Unique Genomic Alterations and Microbial Profiles Identified in Gastric Cancer Patients with African, European and Asian Ancestry: A Novel Path for Precision Oncology?
Miseker Abate*1, Henry Walch2, Chad Vanderbilt5, Teng Fei6, Kanika Arora2, Harrison Drebin1, Smita Sihag7, Shoji Shimada1, Laura Tang5, Masaya Nakauchi1, Santosh Vardhana4, Murray Brennan3, Nikolaus Schultz2, Vivian E. Strong1
1Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY; 2Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, NEW YORK, NY; 3Department of Surgery, Memorial Sloan Kettering Cancer Center, NEW YORK, NY; 4Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, NEW YORK, NY; 5Department of Pathology, Memorial Sloan Kettering Cancer Center, NEW YORK, NY; 6Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, NEW YORK, NY; 7Department of Thoracic Surgery, Memorial Sloan Kettering Cancer Center, NEW YORK, NY
Introduction: Gastric Cancer (GC) is a heterogenous disease with clinicopathologic variations due to a complex interplay of environmental, genomic, and microbial factors, which contribute to differences in oncologic outcomes. However, it is unknown whether biological tumor variations contribute to cancer disparities observed between different patient populations. In this study, we characterize differences in the genetic and microbial profiles of GC patients with African, European and Asian ancestry.
Methods: 1,131 GC patients who underwent next generation sequencing (NGS) of cancer genes by an institutional Integration Mutation Profiling of Actionable Cancer Targets (IMPACT) assay (n=690), and from The Cancer Genomic Atlas (TCGA) database (n=441) were identified. Accurate genetic ancestry inference was derived from an IMPACT ancestry registry and markers captured by the TCGA whole exome sequencing panel. Somatic and germline alterations were compared between GC patients with African, European and Asian ancestry in the IMPACT cohort and correlated with the TCGA cohort. A validated microbiome bioinformatics pipeline that is generalizable across multiple NGS platforms was utilized to characterize differences in microbial enrichment.
Results: 8,023 genomic alterations were investigated and compared between ancestry cohorts. The most frequently altered genes were TP53, ARID1A, KRAS, ERBB2, and CDH1. Compared to the European (n=384) and East Asian (n=89) ancestry groups, patients with African (n=38) ancestry had a significantly higher rate of oncogenic alterations in CCNE1 (13% vs. 4% and 6%) genes, and a significantly lower rate of alterations in KRAS (3% vs. 17% and 9%)(p<0.05), respectively (Figure 1A&B). Compared to the European and African groups, patients with East Asian ancestry had a significantly lower rate of PI3K pathway alterations (2% vs. 9% and 9%)(p<0.05), respectively (Figure1B). Frequency of genetic alterations among ancestry groups correlated with the TCGA cohort. There were no significant differences in fraction genome altered or tumor mutational burden (Figure 1C), or in the germline landscape across ancestry groups. The relative frequencies of microbial enrichments were reported across ancestry groups (Table 1).
Discussion: Distinct and significant patterns of somatic and germline mutations, and relative variation in microbial markers are identified in patients of African, European, and Asian ancestry in the largest GC cohort to date. Identification of high-frequency mutations of genes that are not currently clinically actionable alterations, such as CCNE1, provides crucial insight into how specific patient populations can be better served by precision oncology interventions. Given the limitations of current genetic signatures’ ability to guide cancer treatments, our findings of ancestry-specific biomarkers provide insight into how precision medicine can work to mitigate the oncologic disparities seen in GC.
Table 1. The relative frequency of microbial enrichment in patients of European, Asian and African ancestry groups among the institutional Integration Mutation Profiling of Actionable Cancer Targets (IMPACT) cohort
|Helicobacter||20 (7.2%)||6 (21%)||5 (8.6%)||1 (7.7%)|
|Lactobacillus||49 (18%)||10 (34%)||12 (21%)||0 (0%)|
|Bacteroides||24 (8.7%)||3 (10%)||5 (8.6%)||0 (0%)|
|Prevotella||66 (24%)||9 (31%)||8 (14%)||2 (15%)|
|Streptococcus||116 (42%)||15 (52%)||20 (34%)||4 (31%)|
|Selenomonas||27 (9.7%)||3 (10%)||2 (3.4%)||0 (0%)|
|Fusobacterium||33 (12%)||4 (14%)||4 (6.9%)||2 (15%)|
|Corynebacterium||146 (53%)||22 (76%)||36 (62%)||4 (31%)|
|Sphingomonas||108 (39%)||19 (66%)||20 (34%)||3 (23%)|
|Pseudomonas||201 (73%)||25 (86%)||36 (62%)||8 (62%)|
Figure 1. A) Oncoprint of the genomic alterations in the European (EUR), African (AFR), East Asian (EAS) and South Asian IMPACT population B) Frequency of oncogenic and pathway genomic alterations across ancestry groups C) Frequency of tumor mutation burden and fraction genome altered across ancestry groups.
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