BRST5:The polygenic component of breast cancer susceptibility
Breast Tumours (WHO Classification, 5th ed.)
 | This page is under construction |
(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)
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
Put your text here (Instructions: Include a brief general clinical description, diagnostic criteria, and differential diagnosis if applicable. Include disease context relative to other WHO classification categories, i.e. describe any information relevant to the genetic aspects of the disease from all WHO classification books in which the syndrome is described.)
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) [1][2]. 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[3]. 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[3][4][5].
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[6]. These loci are found in the general population with varying allele frequencies and are being increasingly incorporated into risk prediction models.
Genetic Abnormalities: Germline
Put your text here and fill in the table (Instructions: Describe germline alteration(s) that cause the syndrome. In the notes, include additional details about most common mutations including founder mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetics-related information. If multiple causes of the syndrome, include relative prevalence of genetic contributions to that syndrome. Please include references throughout the table. Do not delete the table.)
| Gene | Genetic Variant or Variant Type | Molecular Pathogenesis | Inheritance, Penetrance, Expressivity | Notes |
|---|---|---|---|---|
| EXAMPLE: BRCA1 | EXAMPLE: Many | EXAMPLE: Multiple variant types leading to loss of function | EXAMPLE: Autosomal recessive,
~30% penetrant for carriers |
|
| EXAMPLE: Gene X | EXAMPLE: List the specific mutation | |||
PLEASE PUT CONTENT FROM OLD TABLE BELOW WHERE YOU WANT IT AND THEN DELETE THE OLD TABLE.
| 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 |
Genetic Abnormalities: Somatic
Put your text here and fill in the table (Instructions: Describe significant second hit mutations, or somatic variants that present as a germline syndrome. In the notes, include details about most common mutations, mechanisms of molecular pathogenesis, alteration-specific prognosis and any other important genetic-related information. Please include references throughout the table. Do not delete the table.)
| 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
Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete the table.)
| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| MAP2K1; ??? | 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 |
| EXAMPLE: KMT2C and ARID1A; Inactivating mutations | EXAMPLE: Histone modification, chromatin remodeling | EXAMPLE: Abnormal gene expression program |
Genetic Diagnostic Testing Methods
Polygenic risk is assessed through genotyping panels or whole-genome SNP arrays followed by computational calculation of the PRS[7][8][2].
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[9].
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[10].
Links
Put a link here or anywhere appropriate in this page (Instructions: Highlight the text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the wiki 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 "http://www." portion.)
References
- ↑ Michailidou, Kyriaki; et al. (2017-11-02). "Association analysis identifies 65 new breast cancer risk loci". Nature. 551 (7678): 92–94. doi:10.1038/nature24284. ISSN 1476-4687. PMC 5798588. PMID 29059683.
- ↑ 2.0 2.1 Mavaddat, Nasim; et al. (2015-05). "Prediction of breast cancer risk based on profiling with common genetic variants". Journal of the National Cancer Institute. 107 (5): djv036. doi:10.1093/jnci/djv036. ISSN 1460-2105. PMC 4754625. PMID 25855707. Check date values in:
|date=(help) - ↑ 3.0 3.1 Sawyer, Elinor; et al. (2014-04). "Genetic predisposition to in situ and invasive lobular carcinoma of the breast". PLoS genetics. 10 (4): e1004285. doi:10.1371/journal.pgen.1004285. ISSN 1553-7404. PMC 3990493. PMID 24743323. Check date values in:
|date=(help) - ↑ Mavaddat, Nasim; et al. (2012-01). "Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)". Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 21 (1): 134–147. doi:10.1158/1055-9965.EPI-11-0775. ISSN 1538-7755. PMC 3272407. PMID 22144499. Check date values in:
|date=(help) - ↑ Kuchenbaecker, Karoline B.; et al. (2014-12-31). "Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers". Breast cancer research: BCR. 16 (6): 3416. doi:10.1186/s13058-014-0492-9. ISSN 1465-542X. PMC 4406179. PMID 25919761.
- ↑ Adam, Kevin; et al. (2018-02). "Histidine kinases and the missing phosphoproteome from prokaryotes to eukaryotes". Laboratory Investigation; a Journal of Technical Methods and Pathology. 98 (2): 233–247. doi:10.1038/labinvest.2017.118. ISSN 1530-0307. PMC 5815933. PMID 29058706. Check date values in:
|date=(help) - ↑ Sawyer, Sarah; et al. (2012-12-10). "A role for common genomic variants in the assessment of familial breast cancer". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 30 (35): 4330–4336. doi:10.1200/JCO.2012.41.7469. ISSN 1527-7755. PMID 23109704.
- ↑ Dite, Gillian S.; et al. (2016-02). "Breast Cancer Risk Prediction Using Clinical Models and 77 Independent Risk-Associated SNPs for Women Aged Under 50 Years: Australian Breast Cancer Family Registry". Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 25 (2): 359–365. doi:10.1158/1055-9965.EPI-15-0838. ISSN 1538-7755. PMC 4767544. PMID 26677205. Check date values in:
|date=(help) - ↑ Kuchenbaecker, Karoline B.; et al. (2017-07-01). "Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers". Journal of the National Cancer Institute. 109 (7): djw302. doi:10.1093/jnci/djw302. ISSN 1460-2105. PMC 5408990. PMID 28376175.
- ↑ Kuchenbaecker, Karoline B.; et al. (2017-07-01). "Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers". Journal of the National Cancer Institute. 109 (7): djw302. doi:10.1093/jnci/djw302. ISSN 1460-2105. PMC 5408990. PMID 28376175.
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):