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) <ref>{{Cite journal|last=Michailidou|first=Kyriaki|last2=Lindström|first2=Sara|last3=Dennis|first3=Joe|last4=Beesley|first4=Jonathan|last5=Hui|first5=Shirley|last6=Kar|first6=Siddhartha|last7=Lemaçon|first7=Audrey|last8=Soucy|first8=Penny|last9=Glubb|first9=Dylan|date=2017-11-02|title=Association analysis identifies 65 new breast cancer risk loci|url=https://pubmed.ncbi.nlm.nih.gov/29059683|journal=Nature|volume=551|issue=7678|pages=92–94|doi=10.1038/nature24284|issn=1476-4687|pmc=5798588|pmid=29059683}}</ref><ref>{{Cite journal|last=Mavaddat|first=Nasim|last2=Pharoah|first2=Paul D. P.|last3=Michailidou|first3=Kyriaki|last4=Tyrer|first4=Jonathan|last5=Brook|first5=Mark N.|last6=Bolla|first6=Manjeet K.|last7=Wang|first7=Qin|last8=Dennis|first8=Joe|last9=Dunning|first9=Alison M.|date=2015-05|title=Prediction of breast cancer risk based on profiling with common genetic variants|url=https://pubmed.ncbi.nlm.nih.gov/25855707|journal=Journal of the National Cancer Institute|volume=107|issue=5|pages=djv036|doi=10.1093/jnci/djv036|issn=1460-2105|pmc=4754625|pmid=25855707}}</ref>. | 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) <ref name=":0">{{Cite journal|last=Michailidou|first=Kyriaki|last2=Lindström|first2=Sara|last3=Dennis|first3=Joe|last4=Beesley|first4=Jonathan|last5=Hui|first5=Shirley|last6=Kar|first6=Siddhartha|last7=Lemaçon|first7=Audrey|last8=Soucy|first8=Penny|last9=Glubb|first9=Dylan|date=2017-11-02|title=Association analysis identifies 65 new breast cancer risk loci|url=https://pubmed.ncbi.nlm.nih.gov/29059683|journal=Nature|volume=551|issue=7678|pages=92–94|doi=10.1038/nature24284|issn=1476-4687|pmc=5798588|pmid=29059683}}</ref><ref name=":1">{{Cite journal|last=Mavaddat|first=Nasim|last2=Pharoah|first2=Paul D. P.|last3=Michailidou|first3=Kyriaki|last4=Tyrer|first4=Jonathan|last5=Brook|first5=Mark N.|last6=Bolla|first6=Manjeet K.|last7=Wang|first7=Qin|last8=Dennis|first8=Joe|last9=Dunning|first9=Alison M.|date=2015-05|title=Prediction of breast cancer risk based on profiling with common genetic variants|url=https://pubmed.ncbi.nlm.nih.gov/25855707|journal=Journal of the National Cancer Institute|volume=107|issue=5|pages=djv036|doi=10.1093/jnci/djv036|issn=1460-2105|pmc=4754625|pmid=25855707}}</ref>. | ||
==Synonyms / Terminology== | ==Synonyms / Terminology== | ||
Polygenic breast cancer risk; Common low-penetrance breast cancer alleles | Polygenic breast cancer risk; Common low-penetrance breast cancer alleles | ||
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Breast tissue (parenchyma) | Breast tissue (parenchyma) | ||
==Morphologic Features== | ==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<ref name=":2">{{Cite journal|last=Sawyer|first=Elinor|last2=Roylance|first2=Rebecca|last3=Petridis|first3=Christos|last4=Brook|first4=Mark N.|last5=Nowinski|first5=Salpie|last6=Papouli|first6=Efterpi|last7=Fletcher|first7=Olivia|last8=Pinder|first8=Sarah|last9=Hanby|first9=Andrew|date=2014-04|title=Genetic predisposition to in situ and invasive lobular carcinoma of the breast|url=https://pubmed.ncbi.nlm.nih.gov/24743323|journal=PLoS genetics|volume=10|issue=4|pages=e1004285|doi=10.1371/journal.pgen.1004285|issn=1553-7404|pmc=3990493|pmid=24743323}}</ref>. | |||
==Immunophenotype== | ==Immunophenotype== | ||
N/A | N/A | ||
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==Gene Mutations (SNV / INDEL)== | ==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<ref name=":2" /><ref>{{Cite journal|last=Mavaddat|first=Nasim|last2=Barrowdale|first2=Daniel|last3=Andrulis|first3=Irene L.|last4=Domchek|first4=Susan M.|last5=Eccles|first5=Diana|last6=Nevanlinna|first6=Heli|last7=Ramus|first7=Susan J.|last8=Spurdle|first8=Amanda|last9=Robson|first9=Mark|date=2012-01|title=Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)|url=https://pubmed.ncbi.nlm.nih.gov/22144499|journal=Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology|volume=21|issue=1|pages=134–147|doi=10.1158/1055-9965.EPI-11-0775|issn=1538-7755|pmc=3272407|pmid=22144499}}</ref><ref>{{Cite journal|last=Kuchenbaecker|first=Karoline B.|last2=Neuhausen|first2=Susan L.|last3=Robson|first3=Mark|last4=Barrowdale|first4=Daniel|last5=McGuffog|first5=Lesley|last6=Mulligan|first6=Anna Marie|last7=Andrulis|first7=Irene L.|last8=Spurdle|first8=Amanda B.|last9=Schmidt|first9=Marjanka K.|date=2014-12-31|title=Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers|url=https://pubmed.ncbi.nlm.nih.gov/25919761|journal=Breast cancer research: BCR|volume=16|issue=6|pages=3416|doi=10.1186/s13058-014-0492-9|issn=1465-542X|pmc=4406179|pmid=25919761}}</ref>. | |||
