Biology subjects

Hu, Y. L.

Publications and source records attributed to Hu, Y. L..

3 recordsLinked to original sources

bioRxiv2026

A Scalable Framework for Pan-Cancer Tumor Evolution Analysis Enables Transfer of Progression Mechanisms Across Tumor Entities

MotivationCancer progression is driven by the stochastic accumulation of interacting genetic alterations, and tumors from different tissues can share common evolutionary patterns despite distinct anatomical origins. While simplified progression models can be applied at scale, the use of expressive models that capture complex inter-event dependencies remains challenging in pan-cancer settings due to their computational demands. ResultsWe present fastMHN, a scalable approximation to Mutual Hazard Network-based cancer progression models, that enables pan-cancer analysis of large genomic datasets with the explicit aim of enabling transfer of progression mechanisms across tumor entities. Applying fastMHN to a large clinical cohort, we identify a tumor-progression group spanning multiple tissues that is characterized by a link between STK11 mutations and poor patient survival. While the clinical relevance of STK11 mutations is well established in non-small cell lung cancer, our results suggest that a similar progression mechanism is present in molecularly defined subgroups of other cancer types. These findings illustrate how scalable pan-cancer progression modeling can facilitate cross-entity transfer of biological and potentially clinical insights. Availability and implementationThe pan-cancer classification workflow and all data are available at github.com/simon-pfahler/fastMHN-classification.

bioinformatics↗

bioRxiv2024

Modeling metastatic progression from cross-sectional cancer genomics data

Metastasis formation is a hallmark of cancer lethality. Yet, metastases are generally unobservable during their early stages of dissemination and spread to distant organs. Genomic datasets of matched primary tumors and metastases may offer insights into the underpinnings and the dynamics of metastasis formation. We present metMHN, a cancer progression model designed to deduce the joint progression of primary tumors and metastases using cross-sectional cancer genomics data. The model elucidates the statistical dependencies among genomic events, the formation of metastasis, and the clinical emergence of both primary tumors and their metastatic counterparts. metMHN enables the chronological reconstruction of mutational sequences and facilitates estimation of the timing of metastatic seeding. In a study of nearly 5000 lung adenocarcinomas, metMHN pinpointed TP53 and EGFR as mediators of metastasis formation. Furthermore, the study revealed that post-seeding adaptation is predominantly influenced by frequent copy number alterations. All datasets and code are available on GitHub at https://github.com/cbg-ethz/metMHN.

bioinformatics↗

bioRxiv2023

Overcoming Observation Bias for Cancer Progression Modeling

Cancers evolve by accumulating genetic alterations, such as mutations and copy number changes. The chronological order of these events is important for understanding the disease, but not directly observable from cross-sectional genomic data. Cancer progression models (CPMs), such as Mutual Hazard Networks (MHNs), reconstruct the progression dynamics of tumors by learning a network of causal interactions between genetic events from their co-occurrence patterns. However, current CPMs fail to include effects of genetic events on the observation of the tumor itself and assume that observation occurs independently of all genetic events. Since a dataset contains by definition only tumors at their moment of observation, neglecting any causal effects on this event leads to the "conditioning on a collider" bias: Events that make the tumor more likely to be observed appear anti-correlated, which results in spurious suppressive effects or masks promoting effects among genetic events. Here, we extend MHNs by modeling effects from genetic progression events on the observation event, thereby correcting for the collider bias. We derive an efficient tensor formula for the likelihood function and learn two models on somatic mutation datasets from the MSK-IMPACT study. In colon adenocarcinoma, we find a strong effect on observation by mutations in TP53, and in lung adenocarcinoma by mutations in EGFR. Compared to classical MHNs, this explains away many spurious suppressive interactions and uncovers several promoting effects. The data, code, and results are available at https://github.com/cbg-ethz/ObservationMHN.

bioinformatics↗