ColotypeR: A tool to classify colon cancers by consensus molecular subtype and subtype-specific risk of recurrence.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 632-632
Author(s):  
Steven Allen Buechler ◽  
Sunil S. Badve ◽  
Yesim Gokmen-Polar ◽  
Emily Herring ◽  
Katelyn Ludwig ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Prognostic Significance ◽  
Response To Treatment ◽  
Training Set ◽  
Risk Of Recurrence ◽  
Molecular Features ◽  
Colon Cancers ◽  
Specific Risk

632 Background: Colon cancer is highly heterogeneous in prognosis and response to treatment. The consensus molecular subtypes (CMS1-4, and mixed) partition colon cancers into distinct groups. CMS4 tumors, a mesenchymal subtype, have the worst prognosis and poor response to standard chemotherapies. There is a critical need for accurate molecular subtyping, and subtype-specific management. Methods: Affymetrix microarrays colon cancer datasets (N = 813; GSE39582, GSE14333) were partitioned into training (AT; N = 370) and validation sets (AV; N = 443) balanced for clinical traits. A novel multistate gene methodology was used to predict CMS, and prognosticate subtype-specific relapse-free survival (RFS) in the training set. Accuracy of CMS prediction and prognostic significance was validated in the AV and TCGA colon cancer (COAD; N = 458) sets. Results: In the training set, a 20-gene panel (ColotypeR-CMS) predicts CMS subtype. Mean accuracy for CMS1-4 prediction was 0.87 in AV and 0.81 in COAD. In AV, 5-year RFS is 0.52 (95%CI 0.43 – 0.63) in the predicted CMS4, and 0.70 (95%CI 0.65 – 0.77) in the non-CMS4 samples. The risk of relapse for non-CMS4 samples was refined by a genomic score (ColotypeR-Risk) computed using expression of 25 genes in the training set. ColotypeR-Risk was prognostic of RFS (p = 0.0004) among the AV non-CMS4 samples, and also prognostic (p = 0.0001) among the stage II non-CMS4 AV samples not treated with chemotherapy. The prognostic significance of ColotypeR-Risk among non-CMS4 samples is independent of tumor location (right or left) and CMS subtype (CMS1-3 or mixed). ColotypeR-Risk was also prognostic of RFS in non-CMS4 samples in COAD (p = 0.005). Conclusions: ColotypeR identifies the consensus molecular subtypes (CMS1, CMS2, CMS3, CMS4, or mixed), and assesses subtype-specific risk of recurrence of colon cancer. ColotypeR identifies prognostic risk and molecular features that could help guide the management of colon cancer patients.

scholarly journals Calretinin expression in molecular subtypes of invasive carcinoma breast

2020 ◽  
Vol 8 (4) ◽  
pp. 1498
Author(s):  
Suryagayathri Venugopal ◽  
Cicy P. J. ◽  
Deepa S. ◽  
Sankar Sundaram
Keyword(s):  
Breast Carcinoma ◽  
Molecular Mechanisms ◽  
Invasive Carcinoma ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Prognostic Significance ◽  
P Value ◽  
Carcinoma Breast ◽  
Low Level ◽  
High Level

Background: Breast cancer is a leading cause of cancer death  in women worldwide. Breast carcinoma is currently managed by assessing clinicopathological features. Elucidation of molecular mechanisms of pathogenesis of breast carcinoma  may lead to the development of new targeted therapies, particularly in triple negative cancers. Literature shows a few studies on the expression of calretinin  in breast carcinoma particularly in basal like type and its prognostic significance.  In this study, authors are trying  to assess the expression of  a new marker calretinin in different molecular subtypes of invasive carcinoma breast.Methods: This study was done in  107 cases of invasive carcinoma breast specimens received in  Department of Pathology, Government Medical college, Kottayam from December  2017 to May 2019.Results: Among the molecular subtypes, Basal like tumours showed 68.4% of cases with high level and 31.6% of cases with low level calretinin expression which is comparable with the study by Farrag et al. All the other molecular subgroups showed predominantly low level of calretinin expression.Conclusions: Different molecular subtypes of invasive carcinoma breast showed varied calretinin expression. High level calretinin expression was significantly associated with grade 3 (p value = 0.002), ER negativity (p = 0.004), PR negativity (p = 0.018)  and Basal like molecular subtype (p : <0.001). This suggests that calretinin might play a role in pathogenesis of basal like breast carcinomas.

scholarly journals Differential methylation of G-protein coupled receptor signaling genes in gastrointestinal neuroendocrine tumors

