Posts by Collection


Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair–Deficient Colorectal Cancer

Published in Cancer Immunology Research, 2019

Tumours with a high number of mutations, in particular those with DNA repair defects such as Microsatellite Instability (MSI), are FDA-approved for immunotherapy; yet not all patients respond. This study aimed at refining our understanding of the link between TMB and immunotherapy response. To this end, we conducted an exploratory analysis of a patient who did not respond to immunotherapy despite having an MSI colorectal tumour.

Recommended citation: Gurjao, C. et al. Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair–Deficient Colorectal Cancer. Cancer Immunol Res 7, 1230–1236 (2019).

Is tumor mutational burden predictive of response to immunotherapy?

Published in eLife, 2020

This study challenges one of the central paradigms in cancer immunology: the notion that a high number of mutations — and the resulting neoantigens, recognized as ‘foreign’ by T-cells — elicits a better antitumour immune response. Several pioneering papershave suggested that tumours with a high load of mutations better respond to immunotherapy; these studies have been the basis of the FDA approval of TMB to prioritize patients who would most likely benefit from immunotherapy. We revisit this claim by conducting a pan-cancer meta-analysis: we aggregate the largest available dataset of immunotherapy patients, reuniting more than 2,500 individuals, with available TMB data and clinical annotations.

Recommended citation: Gurjao, C., Tsukrov, D., Imakaev, M., Luquette, L. J. & Mirny, L. A. Limited evidence of tumour mutational burden as a biomarker of response to immunotherapy. BioRxiv (2020).

Discovery and Features of an Alkylating Signature in Colorectal Cancer

Published in Cancer Discovery, 2021

Colorectal cancer (CRC) is currently the third most common cancer in the world. In the last decade, there has been a concerning trend of early-onset CRC: by 2040, it is predicted to become the leading cause of cancer death in individuals between 20 and 40 years old. Although the reasons for this trend are unclear, diet, in particular red meat consumption, has been hypothesized to play a role. However, no mutagenic role of red meat has been observed in human colons yet. This study presents the mutational signature analysis of a comprehensive CRC molecular profiling study: 900 tumours were sequenced from tissue biopsies collected over four decades. Along with molecular data, this study leveraged detailed information, collected every other year, on the lifestyle of CRC patients. This comprehensive cohort allows us to accurately estimate mutagenic processes in CRC and better understand how they are related to lifestyle factors.

Recommended citation: Gurjao, C. et al. Discovery and Features of an Alkylating Signature in Colorectal Cancer. Cancer Discov. (2021) doi:10.1158/2159-8290.CD-20-1656.


Objective 3

Adjusting methods to analyze and integrate genomic datasets. Large scale genomic data presents specific challenges, notably multiple hypothesis testing and variable selection. Formulating adjusted statistical models can provide meaningful insights into cancer biology.

Objective 2

Leveraging mutational landscapes to inform clinical decisions. The FDA has been approving more and more cancer therapies and combinations of them. Despite being effective for several cancer types, their clinical use is encumbered by a high variability in patient response. Studying the mutational landscape of tumors can inform the best course of treatment and predict the aggressiveness of certain cancers.

Objective 1

Understanding how and where DNA mutations occur. Lifestyle habits and the microbiome can be genotoxic and leave an imprint on tumor DNA. The immune system can shape the mutational landscape as well by weeding out cells with certain mutations (a theory called the “neoantigen theory”). Additionally, DNA-intrinsic features such as the 3D conformation and the 2D base sequence favor mutations at certain loci.