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Publications of the Week

Genetic Architectures of Proximal and Distal Colorectal Cancer Are Partly Distinct

By March 22, 2021No Comments

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This week we profile a recent publication in Gut from Jeroen Huyghe (pictured) in the laboratory of Dr. Ulrike Peters at Fred Hutch. 

Can you provide a brief overview of your lab’s current research focus?

Our lab centers on understanding the underlying risk factors of colorectal cancer that will lead to evidence-based targeted interventions and treatments. We are studying the impact of genetic variants across the genome, as well as interactions of genetic variants with lifestyle and environmental risk factors. We are also conducting large-scale studies to analyze molecular and genetic characteristics of colorectal tumors and their microenvironment in relation to host genomes, lifestyle and environmental risk factors, and survival. To translate our findings into public health practice and clinical care, we are developing comprehensive risk prediction models based on genetic, lifestyle and environmental risk factors to personalize screening decisions.

What is the significance of the findings in this publication?

It has been known for a long time that colorectal cancers (CRCs) that arise in the proximal (right-sided) or distal (left-sided) colorectum differ in age-specific and sex-specific incidence rates, clinical, pathological, and tumor molecular features. Since genome-wide association studies (GWASs) became possible just over a decade ago, over 100 independent common genetic variant associations for overall CRC risk have been identified; over half of these were identified in just the past few years. However, a systematic analysis of the extent to which genetic risk variants differ according to the anatomical location where the tumor arises was lacking. In this large consortium-based study, we analyzed clinical and genome-wide genotype data of 112,373 CRC cases and controls to comprehensively examine whether CRC case subgroups defined by anatomical sublocation have distinct germline genetic architectures. Our analyses revealed substantial, previously unappreciated differences between proximal and distal colorectal cancer, along with 13 new risk variants and new biological insights. Our results provide a resource that will help to better understand the role that specific variants, genes, and pathways play in mechanisms of proximal and distal CRC carcinogenesis. These new insights may ultimately inform the development of new precision prevention strategies, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Additionally, our results demonstrate that studies of etiological risk factors and mechanisms of carcinogenesis should not lump proximal and distal CRC cases.

What are the next steps for this research?

To further look into heterogeneity among colorectal cancer patients, we are conducting in-depth molecular profiling of tumors and investigating the link with germline genetic variants. A large fraction of the genetic variants contributing to CRC risk remains unidentified. We are actively working on expanding discovery efforts by collaborating with other consortia to substantially increase the sample size. Importantly, to better understand potential genetic contributions to health disparities, our current work has a particular focus on the impact of race and ethnicity.

This work was funded by:

This work was supported by grants from the National Cancer Institute (NCI), National Institutes of Health (NIH), US Department of Health and Human Services (U01 CA164930, U01 CA137088, R01 CA059045, R21 CA191312, R01 CA201407, P30 CA015704). Genotyping services were provided by the Center for Inherited Disease Research (CIDR; X01-HG008596 and X01-HG007585). CIDR is fully funded through a federal contract from the NIH to the Johns Hopkins University, contract HHSN268201200008I. The full list of funding and acknowledgments can be found in the supplemental text accompanying the article.

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