3 new grants power colorectal cancer studies

“We aim to deeply characterize the mutational, transcriptional and cellular landscapes of colorectal tumors and their immune microenvironments in 500 Alaska Native patients and link these characteristics to colorectal-specific mortality,” Huyghe said, adding that Fred Hutch will partner closely with ANTHC for this work.

Samples from ANTHC’s unique biorepository, which contains tumor tissue samples from Alaska Native CRC patients that can be linked to comprehensive medical records, were used in a pilot to test the feasibility of the study.

Researchers will compare Alaska Native CRC tumor and microenvironment molecular profiles with those from CRC patients of European ancestry; they’ll also perform whole-exome sequencing of CRC tumors — that is, they’ll sequence all the protein-coding regions of the genes — and will pair normal samples to identify driver genes and clinically actionable mutations particularly relevant to the Alaska Native population. In addition, they’ll analyze mutational signatures that may be linked to environmental exposures and identify germline mutations in high-penetrance CRC risk genes to investigate their role in the increased CRC risk seen in Alaska Native people.

Finally, they’ll apply spatial molecular profiling technologies to identify prognostic biomarkers, characterize tumoral immune response and unveil mechanisms of immune evasion.

“The insights gained through this work may result in improved identification of patients at high risk of dying from CRC, which can be used to guide clinical decision-making,” Huyghe said. “They may also inform the development of novel therapeutic strategies and ultimately decrease mortality.”

Digging into CRC’s gene-environment interactions

Peters and biostatistician Li Hsu, PhD, also received a five-year, $4.4 million grant from the NCI to further investigate colorectal cancer risk. Last year, Peters’ team and collaborators published research on 100 new genetic risk variants for the disease.

Now they plan to investigate gene-environment interactions in a diverse population using an integrative omics approach.

“The extent to which environmental risk factors such as lifestyle, diet, obesity, drug use and other factors modulate genetic risk — or vice versa — is poorly understood,” Peters said. “We urgently need a comprehensive approach that combines high-dimensional multi-omics data with diverse, large and well-characterized study populations and novel statistical approaches.”

Pinpointing which environmental factors influence genetic risk can provide key biological insights as well as provide guidance for personalized screening and actionable targets for interventions. Multi-omics methods, including single-cell technologies, have helped reveal cell-type specific biological processes and how environmental risk factors and genetic variants impact disease development.

But the lack of data on gene regulation in non-Europeans hampers progress.

The NCI grant will allow researchers to profile colorectal samples from 50 healthy racially and ethnically diverse participants as well as investigate “intermediate biomarkers” related to CRC, including glucose, insulin, and inflammatory markers such as interleukin-6 and C-reactive protein.

“We will use genetic instruments to predict biomarkers linked to metabolic dysregulation and inflammation, two important risk factors for CRC, and will incorporate them along with our measured exposures into gene-environment analyses,” Hsu said.

Resources include a data set containing 99,000 colorectal patients and 140,000 healthy participants or “controls,” of which over 21,000 of the cancer patients and over 35,000 of the control participants are of non-European descent.

“These data will be integrated with single-cell and existing biobank data and state-of-the-art resources and technologies to conduct a comprehensive functional-informed genomic gene plus environment examination and risk prediction analysis,” Peters said. “We hope to discover novel interactions by conducting a functionally informed, genome-wide gene-plus-environment interaction scan across the spectrum of key environmental risk factors, including obesity, diabetes, smoking, alcohol, drug use, diet and intermediate biomarkers linked to metabolic dysregulation and chronic inflammation.”

Ultimately, Peters, Hsu and others plan to integrate functional single-cell omics data within the largest CRC genetic-epidemiology database in the world to better understand the extent to which modifiable risk factors impact genetic risk in colorectal cancer (and vice versa).

Findings of this study are expected to impact CRC prevention by guiding lifestyle interventions, personalizing screening decisions and ultimately reducing the burden of this cancer.

Measuring the cost of unequal care

Not only does systemic racism in the U.S. health care system lead to inequitable access to care, it can also lead to higher costs of care.

Fred Hutch biostatistician Carolyn Rutter, PhD, recently received a 5-year, $2.2 million grant from the National Institute on Minority Health and Health Disparities to investigate the health and financial costs of this unequal care in colorectal cancer.

“There is ample evidence of racial disparities in every step of the colorectal cancer care continuum, from early detection to treatment, especially for differences between Black patients and white patients,” Rutter said. “Colorectal cancer care provides a case study.”

Research shows Black people are less likely than white people to be screened for colorectal cancer and are more likely to be diagnosed at a later stage. Black people are also less likely to receive curative treatment — even after accounting for stage at diagnosis, and they have 40% higher mortality and shorter stage-specific survival.

“These differences in care have both health and economic consequences,” Rutter said, pointing to worse outcomes and higher treatment costs.

For the study, Rutter will use her microsimulation model known as CRC-SPIN (Colorectal Cancer Simulated Population model for Incidence and Natural history), which has been used for comparative effectiveness studies of colorectal cancer screening and care. She’ll broaden its use to simulate the natural history of CRC among specific racial and ethnic groups including American Indian/Alaska Native people; Hispanic people; Pacific Islanders and people from Asia; Black/African American people, etc. 

Additionally, Rutter and team will fold in patient characteristics beyond race and ethnicity that impact screening, such as insurance status.

This extended model will be used to simulate the overall impact of disparate care on CRC patient outcomes — measuring life years lost, disease-free life years lost and excess colorectal cancer including late-stage CRC. They’ll also identify elements of the care process that have the largest impact on outcomes to better guide health policy and will measure financial outcomes including screening costs, treatment costs and lost income both overall and for specific racial/ethnic groups.

Finally, they’ll use their model to project impact of policies that reduce racial/ethnic disparities in order to identify what’s most effective.

“We plan to use this information to estimate the extent to which disparities in care explain disparities in CRC outcomes, and to evaluate policies to reduce disparities,” Rutter said.