Biology subjects

Sadanandam, A.

Publications and source records attributed to Sadanandam, A..

5 recordsLinked to original sources

bioRxiv2018

Genomic and transcriptomic determinants of therapy resistance and immune landscape evolution during anti-EGFR treatment in colorectal cancer

Anti-epidermal growth factor receptor (EGFR) antibodies (anti-EGFR-Ab) are effective in a subgroup of patients with metastatic colorectal cancer (CRC). We applied genomic and transcriptomic analyses to biopsies from 35 RAS wild-type CRCs treated with the anti-EGFR-Ab cetuximab in a prospective trial to interrogate the molecular resistance landscape. This validated transcriptomic CRC-subtypes as predictors of cetuximab benefit; identified novel associations of NF1-inactivation and non-canonical RAS/RAF-aberrations with primary progression; and of FGF10- and non-canonical BRAF-aberrations with AR. No genetic resistance drivers were detected in 64% of AR biopsies. The majority of these had switched from the cetuximab-sensitive CMS2-subtype pretreatment to the fibroblast- and growth factor-rich CMS4-subtype at progression. Fibroblast supernatant conferred cetuximab resistance in vitro, together supporting subtype-switching as a novel mechanism of AR. Cytotoxic immune infiltrates and immune-checkpoint expression increased following cetuximab responses, potentially providing opportunities to treat CRCs with molecularly heterogeneous AR with immunotherapy.

cancer biology↗

bioRxiv2017

polyCluster: Defining Communities of Reconciled Cancer Subtypes with Biological and Prognostic Significance

To stratify cancer patients for most beneficial therapies, it is a priority to define robust molecular subtypes using clustering methods and \"big data\". If each of these methods produces different numbers of clusters for the same data, it is difficult to achieve an optimal solution. Here, we introduce \"polyCluster\", a tool that reconciles clusters identified by different methods into context-specific subtype \"communities\" using a hypergeometric test or a measure of relative proportion of common samples. The polycluster was tested using a breast cancer dataset, and latter using uveal melanoma datasets to identify novel subtype communities with significant metastasis-free prognostic differences. Available at: https://github.com/syspremed/polyClustR

genomics↗

bioRxiv2017

A Low-Cost Multiplex Biomarker Assay Stratifies Colorectal Cancer Patient Samples into Clinically-Relevant Subtypes

Previously, we classified colorectal cancers (CRCs) into five CRCA subtypes with different prognoses and potential treatment responses, using a 786-gene signature. We merged our subtypes and those described by five other groups into four consensus molecular subtypes (CMS) that are similar to CRCA subtypes. Here we demonstrate the analytical development and application of a custom NanoString platform-based biomarker assay to stratify CRC into subtypes. To reduce costs, we switched from the standard protocol to a custom modified protocol (NanoCRCA) with a high Pearson correlation coefficient (>0.88) between protocols. Technical replicates were highly correlated (>0.96). The assay included a reduced robust 38-gene panel from the 786-gene signature that was selected using an in-laboratory developed computational pipeline of class prediction methods. We applied our NanoCRCA assay to untreated CRCs including fresh-frozen and formalin-fixed paraffin-embedded (FFPE) samples (n=81) with matched microarray or RNA-Seq profiles. We further compared the assay results with CMS classification, different platforms (microarrays/RNA-Seq) and gene-set classifiers (38 and 786 genes). NanoCRCA classified fresh-frozen samples (n=39; not including those showing a mixture of subtypes) into all five CRCA subtypes with overall high concordance across platforms (89.7%) and with CMS subtypes (84.6%), independent of tumour cellularity. This analytical validation of the assay shows the association of subtypes with their known molecular, mutational and clinical characteristics. Overall, our modified NanoCRCA assay with further clinical assessment may facilitate prospective validation of CRC subtypes in clinical trials and beyond.\n\nNovelty and ImpactWe previously identified five gene expression-based CRC subtypes with prognostic and potential predictive differences using a 786-gene signature and microarray platform. Subtype-driven clinical trials require a validated assay suitable for routine clinical use. This study demonstrates, for the first time, how molecular CRCA subtype can be detected using NanoString Technology-based biomarker assay (NanoCRCA) suitable for clinical validation. NanoCRCA is suitable for analysing FFPE samples, and this assay may facilitate patient stratification within clinical trials.

cancer biology↗

bioRxiv2017

Revealing unidentified heterogeneity in different epithelial cancers using heterocellular subtype classification

Cancers are currently diagnosed, categorised, and treated based on their tissue of origin. However, how different cellular compartments of tissues (e.g., epithelial, immune and stem cells) are similar across cancer types is unknown. Here we used colorectal cancer subtypes and their signatures representing different colonic crypt cell types as surrogates to classify different epithelial cancers into five heterotypic cellular (heterocellular) subtypes. The stem-like and inflammatory heterocellular subtypes are ubiquitous across epithelial cancers so capture intrinsic, tissue-independent properties. Conversely, well-differentiated/specialized goblet-like/enterocyte heterocellular subtypes differ across cancer types due to their colorectum-specific genes. The transit-amplifying heterocellular subtype shows a dynamic range of cellular differentiation with shared common pathways (Wnt, FGFR) in certain cancer types. Importantly, this approach revealed previously unrecognised heterogeneity in pancreatic, breast, microsatellite-instability enriched and KRAS mutation-dependent cancers. Immune cell-type differences are common and useful for patient stratification for immunotherapy. This unique approach identifies cell type-dependent but tissue-independent heterogeneity in different cancers for precision medicine.

bioinformatics↗

bioRxiv2017

A Next Generation Clustering Tool Enables Identification of Functional Cancer Subtypes with Associated Biological Phenotypes

One of the major challenges faced in defining clinically applicable and homogeneous molecular tumor subtypes is assigning biological and/or clinical interpretations to etiological (intrinsic) subtypes. The conventional approach involves at least three steps: Firstly, identify subtypes using unsupervised clustering of patient tumours with molecular (etiological) profiles; secondly associate the subtypes with clinical or phenotypic information (covariates) to infer some biological meaning to the redefined subtypes; and thirdly, identify clinically relevant biomarkers associated with the subtypes. Here, we report the implementation of a tool, phenotype mapping (phenMap), which combines these three steps to define functional subtypes with associated phenotypic information and molecular signatures. phenMap models meta (unobserved) variables as a function of covariates to expose any underlying clustering structure within the data and discover associations between subtypes and phenotypes. We demonstrate how this tool can more avidly identify functional subtypes that are an improvement over already existing etiological subtypes by analysing published breast cancer gene expression data.

genomics↗