Compendium of Cancer Genome Aberrations

BRST5:The polygenic component of breast cancer susceptibility: Difference between revisions

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<span style="color:#0070C0">(''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 [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], 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'' </span><u>''[[Author_Instructions]]''</u><span style="color:#0070C0"> ''and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>].)''</span>
<span style="color:#0070C0">(''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 [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], 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'' </span><u>''[[Author_Instructions]]''</u><span style="color:#0070C0"> ''and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>].)''</span>
==Primary Author(s)*==
==Primary Author(s)*==
Put your text here<span style="color:#0070C0"> (''<span class="blue-text">EXAMPLE:</span>'' Jane Smith, PhD) </span>
Xiaolin Hu, GeneDx
==WHO Classification of Disease==
==WHO Classification of Disease==


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|-
|-
|Book
|Book
|Genetic Tumour Syndromes (5th ed.)
|
|-
|-
|Category
|Category
|Growth factor receptors and related signalling pathways
|
|-
|-
|Family
|Family
|Growth factor receptors
|
|-
|-
|Type
|Type
|Multiple endocrine neoplasia type 2 (RET)
|
|-
|-
|Subtype(s)
|Subtype(s)
|N/A
|
|}
|}


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|+
|+
|Acceptable
|Acceptable
|MEN2 syndrome, MEN2A, MEN2B; familial medullary thyroid carcinoma
|
|-
|-
|Not Recommended
|Not Recommended
|Sipple syndrome; multiple endocrine neoplasia type 3 (MEN3); Gorlin syndrome; Wagenmann-Froboese syndrome; mucosal neuroma syndrome; Farndon syndrome
|
|}
|}
Polygenic breast cancer risk; Common low-penetrance breast cancer alleles


==Definition/Description of Disease==
==Definition/Description of Disease==
Put your text here <span style="color:#0070C0">(''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.'')</span>
Put your text here <span style="color:#0070C0">(''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.'')</span>
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>.  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>.  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>.
==Epidemiology/Prevalence==
==Epidemiology/Prevalence==
Put your text here
Over 170 low-penetrance alleles have been identified, primarily in populations of European descent, accounting for approximately 18% of familial breast cancer risk<ref>{{Cite journal|last=Adam|first=Kevin|last2=Hunter|first2=Tony|date=2018-02|title=Histidine kinases and the missing phosphoproteome from prokaryotes to eukaryotes|url=https://pubmed.ncbi.nlm.nih.gov/29058706|journal=Laboratory Investigation; a Journal of Technical Methods and Pathology|volume=98|issue=2|pages=233–247|doi=10.1038/labinvest.2017.118|issn=1530-0307|pmc=5815933|pmid=29058706}}</ref>. These loci are found in the general population with varying allele frequencies and are being increasingly incorporated into risk prediction models.
==Genetic Abnormalities: Germline==
==Genetic Abnormalities: Germline==
Put your text here and fill in the table <span style="color:#0070C0">(''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.'')</span>
Put your text here and fill in the table <span style="color:#0070C0">(''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.'')</span>
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|}
==Genetic Abnormalities: Somatic==
Put your text here and fill in the table <span style="color:#0070C0">(''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.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene!!Genetic Variant or Variant Type!!Molecular Pathogenesis!!Inheritance, Penetrance, Expressivity
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC / TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!Notes
!'''Diagnostic Significance (Yes, No or Unknown)'''
|-
|<span class="blue-text">EXAMPLE:</span> ''BRCA1''||<span class="blue-text">EXAMPLE:</span> Biallelic inactivation variants||<span class="blue-text">EXAMPLE:</span> Second hit mutation can occur as copy neutral LOH, inactivating mutation, deletion, promoter hypermethylation, or a structural abnormality disrupting the gene.||
|
|-
|<span class="blue-text">EXAMPLE:</span> ''BRCA1''
|<span class="blue-text">EXAMPLE:</span> Reversion mutation
|<span class="blue-text">EXAMPLE:</span> 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 <span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|-
|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|-
|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
|-
|
|
|
|}
==Genetic Diagnostic Testing Methods==
Put your text here <span style="color:#0070C0">(''Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.'')</span>
==Additional Information==
Put your text here
==Links==
Put a link here or anywhere appropriate in this page <span style="color:#0070C0">(''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 "<nowiki>http://www</nowiki>." portion.'')</span>
==References==
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span>
==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 [[Leadership|''<u>Associate Editor</u>'']] 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):  
[[Category:BRST5]][[Category:DISEASE]]
 
 
 
 
 
<span style="color:#0070C0">(''General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ 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 to a table, click nearby within the table and select the > symbol that appears to be given options. 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'' </span><u>''[[Author_Instructions]]''</u><span style="color:#0070C0"> ''and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])''</span>
==Primary Author(s)*==
Xiaolin Hu, GeneDx
==WHO Classification of Disease==
<span style="color:#0070C0">(Will be autogenerated; Book will include name of specific book and have a link to the online WHO site)</span>
{| class="wikitable"
!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) <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==
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<ref>{{Cite journal|last=Adam|first=Kevin|last2=Hunter|first2=Tony|date=2018-02|title=Histidine kinases and the missing phosphoproteome from prokaryotes to eukaryotes|url=https://pubmed.ncbi.nlm.nih.gov/29058706|journal=Laboratory Investigation; a Journal of Technical Methods and Pathology|volume=98|issue=2|pages=233–247|doi=10.1038/labinvest.2017.118|issn=1530-0307|pmc=5815933|pmid=29058706}}</ref>. These loci are found in the general population with varying allele frequencies and are being increasingly incorporated into risk prediction models.
==Clinical Features==
<br />
{| class="wikitable"
|'''Signs and Symptoms'''
|<span class="blue-text">EXAMPLE:</span> Asymptomatic (incidental finding on complete blood counts)
<span class="blue-text">EXAMPLE:</span> B-symptoms (weight loss, fever, night sweats)
 
