Evaluation of the genetic basis of familial-associated early-onset hematologic cancers in an ancestral/ethnically diverse population

Sep 21, 2026

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Genetic predisposition to hematologic malignancies has often been studied using clinical-trial patients and pedigrees from major treatment centers, leaving uncertainty about how inherited risk differs across racial and ethnic groups in population-wide surveillance. Exome sequencing was performed on newborn bloodspots from California sibling pairs with early-onset cancers, using unbiased recruitment across the full state population. Pathogenic/likely pathogenic variants were identified across 1,172 cancer genes, revealing shared variants within families and ancestry-consistent haplotype origins, supporting that rare contributing alleles arise within ancestral parental populations.

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Abstract

Introduction

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; 2 Division of Hematology/Oncology, Department of Medicine, and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL and 3 Departments of Medicine and Laboratory Medicine, University of California, San Francisco, CA, USA Correspondence: J. L. Wiemels [wiemels@usc.edu](wiemels@usc.edu) Received: September 20, 2023. Accepted: December 29, 2023. Early view: January 11, 2024. [https://doi.org/10.3324/haematol.2023.284224](https://doi.org/10.3324/haematol.2023.284224) ©2024 Ferrata Storti Foundation Published under a CC BY-NC license Abstract Genetic predisposition to hematologic malignancies has historically been addressed utilizing patients recruited from clinical 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 hematologic 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 populations. 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 sibling 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 lymphoma 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, demonstrating 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 cancers.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 lymphoblastic leukemia is the most common, accounting for approximately 25% of all cancers diagnosed in children; and other lymphoid maligna

FAQs

What study design was used to assess the genetic basis of familial early-onset hematologic cancers?

The study performed exome sequencing on DNA from newborn bloodspots from California sibling pairs with early-onset cancers, using unbiased recruitment from the full state population.

How many pathogenic/likely pathogenic variants and shared variants were found within families?

Pathogenic/likely pathogenic variants were identified among 1,172 cancer genes, and within 64 subjects from 32 families, nine likely pathogenic variants were shared between siblings, with an additional seven in singleton children not shared with their sibling.

What role did ancestry play in interpreting shared pathogenic variants?

In eight of the shared cases, the ancestral origin of the local haplotype carrying pathogenic variants matched the dominant global ancestry of the study families, supporting ancestry-consistent inheritance patterns.

Sep 21, 2026

Uploaded by Violet