2021 ◽  
Author(s):  
Seyoun Byun ◽  
Kajsa E. Affolter ◽  
Angela K. Snow ◽  
Karen Curtin ◽  
Austin R. Cannon ◽  
...  
Keyword(s):  
Small Intestine ◽  
Neuroendocrine Tumors ◽  
Patient Survival ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Treatment Strategies ◽  
Molecular Features ◽  
Differentially Methylated Genes ◽  
Chromosomal Changes ◽  
Approved Drugs

Abstract Neuroendocrine tumors (NETs) of the small intestine undergo large chromosomal and methylation changes. The objective of this study was to identify methylation differences in NETs and consider how the differentially methylated genes may impact patient survival. Whole genome methylation and chromosomal copy number varation (CNV) of NETs from the small intestine and appendix was measured Tumors were divided into three molecular subtypes according to CNV results: chromosome 18 loss (18LOH), MultiCNV, and NoCNV. Comparison of 18LOH tumors with MultiCNV and NoCNV tumors identified 901 differentially methylated genes which are over represented with sevenG-protein coupled receptor (GPCR) pathways and the gene encoding somatostatin (SST), a clinical target for NETs. Patient survival based on low versus high methylation in all samples identified four significant genes (p-<0.05) OR2S2, SMILR, RNU6-653P and AC010543.1. Within the 18LOH molecular subtype tumors, survival differences were identifiedin high versus low methylation of 24 genes. The most significant is TRHR (p < 0.01), a GPCR with multiple FDA-approved drugs. By separating NETs into different molecular subtypes based on chromosomal changes, we find that multiple GPCRs and their ligands appear to be regulated through methylation and correlated with survival. Opportunities for better treatment strategies based on molecular features exist for NETs.

Tumor sidedness and intrinsic subtypes in patients with stage II/III colon cancer: Analysis of NSABP C-07 (NRG Oncology).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3514-3514 ◽  
Author(s):  
S. Rim Kim ◽  
Nan Song ◽  
Greg Yothers ◽  
Patrick Gavin ◽  
Carmen Joseph Allegra ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Therapy Response ◽  
Stage Ii ◽  
Intrinsic Subtypes ◽  
Treatment Benefit ◽  
Cancer Subtypes ◽  
Metastatic Setting

3514 Background: The predictive value of tumor sidedness in colorectal cancer is currently of interest especially in metastatic setting for anti-EGFR therapy response. We tested whether intrinsic molecular subtype classification predictive of treatment benefit in stage II/III colon cancer is an independent novel marker in association with tumor sidedness. Methods: All available cases included in the NSABP/NRG C-07 trial for which we had both gene expression data and anatomical data (n=1603) were used to determine the molecular subtypes using the following classifiers; the Colorectal Cancer Assigner (CRCA), the Colon Cancer Subtypes (CCS) and the Consensus Molecular Subtypes (CMS). Frequency of tumor sidedness in each subtype and recurrence-free survival were analyzed. Results: Intrinsic subtypes were differentially distributed in right- and left-colon tumors with the exception of the stem-like or CMS4 (mesenchymal) subtype (Table 1). Sidedness was not associated with prognosis (p=0.82, HR: 1.022 [CI: 0.851-1.227]) or prediction of patients with greater benefit from oxaliplatin when combined with 5-Fu+LV (interaction p=0.484). Conclusions: Although tumor sidedness is associated with distribution of intrinsic subtypes in stage II/III colon cancer, it is not predictive of survival benefit from oxaliplatin in C-07. Support: -180868, -180822, U24-CA196067; HI13C2162; PA DOH; Sanofi-Synthelabo Clinical trial information: NCT00004931. [Table: see text]

scholarly journals Differential methylation of G-protein coupled receptor signaling genes in gastrointestinal neuroendocrine tumors

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Seyoun Byun ◽  
Kajsa E. Affolter ◽  
Angela K. Snow ◽  
Karen Curtin ◽  
Austin R. Cannon ◽  
...  
Keyword(s):  
Small Intestine ◽  
G Protein ◽  
Neuroendocrine Tumors ◽  
Patient Survival ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
G Protein Coupled Receptor ◽  
Molecular Features ◽  
Differentially Methylated Genes ◽  
G Protein Coupled

