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Cancer Genomics Project in Southwestern American Indians Aims to Improve Research, Care Disparities

This article has been updated with additional insights from Cheryl Willman about the use of a molecular tumor board and the challenge of accessing treatments based on genomic testing results. 

NEW ORLEANS – A National Cancer Institute-funded effort to advance cancer genomics research, identify personalized medicine opportunities, and build a reference genome for American Indians of Southwestern tribal nations has launched.

At the American Association for Cancer Research's annual meeting, Cheryl Willman, director of the Mayo Clinic Comprehensive Cancer Center, described the framework advanced under the NCI Cancer Moonshot's Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network, which promotes cancer genomic sequencing research that is intended to fill knowledge gaps in understudied populations.

Like all research conducted within the PE-CGS Network, the effort described by Willman, dubbed the "Engagement of American Indians of Southwestern Tribal Nations in Cancer Genome Sequencing," was designed with the input and consent of the community it intends to study.

"In tribal law and tribal lands there's this interesting balance between the consent of the individual and the consent of the target community," said Willman, co-primary investigator of the project, during a presentation at the meeting. "While tribal governors and counselors would want every individual American Indian cancer patient to benefit from science, they also want to consent to the nature of the work because of the tremendous, institutionalized racism and research misconduct [faced by] tribal nations."

As such, the investigators involved in the project — from the Mayo Clinic, University of New Mexico Comprehensive Cancer Center, City of Hope, Black Hills Center for American Indian Health, and the Translational Genome Research Institute (TGen) — sought approval for the design and aims of the cancer genomic sequencing project from Indigenous counsel leaders before submitting the grant.

"This is very much an individual consent with a community consent project," Willman said.

The effort aims to enroll between 800 and 1,000 American Indian cancer patients and survivors using culturally appropriate language and consent materials, conduct in-depth genomic analysis, and collect detailed information on participants' personal and medical history of disease, environmental exposures, and lifestyle.

"The project is just being launched," Willman said. Enrollment will begin at sites in New Mexico in May, and sites in Arizona will open this summer. The project launch, she said, was delayed because investigators couldn't meet with the tribes during the COVID-19 pandemic, which had an outsized impact on American Indian communities.

Seventy percent of cases and 50 percent of the deaths due to COVID-19 in the Southwest during the first phase of the pandemic occurred among Indigenous American Indians. "It really showed the limitations of the tremendous underinvestment in the Indian Health Service by the US government," Willman said.

Members and their descendants from the 574 federally recognized, sovereign American Indian or Alaska Native nations and communities can receive healthcare services provided by the Indian Health Service, an agency under the US Department of Health and Human Services. The IHS serves six Contract Health Service Delivery Areas (CHSDA), and this cancer genome sequencing project will focus on American Indians in the CHSDA serving the Southwestern region.

American Indians in tribal nations have poor access to healthcare, including cancer screening, which leads to late diagnosis. As a result, American Indians have the highest mortality rates in the US from breast, colorectal, liver, and kidney cancer. Moreover, American Indians are understudied and represent a miniscule portion of genomics cohorts that are fueling new precision oncology testing and treatment strategies. Willman bemoaned that there are only 27 American Indian or Alaskan Natives within the 11,000 patients sequenced as part of the Cancer Genome Atlas.

In the genomic sequencing project, researchers hope to delve into the significant genetic diversity among tribal nations and study the underlying genomic factors and social determinants of health contributing to the high cancer mortality burden among American Indians. Willman highlighted, for example, that the air, water, and soil in tribal lands are often contaminated by leached heavy metals such as uranium from abandoned mines. "Whether these are actually behind some of the cancer patterns we see, we don't know, but certainly that's an object of our study," she said.

Indigenous tribal communities also appear to have inherited predispositions to certain cancers, but underlying genetic risk factors are, again, not well studied, raising the question as to "whether there is a different spectrum of genomic mutations causing cancer in American Indian patients?" Willman said.

