Interplay between Chromosomal Alterations and Gene Mutations Shapes the Evolutionary Trajectory of Clonal Hematopoiesis

Teng Gao,Ahmet Zehir,Ross L Levine,Ederlinda Paraiso,Ryma Benayed,Mariko Yabe,Michael F Berger,Barbara Spitzer,Kamal Menghrajani,Kelly L Bolton,David B Solit,Yanming Zhang,Elli Papaemmanuil,Virginia M Klimek,Yangyu Zhou,John Philip,Elsa Bernard,Ryan Ptashkin,Simon Mantha,Juan Medina ,Christopher J Fong ,Luis A Díaz ,Minal Patel ,Nicole M Caltabellotta ,Sebastià Franch‐Expósito ,Juan Arango Ossa ,Daniel Kelly ,Max F Levine ,Lior Z Braunstein ,Sean M Devlin

doi:10.1182/blood-2020-141882

Abstract

Interplay between Chromosomal Alterations and Gene Mutations Shapes the Evolutionary Trajectory of Clonal Hematopoiesis

Highlights

Acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development
The majority of our samples were sequenced by the most recent version of the panel, IMPACT6, which captures the exonic regions of 468 recurrent cancer genes and includes probes against 1042 common single nucleotide polymorphisms (SNPs)
Recent characterizations of somatic mutations in cancer as well as normal tissues suggest that the multi-step process of tumorigenesis is often an interplay between gene mutations and chromosomal alterations[2,3,44]

Summary

Introduction

Acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Putative driver (PD) status, mutation burden and clone size as estimated by variant allele fraction (VAF) of acquired gene mutations are established predictors of disease progression in CH10,11 Such criteria are increasingly being considered clinically to evaluate individuals at risk of leukemic transformation[20,21,22,23]. We develop a method to reliably detect mCAs in data from established prospective sequencing assays used in routine clinical practice We apply this method in a cohort of 32,442 cancer patients and characterize in detail the incidence and presentation of mCAs in the context of concurrent gene mutations. We show that mCAs are independent predictors of progression to hematological neoplasms and demonstrate the value of incorporating mCAs in the reporting and interpretation of CH in cancer patients[22,23]

Objectives

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Results

Conclusion