AbstractNeuroendocrine tumors (NETs) of the small intestine undergo large chromosomal and methylation changes. The objective of this study was to identify methylation differences in NETs and consider how the differentially methylated genes may impact patient survival. Genome-wide methylation and chromosomal copy number variation (CNV) of NETs from the small intestine and appendix were measured. Tumors were divided into three molecular subtypes according to CNV results: chromosome 18 loss (18LOH), Multiple CNV, and No CNV. Comparison of 18LOH tumors with MultiCNV and NoCNV tumors identified 901 differentially methylated genes. Genes from the G-protein coupled receptor (GPCR) pathways are statistically overrepresented in the differentially methylated genes. One of the highlighted genes from the GPCR pathway is somatostatin (SST), a clinical target for NETs. Patient survival based on low versus high methylation in all samples identified four significant genes (p < 0.05) OR2S2, SMILR, RNU6-653P, and AC010543.1. Within the 18LOH molecular subtype tumors, survival differences were identified in high versus low methylation of 24 genes. The most significant is TRHR (p < 0.01), a GPCR with multiple FDA-approved drugs. By separating NETs into different molecular subtypes based on chromosomal changes, we find that multiple GPCRs and their ligands appear to be regulated through methylation and correlated with survival. These results suggest opportunities for better treatment strategies for NETs based on molecular features.

scholarly journals PROGNOSTIC ROLE OF MOLECULAR SUBTYPES OF COLON CANCER. A CURRENT VIEW ON THE PROBLEM

2021 ◽  
Vol 20 (3) ◽  
pp. 107-114
Author(s):  
L. E. Sinyansky ◽  
S. V. Vtorushin ◽  
S. V. Patalyak ◽  
S. G. Afanasyev
Keyword(s):  
Colon Cancer ◽  
World Literature ◽  
Molecular Subtypes ◽  
Prognostic Significance ◽  
Postoperative Treatment ◽  
Cochrane Library ◽  
Current View ◽  
International Studies ◽  
Cancer Subtypes ◽  
Immunohistochemical Markers

Purpose of the study: to review the available data on the heterogeneity of colon cancer and to assess the prognostic significance of colon cancer subtypes.Material and Methods. Medline, PubMed, Cochrane library, elibrary databases were used to identify studies that characterized the current view on the problem of choosing the optimal postoperative treatment for colon cancer.Results. the review showed the results of international studies of colon cancer subtypes based on complex multomics characteristics. Particular attention was paid to the description of modern studies on the search for prognostic markers for colon cancer. The relevance of the study of immunohistochemical markers was confirmed by the analysis of the world literature. the outcomes will make it possible to classify colon cancer into molecular subtypes in real clinical practice and, as a consequence, significantly improve the effectiveness of adjuvant therapy.

scholarly journals Expression of Calretinin in Carcinoma Breast in Correlation with Various Histological and Molecular Subtypes

2021 ◽  
pp. 1-11
Author(s):  
M. B. Sri Hansini ◽  
Hemalatha Ganapathy
Keyword(s):  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Prognostic Significance ◽  
Clinicopathological Parameters ◽  
High Grade ◽  
Proliferative Index ◽  
Carcinoma Breast ◽  
Luminal B ◽  
Grade Ii ◽  
High Proliferative Index

Breast carcinoma is the second most common cancer following lung cancer. The incidence of cancer accounts for 24.2% and cancer death is about 15% among females. There are various prognostic and predictive factors for assessing the patient encountering carcinoma breast. Among the various prognostic factors, histological subtype and molecular subtype play a key role. The calretinin expression in carcinoma breast was seen in high-grade breast carcinomas and basal like subtype of carcinoma breast. Calretinin expression was predominantly noted in high grade II and III carcinomas as in other studies and other histological subtypes like metastatic carcinomas which are considered high grade tumours. The present study aimed to correlate the various clinicopathological parameters with the calretinin expression. The expression of Calretinin was seen mainly in grade II and grade III IDC- NST and metaplastic carcinomas. Among the molecular subtypes, the Basal like subtype and the Luminal B subtype showed calretinin expression. The calretinin expression was associated with tumours with a high proliferative index with Ki67 index >14%. This implies the importance of prognostic significance of calretinin expression, as cases with a high proliferative index are likely to have poor prognosis.

scholarly journals Interconnectivity between molecular subtypes and tumor stage in colorectal cancer

2020 ◽  
Author(s):  
R.R.J. Coebergh van den Braak ◽  
Sanne ten Hoorn ◽  
A.M. Sieuwerts ◽  
J.B. Tuynman ◽  
M. Smid ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colon Cancer ◽  
Molecular Subtypes ◽  
Tnm Classification ◽  
Tumor Biology ◽  
Tumor Stage ◽  
Stage Ii ◽  
Colon Cancers ◽  
Advanced Stages ◽  
Stage Ii Colon Cancer

