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A Swedish Familial Genome-Wide Haplotype Analysis Identified Five Novel Breast Cancer Susceptibility Loci on 9p24.3, 11q22.3, 15q11.2, 16q24.1 and Xq21.31.

ABSTRACT: Most breast cancer heritability is unexplained. We hypothesized that analysis of unrelated familial cases in a GWAS context could enable the identification of novel susceptibility loci. In order to examine the association of a haplotype with breast cancer risk, we performed a genome-wide haplotype association study using a sliding window analysis of window sizes 1-25 SNPs in 650 familial invasive breast cancer cases and 5021 controls. We identified five novel risk loci on 9p24.3 (OR 3.4; p 4.9 × 10^-11), 11q22.3 (OR 2.4; p 5.2 × 10^-9), 15q11.2 (OR 3.6; p 2.3 × 10^-8), 16q24.1 (OR 3; p 3 × 10^-8) and Xq21.31 (OR 3.3; p 1.7 × 10^-8) and confirmed three well-known loci on 10q25.13, 11q13.3, and 16q12.1. In total, 1593 significant risk haplotypes and 39 risk SNPs were distributed on the eight loci. In comparison with unselected breast cancer cases from a previous study, the OR was increased in the familial analysis in all eight loci. Analyzing familial cancer cases and controls enabled the identification of novel breast cancer susceptibility loci.

SUBMITTER: Barnekow E

PROVIDER: S-EPMC10003706 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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A Swedish Familial Genome-Wide Haplotype Analysis Identified Five Novel Breast Cancer Susceptibility Loci on 9p24.3, 11q22.3, 15q11.2, 16q24.1 and Xq21.31.

Barnekow Elin E Hasslow Johan J Liu Wen W Bryant Patrick P Thutkawkorapin Jessada J Wendt Camilla C Czene Kamila K Hall Per P Margolin Sara S Lindblom Annika A

International journal of molecular sciences 20230224 5

Most breast cancer heritability is unexplained. We hypothesized that analysis of unrelated familial cases in a GWAS context could enable the identification of novel susceptibility loci. In order to examine the association of a haplotype with breast cancer risk, we performed a genome-wide haplotype association study using a sliding window analysis of window sizes 1-25 SNPs in 650 familial invasive breast cancer cases and 5021 controls. We identified five novel risk loci on 9p24.3 (OR 3.4; <i>p</i ...[more]

PMID: 36901898

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Project description:The 15q11.2 BP1-BP2 deletion (Burnside-Butler) syndrome is emerging as the most common cytogenetic finding in patients with neurodevelopmental or autism spectrum disorders (ASD) presenting for microarray genetic testing. Clinical findings in Burnside-Butler syndrome include developmental and motor delays, congenital abnormalities, learning and behavioral problems, and abnormal brain findings. To better define symptom presentation, we performed comprehensive cognitive and behavioral testing, collected medical and family histories, and conducted clinical genetic evaluations. The 15q11.2 BP1-BP2 region includes the TUBGCP5, CYFIP1, NIPA1, and NIPA2 genes. To determine if additional genomic variation outside of the 15q11.2 region influences expression of symptoms in Burnside-Butler syndrome, whole-exome sequencing was performed on the parents and affected children for the first time in five families with at least one parent and child with the 15q1l.2 BP1-BP2 deletion. In total, there were 453 genes with possibly damaging variants identified across all of the affected children. Of these, 99 genes had exclusively de novo variants and 107 had variants inherited exclusively from the parent without the deletion. There were three genes (APBB1, GOLGA2, and MEOX1) with de novo variants that encode proteins evidenced to interact with CYFIP1. In addition, one other gene of interest (FAT3) had variants inherited from the parent without the deletion and encoded a protein interacting with CYFIP1. The affected individuals commonly displayed a neurodevelopmental phenotype including ASD, speech delay, abnormal reflexes, and coordination issues along with craniofacial findings and orthopedic-related connective tissue problems. Of the 453 genes with variants, 35 were associated with ASD. On average, each affected child had variants in 6 distinct ASD-associated genes (x¯ = 6.33, sd = 3.01). In addition, 32 genes with variants were included on clinical testing panels from Clinical Laboratory Improvement Amendments (CLIA) approved and accredited commercial laboratories reflecting other observed phenotypes. Notably, the dataset analyzed in this study was small and reported results will require validation in larger samples as well as functional follow-up. Regardless, we anticipate that results from our study will inform future research into the genetic factors influencing diverse symptoms in patients with Burnside-Butler syndrome, an emerging disorder with a neurodevelopmental behavioral phenotype.

Dataset Information

A Swedish Familial Genome-Wide Haplotype Analysis Identified Five Novel Breast Cancer Susceptibility Loci on 9p24.3, 11q22.3, 15q11.2, 16q24.1 and Xq21.31.

Publications

A Swedish Familial Genome-Wide Haplotype Analysis Identified Five Novel Breast Cancer Susceptibility Loci on 9p24.3, 11q22.3, 15q11.2, 16q24.1 and Xq21.31.

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