Dataset Information

Multi-modal meta-analysis of cancer cell line omics profiles identifies ECHDC1 as a novel breast tumor suppressor.

ABSTRACT: Molecular and functional profiling of cancer cell lines is subject to laboratory-specific experimental practices and data analysis protocols. The current challenge therefore is how to make an integrated use of the omics profiles of cancer cell lines for reliable biological discoveries. Here, we carried out a systematic analysis of nine types of data modalities using meta-analysis of 53 omics studies across 12 research laboratories for 2,018 cell lines. To account for a relatively low consistency observed for certain data modalities, we developed a robust data integration approach that identifies reproducible signals shared among multiple data modalities and studies. We demonstrated the power of the integrative analyses by identifying a novel driver gene, ECHDC1, with tumor suppressive role validated both in breast cancer cells and patient tumors. The multi-modal meta-analysis approach also identified synthetic lethal partners of cancer drivers, including a co-dependency of PTEN deficient endometrial cancer cells on RNA helicases.

SUBMITTER: Jaiswal A

PROVIDER: S-EPMC7983037 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Multi-modal meta-analysis of cancer cell line omics profiles identifies ECHDC1 as a novel breast tumor suppressor.

Jaiswal Alok A Gautam Prson P Pietilä Elina A EA Timonen Sanna S Nordström Nora N Akimov Yevhen Y Sipari Nina N Tanoli Ziaurrehman Z Fleischer Thomas T Lehti Kaisa K Wennerberg Krister K Aittokallio Tero T

Molecular systems biology 20210301 3

Molecular and functional profiling of cancer cell lines is subject to laboratory-specific experimental practices and data analysis protocols. The current challenge therefore is how to make an integrated use of the omics profiles of cancer cell lines for reliable biological discoveries. Here, we carried out a systematic analysis of nine types of data modalities using meta-analysis of 53 omics studies across 12 research laboratories for 2,018 cell lines. To account for a relatively low consistency ...[more]

PMID: 33750001

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Project description:Ductal carcinoma in situ (DCIS) is a preinvasive form of breast cancer with a highly variable potential of becoming invasive and affecting mortality of the patients. Due to the lack of accurate markers of disease progression, many women with detected DCIS are currently overtreated. To distinguish those DCIS cases who are likely to require therapy from those who should be left untreated, there is a need for robust and predictive biomarkers extracted from molecular or genetic profiles. We developed a supervised machine learning approach that implements multi-omics feature selection and model regularization for the identification of biomarker combinations that could be used to distinguish low-risk DCIS lesions from those with a higher likelihood of progression. To investigate the genetic heterogeneity of disease progression, we applied this approach to 40 pure DCIS and 259 invasive breast cancer (IBC) samples profiled with genome-wide transcriptomics, DNA methylation, and DNA copy number variation. Feature selection using the multi-omics Lasso-regularized algorithm identified both known genes involved in breast cancer development, as well as novel markers for early detection. Even though the gene expression-based model features led to the highest classification accuracy alone, methylation data provided a complementary source of features and improved especially the sensitivity of correctly classifying DCIS cases. We also identified a number of repeatedly misclassified DCIS cases when using either the expression or methylation markers. A small panel of 10 gene markers was able to distinguish DCIS and IBC cases with high accuracy in nested cross-validation (AU-ROC = 0.99). The marker panel was not specific to any of the established breast cancer subtypes, suggesting that the 10-gene signature may provide a subtype-agnostic and cost-effective approach for breast cancer detection and patient stratification. We further confirmed high accuracy of the 10-gene signature in an external validation cohort (AU-ROC = 0.95), profiled using distinct transcriptomic assay, hence demonstrating robustness of the risk signature.

Project description:BACKGROUND:Recent years have witnessed an increasing interest in multi-omics data, because these data allow for better understanding complex diseases such as cancer on a molecular system level. In addition, multi-omics data increase the chance to robustly identify molecular patient sub-groups and hence open the door towards a better personalized treatment of diseases. Several methods have been proposed for unsupervised clustering of multi-omics data. However, a number of challenges remain, such as the magnitude of features and the large difference in dimensionality across different omics data sources. RESULTS:We propose a multi-modal sparse denoising autoencoder framework coupled with sparse non-negative matrix factorization to robustly cluster patients based on multi-omics data. The proposed model specifically leverages pathway information to effectively reduce the dimensionality of omics data into a pathway and patient specific score profile. In consequence, our method allows us to understand, which pathway is a feature of which particular patient cluster. Moreover, recently proposed machine learning techniques allow us to disentangle the specific impact of each individual omics feature on a pathway score. We applied our method to cluster patients in several cancer datasets using gene expression, miRNA expression, DNA methylation and CNVs, demonstrating the possibility to obtain biologically plausible disease subtypes characterized by specific molecular features. Comparison against several competing methods showed a competitive clustering performance. In addition, post-hoc analysis of somatic mutations and clinical data provided supporting evidence and interpretation of the identified clusters. CONCLUSIONS:Our suggested multi-modal sparse denoising autoencoder approach allows for an effective and interpretable integration of multi-omics data on pathway level while addressing the high dimensional character of omics data. Patient specific pathway score profiles derived from our model allow for a robust identification of disease subgroups.

Dataset Information

Multi-modal meta-analysis of cancer cell line omics profiles identifies ECHDC1 as a novel breast tumor suppressor.

Publications

Multi-modal meta-analysis of cancer cell line omics profiles identifies ECHDC1 as a novel breast tumor suppressor.

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