
Relationship Of ◽  
The Impact

Drug resistance has long been identified as a major reason for therapy failure in cancer patients. Concurrently, work from many laboratories in the past 10 years has established tumor heterogeneity as a phenomenon of critical importance in the natural history of individual neoplasms. The two most sinister aspects of intraneoplastic diversity in human solid tumors are the genesis of clones with metastatic potential, and the existence of drug-resistant variants in primary cancers and their metastases. Thus, recent investigations on drug resistance and on tumor heterogeneity have converged to focus attention on the clonal organization of primary tumors and their metastases as the underlying basis for anticancer drug resistance. This review examines the degree of heterogeneity observed within tumors and the relationship of this diversity to resistance that might be anticipated for any given agent. A question critical to our discussion is "How many subpopulations are there?" The impact of multiple tumor clones on therapy is next discussed in relationship to normal tissue tolerance, the barrier clinicians face regardless of the specific agent used in treatment. Finally, laboratory and clinical approaches are presented for addressing a drug resistance problem that is seemingly overwhelming because of its complex biological roots.

scholarly journals Prognostic Parameters of Metastatic Adrenocortical Carcinoma

2007 ◽  
Vol 92 (1) ◽  
pp. 148-154 ◽  
Author(s):  
Guillaume Assié ◽  
Guillemette Antoni ◽  
Frédérique Tissier ◽  
Bernard Caillou ◽  
Gwenaelle Abiven ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Adrenocortical Carcinoma ◽  
Validation Cohort ◽  
Univariate Analysis ◽  
Mitotic Rate ◽  
Prognostic Parameters ◽  
High Power Field ◽  
Primary Tumors ◽  
Kaplan Meier ◽  
Two Parameters

Abstract Context: Prognostic parameters of metastatic adrenocortical carcinoma (ACC) are poorly characterized. Objective: The objective of the study was to describe the clinical presentation of metastatic ACC and determine prognostic factors for survival. Design: This was a retrospective cohort study (1988–2004). Setting: The study was conducted in an institutional practice. Patients: Participants included 124 consecutive patients with metastatic ACC, 70 from Gustave-Roussy Institute (main cohort) and 54 patients from the Cochin Hospital (validation cohort). Clinical data concerning all patients, histopathologic slides of primary tumors (44 in the main cohort and 40 in the validation cohort), and molecular biology data on 15 primary tumors (main cohort) were analyzed. Intervention: There was no intervention. Main Outcome: The main outcome was the specific survival after discovery of the first metastasis (Kaplan-Meier method). This included univariate analysis on the main cohort, confirmed on the validation cohort and then analyzed in a multivariate analysis. Results: In the main cohort, overall median survival was 20 months. In univariate analysis, the presence of hepatic and bone metastases, the number of metastatic lesions and the number of tumoral organs at the time of the first metastasis, a high mitotic rate (>20 per 50 high-power field), and atypical mitoses in the primary tumor predicted survival (P = 0.05, 0.003, 0.046, 0.001, 0.01, and < 0.001, respectively). The number of tumoral organs and a high mitotic rate were confirmed on the validation cohort (P = 0.009 and 0.03, respectively). These two parameters were confirmed in multivariate analysis (P = 0.0058 and 0.049). Conclusion: Metastatic ACC is a heterogeneous disease with poor outcome. The combination of the number of tumoral organs at the time of the first metastasis and the mitotic rate can predict different outcomes.

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