The Genomic Landscape of a Restricted ALL Cohort from Patients Residing on the U.S./Mexico Border.

Robert Arthur Kirken,Yoshira Marie Ayala-Marin,Georgialina Rodriguez,Elisa Robles-Escajeda,Alice Hernandez Grant,Julie Dutil,Jonathon Edward Mohl

doi:10.3390/ijerph18147345

Abstract

Next-generation sequencing (NGS) has identified unique biomarkers yielding new strategies in precision medicine for the treatment of Acute lymphoblastic leukemia (ALL). Hispanics show marked health disparities in ALL, often absent in clinical trials or cancer research. Thus, it is unknown whether Hispanics would benefit equally from curated data currently guiding precision oncology. Using whole-exome sequencing, nine ALL patients were screened for mutations within genes known to possess diagnostic, prognostic and therapeutic value. Genes mutated in Hispanic ALL patients from the borderland were mined for potentially pathogenic variants within clinically relevant genes. KRAS G12A was detected in this unique cohort and its frequency in Hispanics from the TARGET-ALL Phase II database was three-fold greater than that of non-Hispanics. STAT5B N642H was also detected with low frequency in Hispanic and non-Hispanic individuals within TARGET. Its detection within this small cohort may reflect a common event in this demographic. Such variants occurring in the MAPK and JAK/STAT pathways may be contributing to Hispanic health disparities in ALL. Notable variants in ROS1, WT1, and NOTCH2 were observed in the ALL borderland cohort, with NOTCH2 C19W occurring most frequently. Further investigations on the pathogenicity of these variants are needed to assess their relevance in ALL.

Highlights

The occurrence of KRAS G12X was similar across Hispanics in both the Acute lymphoblastic leukemia (ALL) borderland cohort and the larger database, and three-fold greater than that observed in non-Hispanic whites
Aberrations in the mitogen-activated protein kinase (MAPK) pathway may be contributing to Hispanic health disparities in ALL, while aberrations in the JAK/STAT pathway may be more relevant to health disparities unique to Mexican-Americans or the borderland
One major finding included the detection of KRAS G12A and STAT5B N642H in Hispanic ALL borderland patients

Summary

Introduction

A subgroup does exhibit refractory or ALL relapse, and the five-year free survival rate is reduced to 15–50% [1] This subgroup is disproportionately reported for Hispanic children who experience a 5% lower five-year free survival rate for ALL than their non-Hispanic counterparts [2]. The etiology for ALL relapse is unclear, but advances in stratification based on chromosomal abnormalities and genetic alterations are guiding their prognosis and treatment management [3]. These improvements in stratification are largely derived from next-generation sequencing (NGS) studies that have revealed unique biomarkers associated with diagnostic criteria as well as prognostic relevance of leukemias, yielding to the revised 2016 classifications of acute leukemias by the World Health Organization [4]

Methods

Discussion

Conclusion