BRST5:The polygenic component of breast cancer susceptibility

Breast Tumours (WHO Classification, 5th ed.)

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Primary Author(s)*

Xiaolin Hu, GeneDx

WHO Classification of Disease

Structure	Disease
Book	Breast Tumours (5th ed.)
Category	Genetic tumour syndromes of the breast
Family	Syndromes
Type	Polygenetic component of breast cancer susceptibility
Subtype(s)	N/A

Related Terminology

Acceptable	N/A
Not Recommended	N/A

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

Definition/Description of Disease

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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) . 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. 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.

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.

Genetic Abnormalities: Germline

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Gene	Genetic Variant or Variant Type	Molecular Pathogenesis	Inheritance, Penetrance, Expressivity	Notes
Multiple Genes(FGFR2, MAP3K1, TOX3 etc)	Many SNPs (Common, minor allele frequency >1%)	Affect regulatory region or epigenetics rather than traditional oncogenes/tumor suppressor genes	complex inheritance: non-Mendelian, polygenic pattern; their effects are additive or multiplicative and are often influenced by environment; Penetrance: each SNP confer very modest risk (<1.3 fold), but cumulative penetrance increases with a higher PRS; Expressivity: variable. PRS may influence age of onset, tumor subtype or morphology

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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
	Regulatory/epigenetic, not traditional oncogenes/TSGs	Common, MAF >1%	Varies	Varies	No	Limited	Yes (PRS applications	Target gene expression changes may affect oncogenic pathways

Genetic Abnormalities: Somatic

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Gene	Genetic Variant or Variant Type	Molecular Pathogenesis	Inheritance, Penetrance, Expressivity	Notes
EXAMPLE: BRCA1	EXAMPLE: Biallelic inactivation variants	EXAMPLE: Second hit mutation can occur as copy neutral LOH, inactivating mutation, deletion, promoter hypermethylation, or a structural abnormality disrupting the gene.
EXAMPLE: BRCA1	EXAMPLE: Reversion mutation	EXAMPLE: After exposure to certain therapies (e.g. PARP inhibitors), a second mutation may restore gene function as a resistance mechanism.

Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
MAP3K1	MAPK/ERK pathway	Alters cell survival and signal transduction
FGFR2	FGF signaling	Increases proliferation
TOX3	Chromatin remodeling	Affects transcriptional regulation and stress response
ESR1	Estrogen receptor signaling	Modulates hormonal response in luminal cells
CDKN2B	Cell cycle checkpoint	Dysregulates cell cycle progression

Genetic Diagnostic Testing Methods

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

Additional Information

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.

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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Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):