BRST5:The polygenic component of breast cancer susceptibility: Difference between revisions
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==Definition / Description of Disease== | ==Definition / Description of Disease== | ||
The polygenic component of breast cancer refers to the combined effect of many common SNPs, each conferring a small increase in risk, typically under 1.3-fold. Identified mainly through GWAS, these low-penetrance variants collectively explain 18–20% of familial breast cancer risk and are quantified using a polygenic risk score (PRS). | |||
==Synonyms / Terminology== | ==Synonyms / Terminology== | ||
Polygenic breast cancer risk; Common low-penetrance breast cancer alleles | |||
==Epidemiology / Prevalence== | ==Epidemiology / Prevalence== | ||
Over 170 low-penetrance alleles have been identified, primarily in populations of European descent, accounting for approximately 18% of familial breast cancer risk. These loci are found in the general population with varying allele frequencies and are being increasingly incorporated into risk prediction models. | |||
==Clinical Features== | ==Clinical Features== | ||
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==Sites of Involvement== | ==Sites of Involvement== | ||
Breast tissue (parenchyma) | |||
==Morphologic Features== | ==Morphologic Features== | ||
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==Immunophenotype== | ==Immunophenotype== | ||
N/A | |||
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==Chromosomal Rearrangements (Gene Fusions)== | ==Chromosomal Rearrangements (Gene Fusions)== | ||
N/A | |||
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==Individual Region Genomic Gain / Loss / LOH== | ==Individual Region Genomic Gain / Loss / LOH== | ||
N/A | |||
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==Characteristic Chromosomal Patterns== | ==Characteristic Chromosomal Patterns== | ||
N/A | |||
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!Notes | !Notes | ||
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| | |Multiple SNPs (e.g., FGFR2, MAP3K1, TOX3) | ||
|Regulatory/epigenetic, not traditional oncogenes/TSGs | |||
|Common, MAF >1% | |||
|Varies | |||
|Varies | |||
|No | |||
| | |Limited | ||
|Yes (PRS applications | |||
|Target gene expression changes may affect oncogenic pathways | |||
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|}Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content. | |}Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content. | ||
==Epigenomic Alterations== | ==Epigenomic Alterations== | ||
Common variants are often located in enhancer regions, affecting chromatin accessibility, transcription factor binding, and gene expression regulation (e.g., at ESR1, FGFR2, MAP3K1 loci). | |||
==Genes and Main Pathways Involved== | ==Genes and Main Pathways Involved== | ||
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!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome | !Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome | ||
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| | |MAP3K1 | ||
| | |ERK1/2 cascade | ||
| | |Altered signal transduction | ||
|- | |||
|FGFR2 | |||
|FGF signaling | |||
|Enhanced cell proliferation | |||
|- | |- | ||
| | |TOX3 | ||
| | |Transcriptional regulation | ||
| | |Affects chromatin remodeling | ||
|- | |- | ||
| | |ESR1 | ||
| | |Estrogen signaling | ||
| | |Influences hormone response in breast cancer | ||
|} | |} | ||
==Genetic Diagnostic Testing Methods== | ==Genetic Diagnostic Testing Methods== | ||
Polygenic risk is assessed through genotyping panels or whole-genome SNP arrays followed by computational calculation of the PRS. | |||
==Familial Forms== | ==Familial Forms== | ||
These low-penetrance alleles can act additively or multiplicatively with rare high-penetrance pathogenic variants (e.g., BRCA1, BRCA2) and may modify cancer risk within families with hereditary breast and ovarian cancer syndromes. | |||
==Additional Information== | ==Additional Information== | ||
The utility of PRS in clinical practice is growing, both for general population risk stratification and for risk modification in individuals with known pathogenic variants in high-risk genes. | |||
==Links== | ==Links== | ||
(use the "Link" icon that looks like two overlapping circles at the top of the page) <span style="color:#0070C0">(''Instructions: Highlight text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "<nowiki>http://www</nowiki>." portion.'')</span> | (use the "Link" icon that looks like two overlapping circles at the top of the page) <span style="color:#0070C0">(''Instructions: Highlight text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "<nowiki>http://www</nowiki>." portion.'')</span> | ||