Abstract Background There are profound individual differences in clinical outcome between colorectal cancers (CRCs) presenting with identical stage of disease. Molecular stratification, in conjunction with the traditional TNM staging, is a promising way to predict patient outcomes. We investigated the interconnectivity between tumor stage and tumor biology reflected by the Consensus Molecular Subtypes (CMSs) in CRC, and explored the possible value of these insights in patients with stage II colon cancer. Methods We performed a retrospective analysis using clinical records and gene expression profiling in a meta-cohort of 1040 CRC patients. The interconnectivity of tumor biology and disease stage was assessed by investigating the association between CMSs and TNM classification. In order to validate the clinical applicability of our findings we employed a meta-cohort of 197 stage II colon cancers. Results CMS4 was significantly more prevalent in advanced stages of disease (III-IV). The observed differential gene expression between cancer stages is predominantly explained by the biological differences as reflected by CMS subtypes. Gene signatures for stage III-IV and CMS4 were highly correlated. CMS4 cancers showed an increased progression rate to more advanced stages. Indeed, determining CMSs was a relevant addition to TNM classification in identifying stage II colon cancer patients with high-risk of disease recurrence. Conclusions Considerable interconnectivity between tumor biology and tumor stage in CRC exists. This implies that the TNM stage, in addition to the stage of progression, also reflects distinct biological disease entities. These insights can be utilized to optimize identification of high-risk stage II colon cancers.

Breast Cancer in Women: Epidemiological, Histological, Immunohistochemical and Molecular Sub-Types in the Republic of Congo

2021 ◽  
Vol 11 (5) ◽  
pp. 103-116
Author(s):  
Dimitry Moudiongui Mboungou Malanda ◽  
Anicet Luc Magloire Boumba ◽  
Gervillien Arnold Malonga
Keyword(s):  
Breast Cancer ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Histological Type ◽  
University Hospital ◽  
Response To Treatment ◽  
Proliferation Index ◽  
Molecular Profile ◽  
Republic Of Congo ◽  
The Republic

Introduction: Breast cancer is a heterogeneous disease with a variety of morphological, molecular, treatment response and clinical outcome characteristics. The objective of this work was to assess the epidemiological, histological, immunohistochemical and molecular subtypes of breast cancer in women in the Republic of Congo. Material and Methods: We carried out a cross-sectional descriptive study which took place from January 1, 2014 to December 31, 2020. The study focused on 150 cases of breast cancer in patients diagnosed at the University Hospital of Brazzaville (CHU-B). The epidemiological, clinical, histological, immunohistochemical and molecular subtypes were the variables studied. Results: The mean age was 48.09 ± 13.87 years with the extremes of 22 years and 80 years. The study of the profession; the most represented in our study was that of the cultivator 20.67%. A predominance of breast cancer localization was observed in the left breast in 47.33%. The frequency of a family history was 7.33% or 11 cases. The most frequently represented histologic type was 62% invasive non-specific type carcinoma (CITNS). The most represented histological grade was Scarff Bloom Richardson grade II (51.33%), followed by grade III 24% and grade I in 12% of cases. Regarding the results of IHC; of the 150 cases, 102 (68%) had positive hormone receptors (HR +). The ORs were positive in 102 cases (68%) while the PRs were positive in 98 cases (65.33%). The Her2 oncogene was over expressed in 38 cases (25.3%). The Ki-67 proliferation index was known for the 150 cases, including 77 (51.33%) less than 15% and 73 (48.67%) greater than or equal to 15%. The distribution of molecular subtypes was 46% luminal A, 22% triple negative, 17% luminal B and 10% Her2 +. Tumors of unknown molecular profile were 5%. The correlation was found between molecular subtype and histological type. This result was statistically significant (p <0.05). For the rest. There was no correlation between age and SBR grade (p> 0.05). The correlation was found between molecular subtype and histological type. This result was statistically significant (p <0.05). For the rest. There was no correlation between age and SBR grade (p> 0.05). The correlation was found between molecular subtype and histological type. This result was statistically significant (p <0.05). For the rest. There was no correlation between age and SBR grade (p> 0.05). Conclusion: It should be noted that the association between histological and immunohistochemical diagnosis can help determine the phenotype of breast cancer, with the aim of guiding treatment and therefore improving response to treatment. Key words: Epidemiology, Histology, Immunohistochemistry, molecular subtypes, breast cancer, Republic of Congo.

