Compendium of Cancer Genome Aberrations

BRST5:Papillary ductal carcinoma in situ: Difference between revisions

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{{DISPLAYTITLE:Papillary ductal carcinoma in situ}}
{{DISPLAYTITLE:Papillary ductal carcinoma in situ}}
[[BRST5:Table_of_Contents|Breast Tumours (WHO Classification, 5th ed.)]]
[[BRST5:Table_of_Contents|Breast Tumours (WHO Classification, 5th ed.)]]
{{Under Construction}}
<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>
Sresi Singh and Katherine Geiersbach, MD
==WHO Classification of Disease==
==WHO Classification of Disease==


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==WHO Essential and Desirable Genetic Diagnostic Criteria==
<span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span>
{| class="wikitable"
|+
|WHO Essential Criteria (Genetics)*
|
|-
|WHO Desirable Criteria (Genetics)*
|
|-
|Other Classification
|
|}
<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the [https://tumourclassification.iarc.who.int/home <u>WHO Classification of Tumours</u>].
==Related Terminology==
==Related Terminology==


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==Gene Rearrangements==
==Gene Rearrangements==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
No recurrent gene rearrangements have been identified in papillary DCIS, which is primarily characterized by mutations and copy number alterations.
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''||<span class="blue-text">EXAMPLE:</span> ''BCR::ABL1''||<span class="blue-text">EXAMPLE:</span> The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.||<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)
|<span class="blue-text">EXAMPLE:</span> Common (CML)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN)
|<span class="blue-text">EXAMPLE:</span>
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). BCR::ABL1 is generally favorable in CML (add reference).
|-
|<span class="blue-text">EXAMPLE:</span> ''CIC''
|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
|<span class="blue-text">EXAMPLE:</span> Typically, the last exon of ''CIC'' is fused to ''DUX4''. The fusion breakpoint in ''CIC'' is usually intra-exonic and removes an inhibitory sequence, upregulating ''PEA3'' genes downstream of ''CIC'' including ''ETV1'', ''ETV4'', and ''ETV5''.
|<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13)
|<span class="blue-text">EXAMPLE:</span> Common (CIC-rearranged sarcoma)
|<span class="blue-text">EXAMPLE:</span> D
|
|<span class="blue-text">EXAMPLE:</span>
''DUX4'' has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
|-
|<span class="blue-text">EXAMPLE:</span> ''ALK''
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''
Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
|<span class="blue-text">EXAMPLE:</span> Fusions result in constitutive activation of the ''ALK'' tyrosine kinase. The most common ''ALK'' fusion is ''EML4::ALK'', with breakpoints in intron 19 of ''ALK''. At the transcript level, a variable (5’) partner gene is fused to 3’ ''ALK'' at exon 20. Rarely, ''ALK'' fusions contain exon 19 due to breakpoints in intron 18.
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|<span class="blue-text">EXAMPLE:</span>
Both balanced and unbalanced forms are observed by FISH (add references).
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Intragenic deletion of exons 2–7 in ''EGFR'' removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|
|-
|-
|
|
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|}
|}
==Individual Region Genomic Gain/Loss/LOH==
==Individual Region Genomic Gain/Loss/LOH==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.'') </span>
Copy-number alterations are common genomic events in ductal carcinoma in situ and other papillary breast neoplasms. Recurrent chromosomal changes include gains of chromosome arms 1q and 8q, loss of 16q. Amplification of 17q12 containing the ''ERBB2'' gene contributes to HER2 overexpression in a subset of lesions and has been associated with malignancy rather than DCIS.<ref name=":0">{{Cite journal|last=Rakha|first=Emad A.|last2=Tan|first2=Puay Hoon|last3=Raymond|first3=Wendy A.|date=2026-03|title=The spectrum of breast in situ papillary carcinomas with invasion and invasive breast carcinomas with papillary features: an overview of histological subtypes and diagnostic challenges|url=https://pubmed.ncbi.nlm.nih.gov/41404713|journal=Histopathology|volume=88|issue=4|pages=747–768|doi=10.1111/his.70072|issn=1365-2559|pmc=12891923|pmid=41404713}}</ref>  
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|1
7
|Gain
|<span class="blue-text">EXAMPLE:</span> Loss
|1q
|<span class="blue-text">EXAMPLE:</span>
|
chr7
|P
|<span class="blue-text">EXAMPLE:</span>
|No
Unknown
|Gain of chromosome 1q is frequently observed in early breast neoplasia including DCIS and contributes to tumor progression. In papillary lesions, 1q gains including 1q21.3-1q23.1 (including PRCC and NTRK1) have been associated with intracystic papillary carcinoma but not concurrent DCIS.<ref name=":1">{{Cite journal|last=Khoury|first=Thaer|last2=Hu|first2=Qiang|last3=Liu|first3=Song|last4=Wang|first4=Jianmin|date=2014-02|title=Intracystic papillary carcinoma of breast: interrelationship with in situ and invasive carcinoma and a proposal of pathogenesis: array comparative genomic hybridization study of 14 cases|url=https://pubmed.ncbi.nlm.nih.gov/23907150|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=27|issue=2|pages=194–203|doi=10.1038/modpathol.2013.136|issn=1530-0285|pmc=4389629|pmid=23907150}}</ref>  
