• Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.Methods: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.Results: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 x 10(-6)) and AC058822.1 (P = 1.47 x 10(-4)), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C.Conclusions: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 x 10(-5)), demonstrating the importance of diversifying study cohorts.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Nyckelord

Breast cancer susceptibility

Diverse ancestry

Rare variants

Gene regulation

Genome-wide association study

Breast cancer susceptibility

Diverse ancestry

Gene regulation

Genome-wide association study

Rare variants

African

ancestry group

Article

Asian

boredom susceptibility

breast cancer

cancer prognosis

CBLB gene

cohort analysis

controlled study

ESR1 gene

European

FGFR2 gene

FMNL3 gene

gene base aggregation

gene expression level

gene structure

genetic association

genetic association study

genetic code

genetic variability

Hispanic

human

human cell

human tissue

LSP1 gene

major clinical study

MAP3K1 gene

meta analysis (topic)

South and Central America

SRGAP2C gene

statistical significance

tumor-related gene

Black person

breast tumor

female

genetic predisposition

genetic screening

genetics

genome-wide association study

meta analysis

procedures

single nucleotide polymorphism

FMNL3 protein, human

methenamine

Black People

Breast Neoplasms

Female

Formins

Genetic Predisposition to Disease

Genetic Testing

Genome-Wide Association Study

Humans

Polymorphism, Single Nucleotide

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)