Identification of Risk Molecular Subtype of Colon Cancer with Lymphovascular Invasion

2021 ◽  
Vol 16 ◽  
Author(s):  
Qing Jin ◽  
Binhua Liang ◽  
Xiujie Chen ◽  
Huiwen Liu
Keyword(s):  
Colon Cancer ◽  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Molecular Basis ◽  
Lymphovascular Invasion ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Tumor Stage ◽  
Stage Ii ◽  
Genetic Mutations

Background: Although surgical resection generally yields excellent outcomes, a part of colon cancer patients still have relapse or metastasis after surgery. Adjuvant chemotherapy in tumor stage III has been demonstrated to eradicate micrometastasis and improve survival, whereas the benefits of adjuvant chemotherapy in tumor stage II remain controversial. The leading cause is the lack of understanding of the molecular basis of underlying metastatic mechanisms. Objective: The aim of this study was to identify molecular subtype(s) of colon cancer with a high risk for metastasis and provide potential biomarkers for prognostic prediction in tumor stage II. Method: Based on the assumption that colon cancer evolves due to the stepwise accumulation of a series of genetic mutations, we performed a systematic investigation on the molecular basis of colon cancer by applying restart random walk on the PPI network. To compare the functional similarity of patients, we extracted mutation-propagating modules of each patient and calculated their enrichment score in 50 hallmark gene sets. According to the functional similarity matrix, we classified colon cancers with positive lymphovascular invasion and the prognosis of molecular subtypes. We determined the molecular characteristics of subtypes by conducting an enrichment analysis of subtype-specific genetic mutations. Additionally, we identified potential biomarkers for predicting patients with a high risk for metastasis in stage II through differential analysis of miRNA expression profile of subtypes. Then, we used two independent data sets to construct a random forest classifier and performed 10-fold cross-validation of miRNA biomarkers. Results: Firstly, we identified two molecular subtypes of colon cancer with positive lymphovascular invasion as well as their associated biological characteristics: LVI1=Canonical subtype (110, 85%); LVI2=Metastatic subtype (20, 15%). Secondly, we identified 11 miRNA biomarkers for predicting patients with a high risk for metastasis in tumor stage II. Conclusion: Our findings put forward a detailed classification of colon cancer and provided risk biomarkers for stage II patients to determine whether to take adjuvant chemotherapy after surgery.

scholarly journals Predicting Endometrial Cancer Subtypes and Molecular Features from Histopathology Images Using Multi-resolution Deep Learning Models

2020 ◽  
Author(s):  
Runyu Hong ◽  
Wenke Liu ◽  
Deborah DeLair ◽  
Narges Razavian ◽  
David Fenyö
Keyword(s):  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Characteristic Curve ◽  
The Cancer Genome Atlas ◽  
Diagnostic Process ◽  
Histological Subtypes ◽  
Neural Network Models ◽  
Molecular Subtyping ◽  
Cancer Subtypes ◽  
Molecular Features

AbstractThe determination of endometrial carcinoma histological subtypes is a critical diagnostic process that directly affects patients’ prognosis and treatment options. Recently, molecular subtyping and mutation status are increasingly utilized in clinical practice as they offer better inform prognosis and offer the possibility of individualized therapies. Compared to the histopathological approach, however, the availability of molecular subtyping is limited as it can only be obtained by genomic sequencing, which may be cost prohibitive. Here, we implemented deep convolutional neural network models that predict not only the histological subtypes, but also molecular subtypes and 18 common gene mutations based on digitized H&E stained pathological images. Taking advantage of the multi-resolution nature of the whole slide images, we introduced a customized architecture, Panoptes, to integrate features of different magnification. The model was trained and evaluated with images from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium. Our models achieved an area under the receiver operating characteristic curve (AUROC) of 0.969 in predicting histological subtype and 0.934 to 0.958 in predicting the copy number high (CNV-H) molecular subtype. The prediction tasks of 4 mutations and microsatellite high (MSI-H) molecular subtype also achieved a high performance with AUROC ranging from 0.781 to 0.873. Panoptes showed a significantly better performance than InceptionResnet in most of these top predicted tasks by up to 18%. Feature extraction and visualization revealed that the model relied on human-interpretable patterns. Our results suggest that Panoptes can help pathologists determine molecular subtypes and mutations without sequencing, and our models are generalizable to independent datasets.

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