Addressing Underrepresented Populations in Lung Cancer Research: The Hispanic/Latino Lung Cancer Registry Identifies Distinct Mutation Profiles for NSCLC

Precision medicine in oncology has been fundamentally shaped by the foundations laid through the molecular and genetic characterization of vast cohorts of clinical tumor specimens. The initiative to characterize these cohorts of cancer specimens began in late 2005 with the National Institutes of Health announcement of the cancer genome initiative only 4 years after official publication of the human genome.¹ This announcement resulted in the origins of The Cancer Genome Atlas (TCGA), a multi-center and multidisciplinary investigative team that played a pivotal role in mapping the current iterations of the cancer genome. In lung cancer, the first comprehensive TCGA genome was made publically available with publication of the squamous cell carcinoma genome in 2012, featuring the genomic and epigenetic characterization of 178 squamous cell carcinomas.² Then in 2014, the comprehensive adenocarcinoma genome was published, featuring the genetic and genomic characterization of 230 resected adenocarcinoma specimens.³ Through this seminal work, TCGA researchers were able to identify commonly occurring driver mutations and amplifications in the two most prevalent histopathological types of NSCLC. As such, these identified driver genes have been the primary targets of an immense amount of targeted drug development. Moreover, the TCGA publications on lung cancer laid the groundwork for our current understanding of the fundamental genome architecture of NSCLC and accordingly have resulted in a staggering 1702 citations to date. And yet, fewer than 3% of the samples in this widely renowned and publically available database of characterized NSCLC specimens originated from Hispanic/Latino individuals, who constitute a growing population in the United States that is expected to account for an increasing number of lung cancer cases as the population continues to age.

Gimbrone et al. sought to address this lack of molecularly characterized and publically available Hispanic/Latino NSCLC samples through establishment of the Latino Lung Cancer Registry.⁴ The registry is an international/multicenter effort between the University of South Florida, Ponce Health Sciences University of Puerto Rico, and the Universidad Perúana Cayetano Heredia in Peru; it consists of data on 163 Hispanic/Latino individuals with recently diagnosed NSCLC. The authors performed targeted exome sequencing on specimens from these 163 individuals with NSCLC to determine how patient ethnicity may affect NSCLC tumor mutation profiles. Additionally, the authors conducted genetic ancestry analysis to better understand the relative proportions of genetic admixture in their cohort to determine how ancestry might further affect mutation rates and burden. Their findings indicated that lung tumors from Hispanic/Latino individuals were much more likely to contain EGFR mutations and less likely to contain KRAS and serine/threonine kinase 11 gene (STK11) mutations than those of their white counterparts in the TCGA data on lung cancer. Likewise, tumor protein p53 gene (TP53) mutations were equally as likely to occur in the Hispanic/Latino cohort as in the white cohort. Ancestral clustering analysis revealed that the cohort was primarily of European ancestry (67%), followed by indigenous American ancestry (21%) and African ancestry (12%). The mutation rates of major lung cancer driver genes appeared to vary by patients’ genetic ancestry, with EGFR mutations occurring much more frequently and TP53 mutations occurring less frequently in patients with higher percentages of indigenous American ancestry than in those of European and African ancestry. These findings suggest that driver mutations among Hispanic/Latino individuals more closely mirror those found in East Asian populations than those found in white populations, with a predominance of EGFR-driven NSCLC. It is important, however, to evaluate mutation frequency with respect to other contributing factors, such as smoking history, sex, and histologic type, all of which play a role in driver mutation determination. Because of the lack of complete smoking history paired with smaller sample sizes in stratified analyses, the authors were unable to determine how differences in smoking rates and exposure amounts might affect EGFR, KRAS, STK11, and TP53. Substantial variation in the distribution of sex, smoking history, and ancestry is evident between the three Latino cohorts included in the registry, indicating the potential complexity in untangling the factors contributing to driver mutation frequencies.

The formation of the Latino Lung Cancer Registry represents progress in developing a foundation to drive precision oncology in the Hispanic/Latino population, but a great deal of additional funding, enrollment, and data collection will be necessary for this registry and other collections of samples in minority populations to reach maturity. First and foremost, detailed clinical characteristics such as quantitative smoking history, age at diagnosis, tumor stage, treatment, and patient outcomes will need to be collected and made publically available for additional analyses. Second, whole exome sequencing, as an alternative to the targeted sequencing of specimens, will expand discovery efforts in the Hispanic/Latino population and allow for future comparison studies with the TCGA cancer genome database. Finally, whole exome specimen sequencing will require properly matched normal tissue to enable researchers to identify and filter germline contributors to the mutational process in tumor samples in the Hispanic/Latino population. The authors have established a foundational cohort to pursue genome-scale lung cancer research in the Hispanic/Latino population to ultimately improve oncology care in this population. With the rapid pace at which precision oncology has been advancing, data collection efforts for underrepresented, minority populations are essential if the advances in targeted treatment are to be applied effectively in these populations.