Genome Characterization Unit

While sovereign American Indian and Alaskan Native (AI/AN) tribes and communities across the United States have distinct languages and cultures, there is one unfortunate characteristic they share: extremely poor cancer health outcomes. Compounded by lower rates of cancer screening and more limited access to healthcare, AI/AN are more often diagnosed at later stages of disease and have the poorest outcomes for all types of cancer when compared to any other population in the United States. While the cause of these poor cancer health outcomes is likely multifactorial, a potential and largely unexplored factor is variation in the molecular genetic profiles of cancers arising in AI/AN. AI/AN populations were strikingly understudied in The NIH Cancer Genome Atlas Project (TCGA), accounting for < 0.5% of the cancer patients studied from across the nation. Of the nearly 11,000 patients sequenced in TCGA, only 27 (0.25%) were identified as AI/AN. It is our hypothesis that through appropriate, respectful AI/AN participant and community engagement and comprehensive genomic sequencing, we will discover novel germline and somatic tumor mutations, differences in the spectrum and/or frequency of cancer-promoting mutations, and genome-wide mutational signatures reflective of distinct exposures. It is our goal to translate these discoveries to improved cancer screening, precision prevention, and therapeutic intervention for AI participants and their communities. These studies will contribute new knowledge that benefits all U.S. populations. In this PE-CGS Center, while all cancers are under study, we are focusing on the molecular characterization of cancers that occur with increased frequency or those which are associated with particularly poor outcomes in AI communities in the American Southwest including: gastrointestinal and hepatobiliary cancers (stomach, colorectal, pancreatic, liver, biliary tract); genitourinary cancers (kidney, prostate); and other hormone-dependent cancers (breast, ovarian cancers). Our Specific Aims are to develop respectful and trusted means to: 1) Engage AI participants (cancer patients, survivors), Tribal Advisory and Governance Committees, and communities in participatory research studies of the molecular characterization of cancer, particularly focusing on cancers that display striking differences in incidence and outcome in Tribal Nations in the Southwest; 2) Discover novel somatic and germline mutations and/or differences in the spectrum and frequency of cancer-promoting mutations, and genome-wide mutational signatures reflective of specific exposures in AI participants, relative to other U.S. populations; 3) Disseminate clinical grade sequencing results and knowledge gained directly to cancer patient participants and their healthcare providers for their beneficence, supported with genetic counseling and navigation to treatment; and 4) Share anonymized, deidentified data and knowledge gained to Tribal participants, Advisory Committees, leaders, and communities using respectful means of engagement and communication, and also with the broader scientific community through the NCI Genome Data Commons and publication of scientific results in accordance with NIH Data Sharing Policies and Tribal Data Use Agreements.