Understanding the Impact of Population Genetics on Cancer Treatment

Amin Nassar, MD

My research in population genetics integrates genetics and large-scale electronic health record data to identify meaningful biomarkers of treatment consequences and develop algorithmic models to support clinical decision-making. Additionally, it emphasizes that genomic inequities aggravate existing health disparities and bias genetic discoveries toward more represented populations. As such, I focus on the identification of genomic biomarkers across ancestral populations with cancer. This has culminated in several high-impact publications, which include but are not limited to as follows:

1. The identification of the distribution of KRAS G12C mutations¹ across cancer types and by sex and race. As KRAS G12C mutations are important targetable drivers, this was the first comprehensive description of the prevalence of this mutation across different populations.
2. Germline variant contamination has varying impacts on tumor mutational burden (TMB). Pembrolizumab (Keytruda) is an FDA-approved immune checkpoint inhibitor (ICI) for patients with high TMB (≥ 10 variants/megabase) based on the tumor-only sequencing panel from FoundationOne. In work published in Cancer Cell,² we hypothesized that because of germline variant contamination, tumor-only sequencing panels likely lead to more pronounced TMB inflation in non-European patients relative to European patients. We leveraged 3 different cohorts: The Cancer Genome Atlas, DanaFarber Cancer Institute, and Memorial Sloan Kettering Cancer Center, all of patients diagnosed with solid tumors. Results showed that tumor mutational biomarker calculation can be inflated if based on tumor-only sequencing, especially in non-European patients. They further showed that this impacts clinical outcomes among patients treated with ICIs. Similar to patients with low TMB, patients with falsely high TMB estimates have significantly worse outcomes compared with patients with true TMB-high tumors when treated with ICIs. We then went on to develop and validate a methodology to calibrate TMB derived from tumor-only sequencing platforms. This work has gained widespread recognition globally, led to invited talks at American Association for Cancer Research, Korean Society of Medical Oncology, and Tempus grand rounds, and has been highlighted in more than 10 media outlets, with several editorials published in Cancer Cell, Nature, and Nature Reviews Genetics.
3. Different ancestries lead to varying dispositions. We also published work in Cell Reports³ interrogating germline mutations in patients with kidney cancer across different ancestries and highlighting that European and Black patients have different germline mutations that predispose them to kidney cancer. From an epigenetic standpoint, I have pioneered work that maps the epigenetic landscape of 3 subtypes of renal cell carcinoma (RCC): clear cell, chromophobe, and papillary; using different sequencing techniques to map the chromatin and transcriptional landscapes. Our team showed that the epigenome of chromophobe RCC differs from that of clear cell and papillary. Along with the team, we developed an integrated approach that identified 50 candidate histology-specific master transcription factors, which can be further leveraged to better understand RCC pathogenesis. We also leveraged a methodology based on preferential transcription of certain gene alleles, termed allelic imbalance, that can nominate and prioritize causal risk single-nucleotide polymorphisms that are likely to alter transcription factor binding sites.⁴

The Link Between HIV and Cancer

Finally, I have spent many of my research efforts on underserved populations, which also spans people living with HIV (PWH). PWH are more likely to develop and/or die from cancer vs people living without HIV (PWOH).

ICIs changed the cancer treatment paradigm, but PWH have either been excluded from clinical trials or included with stringent inclusion criteria. As such, addressing the safety and efficacy of ICIs and other systemic treatments in PWH remains of utmost importance as oncologists expand treatment options for PWH. Where trials fall short or lag behind, real-world studies present an opportunity to address knowledge gaps and guide clinical decision-making for PWH.

Cancer Therapy using Checkpoint inhibitors in PWH-International (CATCH-IT) is an international consortium focused on the outcomes of PWH receiving ICIs. The consortium consists of 33 national and international cancer centers focused on improving the care for PWH.

In the first study from CATCH-IT, the team investigated the safety and efficacy of ICIs in 451 PWH. They showed that ICIs were safe with no unexpected adverse effects. Moreover, they showed that clinical outcomes, including overall survival and progression-free survival, were similar among PWH and PWOH. This work, now published in the Journal of Clinical Oncology,⁵ supports inclusion of PWH in ICI-based trials and motivates clinicians to offer ICIs to patients.

References

1. Nassar AH, Adib E, Kwiatkowski DJ. Distribution of KRASG12C somatic mutations across race, sex, and cancer type. N Engl J Med. 2021;384(2):185-187. doi:10.1056/NEJMc2030638
2. Nassar AH, Adib E, Abou Alaiwi S, et al. Ancestry-driven recalibration of tumor mutational burden and disparate clinical outcomes in response to immune checkpoint inhibitors. Cancer Cell. 2022;40(10):1161-1172.e5. doi:10.1016/j.ccell.2022.08.022
3. Abou Alaiwi S, Nassar AH, Adib E, et al. Trans-ethnic variation in germline variants of patients with renal cell carcinoma. Cell Rep. 2021;34(13):108926. doi:10.1016/j.celrep.2021.108926
4. Nassar AH, Abou Alaiwi S, Baca SC, et al. Epigenomic charting and functional annotation of risk loci in renal cell carcinoma. Nat Commun. 2023;14(1):346. doi:10.1038/s41467-023-35833-5
5. El Zarif T, Nassar AH, Adib E, et al. Safety and activity of immune checkpoint inhibitors in people living with HIV and cancer: a real-world report from the cancer therapy using checkpoint inhibitors in people living with HIV-International (CATCH-IT) Consortium. J Clin Oncol. Published online May 16, 2023. doi:10.1200/ JCO.22.02459