{| class="wikitable sortable" | {| class="wikitable sortable" | ||
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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). | 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) <ref>{{Cite journal|last=Rivandi|first=Mahdi|last2=Martens|first2=John W. M.|last3=Hollestelle|first3=Antoinette|date=2018|title=Elucidating the Underlying Functional Mechanisms of Breast Cancer Susceptibility Through Post-GWAS Analyses|url=https://pubmed.ncbi.nlm.nih.gov/30116257|journal=Frontiers in Genetics|volume=9|pages=280|doi=10.3389/fgene.2018.00280|issn=1664-8021|pmc=6082943|pmid=30116257}}</ref><ref name=":0" />. | ||
==Genes and Main Pathways Involved== | ==Genes and Main Pathways Involved== | ||
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==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. | Polygenic risk is assessed through genotyping panels or whole-genome SNP arrays followed by computational calculation of the PRS<ref>{{Cite journal|last=Sawyer|first=Sarah|last2=Mitchell|first2=Gillian|last3=McKinley|first3=Joanne|last4=Chenevix-Trench|first4=Georgia|last5=Beesley|first5=Jonathan|last6=Chen|first6=Xiao Qing|last7=Bowtell|first7=David|last8=Trainer|first8=Alison H.|last9=Harris|first9=Marion|date=2012-12-10|title=A role for common genomic variants in the assessment of familial breast cancer|url=https://pubmed.ncbi.nlm.nih.gov/23109704|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=30|issue=35|pages=4330–4336|doi=10.1200/JCO.2012.41.7469|issn=1527-7755|pmid=23109704}}</ref><ref>{{Cite journal|last=Dite|first=Gillian S.|last2=MacInnis|first2=Robert J.|last3=Bickerstaffe|first3=Adrian|last4=Dowty|first4=James G.|last5=Allman|first5=Richard|last6=Apicella|first6=Carmel|last7=Milne|first7=Roger L.|last8=Tsimiklis|first8=Helen|last9=Phillips|first9=Kelly-Anne|date=2016-02|title=Breast Cancer Risk Prediction Using Clinical Models and 77 Independent Risk-Associated SNPs for Women Aged Under 50 Years: Australian Breast Cancer Family Registry|url=https://pubmed.ncbi.nlm.nih.gov/26677205|journal=Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology|volume=25|issue=2|pages=359–365|doi=10.1158/1055-9965.EPI-15-0838|issn=1538-7755|pmc=4767544|pmid=26677205}}</ref><ref name=":1" />. | ||
==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. | 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<ref>{{Cite journal|last=Kuchenbaecker|first=Karoline B.|last2=McGuffog|first2=Lesley|last3=Barrowdale|first3=Daniel|last4=Lee|first4=Andrew|last5=Soucy|first5=Penny|last6=Dennis|first6=Joe|last7=Domchek|first7=Susan M.|last8=Robson|first8=Mark|last9=Spurdle|first9=Amanda B.|date=2017-07-01|title=Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers|url=https://pubmed.ncbi.nlm.nih.gov/28376175|journal=Journal of the National Cancer Institute|volume=109|issue=7|pages=djw302|doi=10.1093/jnci/djw302|issn=1460-2105|pmc=5408990|pmid=28376175}}</ref>. | ||
==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. | 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<ref>{{Cite journal|last=Kuchenbaecker|first=Karoline B.|last2=McGuffog|first2=Lesley|last3=Barrowdale|first3=Daniel|last4=Lee|first4=Andrew|last5=Soucy|first5=Penny|last6=Dennis|first6=Joe|last7=Domchek|first7=Susan M.|last8=Robson|first8=Mark|last9=Spurdle|first9=Amanda B.|date=2017-07-01|title=Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers|url=https://pubmed.ncbi.nlm.nih.gov/28376175|journal=Journal of the National Cancer Institute|volume=109|issue=7|pages=djw302|doi=10.1093/jnci/djw302|issn=1460-2105|pmc=5408990|pmid=28376175}}</ref>. | ||
==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> | ||
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==Notes== | ==Notes== | ||
<nowiki>*</nowiki>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 CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome. | <nowiki>*</nowiki>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 CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome. | ||
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