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Genetic ancestry and genomic alterations of cervical cancer in a diverse patient population
Abstract
Objectives This study aimed to evaluate the influence of genetic ancestry (GA) on the genomic landscape of cervical cancer in an ethnically diverse patient population. Methods Whole exome sequencing (WES) of DNA extracted from archival tissue (93 tumors and 29 paired normal endometrium samples) was performed using Exome 2.0 exome capture (Twist Bioscience) and Illumina NovaSeq X reagents and instrument. Tumor-only variant calling was performed using TGen's Tempe pipeline. GA was estimated from WES data using genome-wide single nucleotide polymorphism weights from large external reference panels. The frequency of genomic alterations was compared between GA groups. MafTools functions (oncodrive, mafCompare, clinicalEnrichment, oncogenicPathways) were used to evaluate differences in enrichment of gene or pathway mutations by genetic ancestry group. Results The cohort consisted of 93 genetically diverse individuals: 33.3 % (n = 31) with Latin American-like (LAM) GA, 52.7 % (n = 49) European-like GA, 8.6 % (n = 8) East Asian-like GA and 5.4 % (n = 5) African-like GA. Of the 93 tumor samples, 62 were from the primary cervical tumor, 15 from lymph nodes, 12 from recurrent tumors and four from other sites. Cancer genes found to be recurrently mutated across the cohort included PIK3CA (19 %), KMT2C (17 %), KMT2D (18 %) and TP53 (8 %). PIK3CA mutations were enriched within tumors from LAM-like individuals (11/31, 35.5 %) versus tumors from EUR-like individuals (5/49, 10.2 %, P = 0.0092). An unbiased analysis comparing mutational frequency for all genes between the LAM and EUR cohorts identified five genes with mutations enriched in the LAM cohort (GALNT12, DNAH17, PIK3CA, MYO16 and ZNF678) and four genes with mutations enriched in the EUR cohort (E2F5, KIR3DL2, GYPB and OR10G9). Collapsing gene mutations into pathways, the PI3K pathway showed a significant increase in mutational frequency in LAM tumors (15/31, 48.4 %) versus EUR tumors (12/49, 24.5 %, P = 0.0324). Conclusions The genomic landscape of cervical cancer tumors from individuals of Latin American GA is different than that of those with European GA in our cohort. Specifically, the finding that PIK3CA mutations occur more frequently in tumors from women of Latin American GA may have implications for treatment and inclusive clinical trial design.
Product Used
NGS
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