Page 71 - Haematologica Vol. 109 - July 2024

ARTICLE - Acute Lymphoblastic Leukemia
Evaluation of the genetic basis of familial-associated early-onset hematologic cancers in an ancestral/ethnically diverse population
Qianxi Feng,1 Keren Xu,1 Mancy Shah,2 Shaobo Li,1 Andrew D. Leavitt,3 Lucy A. Godley,2 Adam J. de Smith1 and Joseph L. Wiemels1
1Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA; 2Division of Hematology/Oncology, Department of Medicine, and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL and 3Departments of Medicine and Laboratory Medicine, University of California, San Francisco, CA, USA
Abstract
Genetic predisposition to hematologic malignancies has historically been addressed utilizing patients recruited from clini- cal trials and pedigrees constructed at major treatment centers. Such efforts leave unexplored the genetic basis of variations in risk by race/ethnic group shown in population-based surveillance data where cancer registration, compulsory by law, delivers universal enrollment. To address this, we performed exome sequencing on DNA isolated from newborn bloodspots derived from sibling pairs with early-onset cancers across California in which at least one of the siblings developed a he- matologic cancer, using unbiased recruitment from the full state population. We identified pathogenic/likely pathogenic (P/ LP) variants among 1,172 selected cancer genes that were private or present at low allele frequencies in reference popula- tions. Within 64 subjects from 32 families, we found 9 LP variants shared between siblings, and an additional 7 such variants in singleton children (not shared with their sibling). In 8 of the shared cases, the ancestral origin of the local haplotype that carries P/LP variants matched the dominant global ancestry of study participant families. This was the case for Latino sib- ling pairs on FLG and CBLB, non-Latino White sibling pairs in TP53 and NOD2, and a shared GATA2 variant for a non-Latino Black sibling pair. A new inherited mutation in HABP2 was identified in a sibling pair, one with diffuse large B-cell lympho- ma and the other with neuroblastoma. Overall, the profile of P/LP germline variants across ancestral/ethnic groups suggests that rare alleles contributing to hematologic diseases originate within their race/ethnic origin parental populations, demon- strating the value of this discovery process in diverse, population-based registries.
Introduction
Hematologic malignancies (including leukemias, lymphomas, and multiple myeloma) are the most commonly diagnosed early-onset cancers among children, adolescents, and young adults.1 Inherited and de novo mutation of genes within critical cell development and growth/signaling pathways are central oncogenic events in the pathogenesis of hematologic can- cers.2 Pathogenic/likely pathogenic (P/LP) germline variants were identified in approximately 10% of pediatric hematologic cancer patients regardless of family history.3-6 The risk of early-onset cancers (of any type) diagnosed under 26 years of age is 2.97 times higher among siblings and mothers who have a proband with hematologic cancer in the same family,7 indicating that inherited germline variants may contribute to this excessive cancer risk. This risk varies among ancestral/
ethnic groups,7 suggesting that predisposition variants may vary by identity or frequency among groups.
Among early-onset hematologic malignancies, acute lym- phoblastic leukemia is the most common, accounting for approximately 25% of all cancers diagnosed in children; and other lymphoid malignancies account for an additional 10% of all cancers.1,8 In our examination of linked popula- tion registries in California, the relative early-onset cancer risk is 2.87 times higher among siblings and mothers given a proband with leukemia, and 4.66 times higher given a proband with lymphoma.7 Acute lymphoblastic leukemia (ALL) is the most common leukemia in children and young adults. Recent studies have identified deleterious germline variants in TP53, PAX5, IKZF1, and ETV6 as risk factors for ALL9-11 but have not assessed the spectrum of deleterious germline variants among ancestral groups or in individuals
Haematologica | 109 July 2024
2085
Correspondence: J.L. Wiemels wiemels@usc.edu
Received: Accepted: Early view:
September 20, 2023. December 29, 2023. January 11, 2024.
https://doi.org/10.3324/haematol.2023.284224
©2024 Ferrata Storti Foundation Published under a CC BY-NC license