De novo individualized disease modules reveal the synthetic penetrance of genes and inform personalized treatment regimens

Current understandings of individual disease etiology and therapeutics are limited despite great need. To fill the gap, we propose a novel computational pipeline which collects potent disease gene cooperative pathways to envision individualized disease etiology and therapies. Our algorithm constructs individualized disease modules de novo which enable us to elucidate the importance of mutated genes in specific patients and to understand the synthetic penetrance of these genes across patients. We reveal that importance of notorious cancer drivers TP53 and PIK3CA fluctuate widely across breast cancers and peak in tumors with distinct numbers of mutations, and that rarely mutated genes such as XPO1 and PLEKHA1 have high disease module importance in specific individuals. Furthermore, individualized module disruption enables us to devise customized singular and combinatorial target therapies which were highly varied across patients demonstrating the need for precision therapeutics pipelines. As the first analysis of de novo individualized disease modules, we illustrate the power of individualized disease modules for precision medicine by providing deep novel insights on the activity of diseased genes in individuals.

Role and Clinical Utility of Cancer/Testis Antigens in Head and Neck Squamous Cell Carcinoma

Cancer/testis (CT) antigens exhibit selective expression predominantly in immunoprivileged tissues in non-pathological contexts but are aberrantly expressed in diverse cancers. Due to their expression pattern, they have historically been attractive targets for immunotherapies. A growing number of studies implicate CT antigens in almost all hallmarks of cancer, suggesting that they may act as cancer drivers. CT antigens are expressed in head and neck squamous cell carcinomas. However, their role in the pathogenesis of these cancers remains poorly studied. Given that CT antigens hold intriguing potential as therapeutic targets and as biomarkers for prognosis and that they can provide novel insights into oncogenic mechanisms, their further study in the context of head and squamous cell carcinoma is warranted.

Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes

To obtain a comprehensive picture of composite genetic driver events and clonal dynamics in subtypes of paediatric acute lymphoblastic leukaemia (ALL) we analysed tumour-normal whole genome sequencing and expression data from 361 newly diagnosed patients. We report the identification of both structural drivers, as well as recurrent non-coding variation in promoters. Additionally we found the transcriptional profile of histone gene cluster 1 and CTCF altered tumours shared hallmarks of hyperdiploid ALL suggesting a ‘hyperdiploid like’ subtype. ALL subtypes are driven by distinct mutational processes with AID mutagenesis being confined to ETV6-RUNX1 tumours. Subclonality is a ubiquitous feature of ALL, consistent with Darwinian evolution driving selection and expansion of tumours. Driver mutations in B-cell developmental genes (IKZF1, PAX5, ZEB2) tend to be clonal and RAS/RTK mutations subclonal. In addition to identifying new avenues for therapeutic exploitation, this analysis highlights that targeted therapies should take into account composite mutational profile and clonality.

Role and Clinical Utility of Cancer/Testis Antigens in Head and Neck Squamous Cell Carcinoma

Cancer/testis (CT) antigens exhibit selective expression predominantly in immunoprivileged tissues in non-pathological contexts but are aberrantly expressed in diverse cancers. Because of their expression pattern, they have historically been attractive targets for immunotherapies. The investigation of mechanistic roles of CT antigens in promoting oncogenesis has historically been a prominent research question, and a growing number of studies implicate CT antigens in promoting almost all the hallmarks of cancer. This suggests that CT antigens may act as cancer drivers. CT antigens are expressed in head and neck squamous cell carcinomas, although their role in the pathogenesis, prognostication, and treatment for this family of cancers remains poorly studied. Given that CT antigens hold intriguing potential as therapeutic targets and as biomarkers for prognosis and therapeutic response and that they can provide novel insights into oncogenic mechanisms, their further study in the context of head and squamous cell carcinoma is warranted.

Protein Structure Readouts of Cancer Drivers for Precision Medicine

Cancer is fundamentally a disease of perturbed genes. Although many mutations can be marked in the genome of a cancer or transformed cell, the initiation and progression were shown to be driven by only a few mutational events viz. driver mutations that progressively govern and execute the functional impacts. The driver mutations are thus believed to dictate and dysregulate the subsequent cellular proliferative function/decisions thereby producing a cancerous state. Therefore, identifying the driver events from the genomic alterations in a patient’s cancer cell gained large attention recently for designing better targeting therapies towards paving way for the precision cancer medicine. With rolling advancements in high-throughput omics technologies, analysis of genetic variations and gene expression profiles for cancer patients has become a routine clinical practice. However, it is anticipated that protein structural alterations resulting from such driver mutations can provide more direct and clinically relevant evidence of disease states than genetic signatures alone. This review comprehensively discusses various aspects and approaches that have been developed for the prediction of cancer drivers using genetic signatures and protein structures, and their potential application in developing precision cancer therapies.Keywords: