BRST5:The polygenic component of breast cancer susceptibility

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Primary Author(s)*

Xiaolin Hu, GeneDx

WHO Classification of Disease

(Will be autogenerated; Book will include name of specific book and have a link to the online WHO site)

Structure	Disease
Book
Category
Family
Type
Subtype(s)

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

Polygenic breast cancer risk; Common low-penetrance breast cancer alleles

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

Signs and Symptoms	EXAMPLE: Asymptomatic (incidental finding on complete blood counts) EXAMPLE: B-symptoms (weight loss, fever, night sweats) EXAMPLE: Lymphadenopathy (uncommon)
Laboratory Findings	EXAMPLE: Cytopenias EXAMPLE: Lymphocytosis (low level)

Sites of Involvement

Breast tissue (parenchyma)

Morphologic Features

There are no specific histologic features directly attributable to polygenic risk alleles. However, these variants tend to be enriched in specific breast cancer subtypes. For example, ER-positive tumors, which are estrogen receptor–driven and often of ductal histology, are more strongly associated with many common susceptibility alleles. In contrast, ER-negative tumors, including those seen more frequently in BRCA1 mutation carriers, show enrichment for a smaller subset of variants. Similarly, lobular carcinomas—characterized by a lack of E-cadherin expression—have been associated with unique risk variants distinct from those found in ductal carcinomas.

Immunophenotype

N/A

Finding	Marker
Positive (universal)	EXAMPLE: CD1
Positive (subset)
Negative (universal)
Negative (subset)

Chromosomal Rearrangements (Gene Fusions)

N/A

Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: 3'ABL1 / 5'BCR	EXAMPLE: der(22)	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add reference)	EXAMPLE: Yes	EXAMPLE: No	EXAMPLE: Yes	EXAMPLE: The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).

Individual Region Genomic Gain / Loss / LOH

N/A

Chr #	Gain / Loss / Amp / LOH	Minimal Region Genomic Coordinates [Genome Build]	Minimal Region Cytoband	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7:1-159,335,973 [hg38]	EXAMPLE: chr7	EXAMPLE: Yes	EXAMPLE: Yes	EXAMPLE: No	EXAMPLE: Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8:1-145,138,636 [hg38]	EXAMPLE: chr8	EXAMPLE: No	EXAMPLE: No	EXAMPLE: No	EXAMPLE: Common recurrent secondary finding for t(8;21) (add reference).

Characteristic Chromosomal Patterns

N/A

Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: Co-deletion of 1p and 18q	EXAMPLE: Yes	EXAMPLE: No	EXAMPLE: No	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

Gene Mutations (SNV / INDEL)

SNPs in FGFR2 are more common in ER-positive ductal carcinoma; variants in 7q34 are associated with lobular carcinoma; ER-negative cancers (e.g., seen in BRCA1 carriers) are linked to 19p13.1 variants.

Gene; Genetic Alteration	Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)	Prevalence (COSMIC / TCGA / Other)	Concomitant Mutations	Mutually Exclusive Mutations	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
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

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

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

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
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

Polygenic risk is assessed through genotyping panels or whole-genome SNP arrays followed by computational calculation of the PRS.

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

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

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References

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Notes

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