Gene and pathway based burden analyses in familial lymphoid cancer cases: Rare variants in immune pathway genes

Genome-wide association studies have revealed common genetic variants with small effect sizes associated with diverse lymphoid cancers. Family studies have uncovered rare variants with high effect sizes. However, these variants explain only a portion of the heritability of these cancers. Some of the...

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Bibliographic Details
Published in:PloS one 2023-06, Vol.18 (6), p.e0287602
Main Authors: Ralli, Sneha, Jones, Samantha J, Leach, Stephen, Lynch, Henry T, Brooks-Wilson, Angela R
Format: Article
Language:English
Subjects:
Adaptive systems
Analysis
B cells
Biology and Life Sciences
Cancer
Consortia
Control data (computers)
Diagnosis
Exome Sequencing
Family studies
Genes
Genetic aspects
Genetic diversity
Genetic Predisposition to Disease
Genetic variance
Genome-wide association studies
Genome-Wide Association Study
Genomes
Genomics
Germ-Line Mutation
Health aspects
Heritability
Humans
Immune system
Leukemia
Lymphoid tissue
Lymphoma
Medicine and Health Sciences
Neoplasms
Odorant receptors
T cells
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Summary:Genome-wide association studies have revealed common genetic variants with small effect sizes associated with diverse lymphoid cancers. Family studies have uncovered rare variants with high effect sizes. However, these variants explain only a portion of the heritability of these cancers. Some of the missing heritability may be attributable to rare variants with small effect sizes. We aim to identify rare germline variants associated with familial lymphoid cancers using exome sequencing. One case per family was selected from 39 lymphoid cancer families based on early onset of disease or rarity of subtype. Control data was from Non-Finnish Europeans in gnomAD exomes (N = 56,885) or ExAC (N = 33,370). Gene and pathway-based burden tests for rare variants were performed using TRAPD. Five putatively pathogenic germline variants were found in four genes: INTU, PEX7, EHHADH, and ASXL1. Pathway-based association tests identified the innate and adaptive immune systems, peroxisomal pathway and olfactory receptor pathway as associated with lymphoid cancers in familial cases. Our results suggest that rare inherited defects in the genes involved in immune system and peroxisomal pathway may predispose individuals to lymphoid cancers.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0287602