In this project, researchers will collect cancer tumor tissue, blood, sputum, and stool samples for extensive genomic and microbiome analysis. Exact Sciences is providing clinical-grade tumor/normal whole-exome sequencing and transcriptomic analysis of more than 19,000 genes and 169 introns. The firm will sequence 441 cancer genes at 800X average coverage and the rest of the genome at 400X coverage. Invitae will conduct clinical-grade germline genetic analysis. Researchers will also monitor patients' cancers using cell-free DNA analysis.

"We're directly engaging with our participants to deliver clinical-grade cancer genome sequencing that has a direct benefit to them," Willman said.

TGen will conduct whole-genome and microbiome sequencing and conduct genomic data analysis for the project. These efforts will be led by Jeffrey Trent, president and research director at TGen, whose team already has a good relationship with American Indian tribal communities through prior in-depth, collaborative genome sequencing research projects.

Willman noted that her past leukemia research in Indigenous and Hispanic populations showed that there are unique genomic cancer-causing variants in these populations. Based on that and similar findings in other studies, the investigators decided not to use marketed NGS cancer panels and risk missing identifying novel genomic cancer associations and treatment opportunities.

"We're not going to use panel sequencing," Willman said. "We don't even have an American Indian reference genome … [without which] it's going to be difficult to understand the significance of undetermined variants."

She noted that the reference genome used in research today is developed from a small number of people of largely European or African ancestry. "American Indians of the Southwest are less than 1 percent of the reference genome," Willman said, highlighting that a major aspect of this project spearheaded by Trent's team at TGen will be "the actual creation of an American Indian reference genome."

The researchers also hope to discover new somatic and germline mutations associated with cancer among members of American Indian tribal communities and genome-wide mutational signatures associated with behaviors and environmental exposures specific to these groups. Beyond research, though, the researchers have made a commitment to apply the learnings to improve cancer screening, precision prevention strategies, and personalized treatment that directly benefit American Indians.

"We have developed our project with very detailed clinical laboratory protocols … to provide real-time return of results" to patients' electronic medical records within 14 days of testing, Willman said. "It will allow for this information to be used for their therapeutic intervention."

Willman said that patients will receive information about any variants of unknown significance that they may harbor as well as known cancer-associated mutations that will inform treatment decisions. "These results will be considered in formal molecular tumor boards," she said. Participants and their families will be able to visit with a genetic counselor to discuss inherited cancer risks.

Even when actionable biomarkers are found through genomic testing, patients often miss out on the chance to receive the drugs and interventions that testing points to due to lack of insurance, advanced disease, or stringent clinical trial enrollment criteria. This issue of co-morbidities impacting clinical trial enrollment "is a major challenge when working with all patients but particularly minority and underserved communities," Willman said. She added that UNM's Comprehensive Cancer Center, one of the institutions where patients will be enrolled for this project, has a longstanding commitment to treat all patients regardless of their insurance status. 

"All of our patients will have access to outstanding care and clinical trials," said Willman, who for 21 years was director of UNM's cancer center. "This has always been our mission."

Engagement with Southwestern tribes and community consent was a key part of designing the project, and as enrollment, genomic testing, and data analysis progresses, a tribal advisory council, including patients, patient advocates, and leaders of Southwest Indigenous tribes, will continue to provide guidance, review emerging data, and oversee data sharing within the project.

The council has already impacted the project in important ways. For example, it became clear through conversations with the advisory council that there were sensitivities around the extensive collection of biospecimens in this project. As a result, the consent processes were made more flexible so participants can decide to have residual samples destroyed or provide a separate consent to allow their use in future research.

American Indian tribes in the Southwest also have strict rules about who can be members based on how closely they are related to an original tribe member on census rolls. This type of calculation, usually conducted by a tribal official, may not align with genetic ancestry analysis. As such, while researchers will conduct genetic ancestry research within this project, Willman said the investigators had to assure tribal leaders that this type of data will not be disclosed and "will never be used for tribal and cultural identification," Willman said.

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