Recent advances in targeted treatment for lung cancer, including against EGFR mutations and ALK rearrangements, have their origins in genomic analyses of tumors. Further, the identification of a synthetic lethal interaction between PARP inhibitors and BRCA loss of function is changing how some breast and ovarian cancers are treated and even the once considered undruggable KRAS G12C mutation, found in approximately 25% of all cancers, now seems to be a clinical target. One of the central observations of the EGFR mutation story is its geographic diversity; these mutations are far more common among Asian populations than in European or American populations. This is because EGFR mutations are more likely to occur in lung tumors of never smokers and the proportion of never smoking lung cancer cases is higher in Asian countries (the etiology of lung cancer in these never smoking individuals is, in part, tied to exposure to secondhand smoke and indoor cooking fumes).
Here in the U.S., most genomic characterization of lung cancer, or indeed any cancer, has not had adequate representation of minority populations. For example, the majority of tumor samples across TCGA are from individuals of European descent, with African Americans comprising just 8.5% of tumor samples. Over the past number of years, our group has been driven to ensure that advances in lung cancer treatment and therapy can be applied equally. To do that, it is necessary to have an understanding of lung tumor biology that is representative of all populations in the U.S., not just those of European descent.
In studying lung tumor biology from European Americans and African Americans, we had discovered that a majority of tumor biology is shared. Given that the single strongest etiological factor associated with lung cancer in the U.S. is smoking, this wasn’t an unexpected result. However, in a study we published in 2019, we discovered somatic mutations in two genes that occur at a frequency of 30% in lung adenocarcinomas from African American patients and just 10% of European Americans. The exciting part of this observation was that the two genes are in the same pathway and we are now trying to figure out if these mutations are actionable. Fundamentally, that study taught us that population differences in lung tumor biology exist and that finding these differences may have helped us identify a vulnerability.
In this new paper, two very talented fellows in our group (Sanju Sinha and Khadijah Mitchell) took on the challenge of trying to further characterize the breadth of somatic genomic differences between European Americans and African Americans. We are fortunate to have access to patient samples through the NCI-Maryland case control study, where we have both an over-representation of African Americans and a well characterized cohort in terms of demographic and clinical data. The study design was simple and empirical: copy number analysis of 222 lung tumors from African Americans and European Americans. The results, however, were wide-ranging and, in some ways, raise more questions for us.
Collaborating with Dr Eytan Ruppin who had recently moved to NCI, we found that lung tumors, and especially lung squamous cell carcinomas from African Americans, have higher genomic instability and homologous recombination deficiency compared with European Americans. We are not sure yet why this is seen in the squamous histological subtype and not adenocarcinoma, but Sanju decided to leverage TCGA’s database of germline pathogenic variants, catalogued through sequencing of more than 10,000 patients’ PBMCs. Using this dataset, we counted the number of pathogenic variants in homologous recombination repair-related genes in each patient and found that African American patients with squamous cell carcinoma have a higher extent of germline pathogenic variants in this gene set than European American patients. This wasn’t seen in adenocarcinomas. To us, this suggests a possible germline origin to the increased homologous recombination deficiency we observe.
We also leveraged TCGA to ask whether the phenomenon we saw in lung cancer extended to other cancer types and it was remarkable to see that increased genomic instability and homologous recombination deficiency among African American patients is seen across many cancer types. Our lab tries to view our studies with a translational lens, all the while knowing that the line between initial observation and clinical translation is far from straight. One interpretation of our data however, is that some cancer types that have not typically been considered amenable to PARP inhibition may harbor this deficiency in a subset of tumors partly defined by racial ancestry; African Americans may be more likely to benefit from PARP inhibition given their higher likelihood of having a cancer with homologous recombination deficiency. This is something we want to test.
Since records began tracking cancer incidence by racial and ethnic group in the U.S., data show that African Americans (and especially men) have a higher incidence compared with all other racial and ethnic groups. While it is likely that some facet of smoking exposure explains these disparities, we haven’t been able to figure it out yet, but it is something we continue to work on. The differences that we find in tumor biology by race do not explain why we see more lung cancer in African Americans, nor do they explain why African American lung cancer patients persistently have worse clinical outcomes—the latter is primarily driven by access to quality health care. But, to the degree that tumor biology can be a footprint that reflects the cumulative effect of exposures that lead to cancer in the first place, it could offer some clues. And so, while one lens of our work looks forward towards a translational view of things, another is reflective.
It has been exciting to see the expanse of genomics research in recent years and, more specifically, its application to minority and under-represented populations. In our ongoing studies, we are looking at further genomic layers. And, as with all of our work to date, even if no differences are found, we firmly believe that it is important to at least ask the question. This will help ensure equitable translation of progress in precision medicine to all populations and all individuals.