<span class="blue-text">EXAMPLE:</span> Lymphadenopathy (uncommon)
|-
|'''Laboratory Findings'''
|<span class="blue-text">EXAMPLE:</span> Cytopenias
<span class="blue-text">EXAMPLE:</span> 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<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==
N/A
{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||<span class="blue-text">EXAMPLE:</span> CD1
|-
|Positive (subset)||
|-
|Negative (universal)||
|-
|Negative (subset)||
|}
==Chromosomal Rearrangements (Gene Fusions)==
N/A
{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
!Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)||<span class="blue-text">EXAMPLE:</span> 3'ABL1 / 5'BCR||<span class="blue-text">EXAMPLE:</span> der(22)||<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)
|Multiple SNPs (e.g., FGFR2, MAP3K1, TOX3)
<span class="blue-text">EXAMPLE:</span> 30% (add reference)
|Regulatory/epigenetic, not traditional oncogenes/TSGs
|<span class="blue-text">EXAMPLE:</span> Yes
|Common, MAF >1%
|<span class="blue-text">EXAMPLE:</span> No
|Varies
|<span class="blue-text">EXAMPLE:</span> Yes
|Varies
|<span class="blue-text">EXAMPLE:</span>
|No
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).
|Limited
|}
|Yes (PRS applications
==Individual Region Genomic Gain / Loss / LOH==
|Target gene expression changes may affect oncogenic pathways
N/A
{| class="wikitable sortable"
|-
!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
|-
|<span class="blue-text">EXAMPLE:</span>
7
|<span class="blue-text">EXAMPLE:</span> Loss
|<span class="blue-text">EXAMPLE:</span>
chr7:1-159,335,973 [hg38]
|<span class="blue-text">EXAMPLE:</span>
chr7
|<span class="blue-text">EXAMPLE:</span> Yes
|<span class="blue-text">EXAMPLE:</span> Yes
|<span class="blue-text">EXAMPLE:</span> No
|<span class="blue-text">EXAMPLE:</span>
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).
|-
|<span class="blue-text">EXAMPLE:</span>
8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>
chr8:1-145,138,636 [hg38]
|<span class="blue-text">EXAMPLE:</span>
chr8
|<span class="blue-text">EXAMPLE:</span> No
|<span class="blue-text">EXAMPLE:</span> No
|<span class="blue-text">EXAMPLE:</span> No
|<span class="blue-text">EXAMPLE:</span>
Common recurrent secondary finding for t(8;21) (add reference).
|}
==Characteristic Chromosomal Patterns==
N/A
{| class="wikitable sortable"
|-
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|<span class="blue-text">EXAMPLE:</span>
Co-deletion of 1p and 18q
|<span class="blue-text">EXAMPLE:</span> Yes
|<span class="blue-text">EXAMPLE:</span> No
|<span class="blue-text">EXAMPLE:</span> No
|<span class="blue-text">EXAMPLE:</span>
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<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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Line 278: Line 102:
|Yes (PRS applications
|Yes (PRS applications
|Target gene expression changes may affect oncogenic pathways
|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==
==Genetic Abnormalities: Somatic==
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" />.
Put your text here and fill in the table <span style="color:#0070C0">(''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.'')</span>
{| class="wikitable sortable"
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!Gene!!Genetic Variant or Variant Type!!Molecular Pathogenesis!!Inheritance, Penetrance, Expressivity
!Notes
|-
|<span class="blue-text">EXAMPLE:</span> ''BRCA1''||<span class="blue-text">EXAMPLE:</span> Biallelic inactivation variants||<span class="blue-text">EXAMPLE:</span> Second hit mutation can occur as copy neutral LOH, inactivating mutation, deletion, promoter hypermethylation, or a structural abnormality disrupting the gene.||
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|-
|<span class="blue-text">EXAMPLE:</span> ''BRCA1''
|<span class="blue-text">EXAMPLE:</span> Reversion mutation
|<span class="blue-text">EXAMPLE:</span> After exposure to certain therapies (e.g. PARP inhibitors), a second mutation may restore gene function as a resistance mechanism.
|
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|}
==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
<br />
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|MAP3K1
|''MAP2K1''; ???
|ERK1/2 cascade
|ERK1/2 cascade
|Altered signal transduction
|Altered signal transduction
|-
|-
|FGFR2
|''FGFR2''; ???
|FGF signaling
|FGF signaling
|Enhanced cell proliferation
|Enhanced cell proliferation
|-
|-
|TOX3
|''TOX3''; ???
|Transcriptional regulation
|Transcriptional regulation
|Affects chromatin remodeling
|Affects chromatin remodeling
|-
|-
|ESR1
|''ESR1''; ???
|Estrogen signaling
|Estrogen signaling
|Influences hormone response in breast cancer
|Influences hormone response in breast cancer
|-
|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
|}
|}
==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<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" />.
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==
==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<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>.
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==
 
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>.
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>
Put a link here or anywhere appropriate in this page <span style="color:#0070C0">(''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 "<nowiki>http://www</nowiki>." portion.'')</span>
==References==
==References==
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted.''</span> <span style="color:#0070C0">''If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span>
[[Category:BRST5]]
[[Category:DISEASE]]
<references />
==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 [[Leadership|''<u>Associate Editor</u>'']] 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.  
<references />
 
Prior Author(s):  
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