|<span class="blue-text">EXAMPLE:</span> D, P
|-
|<span class="blue-text">EXAMPLE:</span> No
|8
|<span class="blue-text">EXAMPLE:</span>
|Gain
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 references).
|8q22-8q24
|''SPAG1'', ''RHPN1'', MYC
|P
|No
|Gain of 8q results in ''MYC'' activation and increased cell proliferation in breast tumors. In papillary DCIS, gains on 8q including SPAG1 (8q22) RHPN1 (8q24) are associated with increased cell motility and cell adhesion programs.<ref name=":1" />
|-
|11
|Gain
|11q13
|''CCND1''
|P
|No
|Amplification of ''CCND1'' leads to dysregulated cell cycle progression and has been reported in breast tumors.
|-
|13
|Loss
|13q14
|''RB1''
|P
|No
|Loss of ''RB1'' contributes to cell cycle dysregulation in breast cancer.
|-
|16
|LOH
|16p13
|''TSC2'', ''PKD1''
|D
|No
|LOH on chromosome 16p13 was present in 10 of 16 (63%) informative cases of either papillary carcinoma or carcinoma arising in a papilloma as well as in 6 of 10 (60%) informative cases of intraductal papilloma with florid epithelial hyperplasia (IDH) in a 1998 study from the Armed Forces Institute of Pathology (AFIP), suggesting the presence of a tumor suppressor gene mutated early in papillary neoplasia. <ref>{{Cite journal|last=Lininger|first=R. A.|last2=Park|first2=W. S.|last3=Man|first3=Y. G.|last4=Pham|first4=T.|last5=MacGrogan|first5=G.|last6=Zhuang|first6=Z.|last7=Tavassoli|first7=F. A.|date=1998-10|title=LOH at 16p13 is a novel chromosomal alteration detected in benign and malignant microdissected papillary neoplasms of the breast|url=https://pubmed.ncbi.nlm.nih.gov/9781650|journal=Human Pathology|volume=29|issue=10|pages=1113–1118|doi=10.1016/s0046-8177(98)90422-1|issn=0046-8177|pmid=9781650}}</ref>
|-
|16
|Loss / LOH
|16q
|''CDH1''
|P
|No
|Loss of chromosome arm 16q is commonly associated with low-grade breast tumors and ductal carcinoma in situ. In papillary lesions, 16q LOH is associated with malignancy.<ref>{{Cite journal|last=Di Cristofano|first=Claudio|last2=Mrad|first2=Karima|last3=Zavaglia|first3=Katia|last4=Bertacca|first4=Gloria|last5=Aretini|first5=Paolo|last6=Cipollini|first6=Giovanna|last7=Bevilacqua|first7=Generoso|last8=Ben Romdhane|first8=Kaled|last9=Cavazzana|first9=Andrea|date=2005-03|title=Papillary lesions of the breast: a molecular progression?|url=https://pubmed.ncbi.nlm.nih.gov/15770529|journal=Breast Cancer Research and Treatment|volume=90|issue=1|pages=71–76|doi=10.1007/s10549-004-3003-3|issn=0167-6806|pmid=15770529}}</ref><ref>{{Cite journal|last=Yoshida|first=Miwa|last2=Tsuda|first2=Hitoshi|last3=Yamamoto|first3=Sohei|last4=Kinoshita|first4=Takayuki|last5=Akashi-Tanaka|first5=Sadako|last6=Hojo|first6=Takashi|last7=Fukutomi|first7=Takashi|date=2012-05|title=Loss of heterozygosity on chromosome 16q suggests malignancy in core needle biopsy specimens of intraductal papillary breast lesions|url=https://pubmed.ncbi.nlm.nih.gov/22476400|journal=Virchows Archiv: An International Journal of Pathology|volume=460|issue=5|pages=497–504|doi=10.1007/s00428-012-1200-8|issn=1432-2307|pmid=22476400}}</ref>
|-
|17
|Amp
|17q12
|''ERBB2''
|D, P, T
|Yes (NCCN)
|Amplification of ''ERBB2'' results in HER2 overexpression and may guide targeted therapy decisions in breast cancer. In papillary lesions, ERBB2 amplification / overexpression (HER2 positive status) is primarily associated with solid papillary carcinoma and encapsulated papillary carcinoma with apocrine features.<ref name=":0" />
|-
|-
|<span class="blue-text">EXAMPLE:</span>
8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>
chr8
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|
|
|<span class="blue-text">EXAMPLE:</span>
Common recurrent secondary finding for t(8;21) (add references).
|-
|<span class="blue-text">EXAMPLE:</span>
17
|<span class="blue-text">EXAMPLE:</span> Amp
|<span class="blue-text">EXAMPLE:</span>
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
|<span class="blue-text">EXAMPLE:</span>
''ERBB2''
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|
|<span class="blue-text">EXAMPLE:</span>
|
Amplification of ''ERBB2'' is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.
|
|
|
|
|-
|-
|
|
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|}
|}
==Characteristic Chromosomal or Other Global Mutational Patterns==
==Characteristic Chromosomal or Other Global Mutational Patterns==
Put your text here and fill in the table <span style="color:#0070C0">(I''nstructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
Breast neoplasms including ductal carcinoma in situ frequently demonstrate chromosomal instability and aneuploidy, which contribute to copy-number alterations and genomic heterogeneity. In some tumors, defects in DNA repair pathways such as homologous recombination also contribute to mutational accumulation.  
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|Chromosomal instability (CIN)
Co-deletion of 1p and 18q
|Accumulation of chromosomal gains and losses due to defects in mitotic segregation and DNA repair pathways
|<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).
|Common (>20%)
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|P
|<span class="blue-text">EXAMPLE:</span> D, P
|No
|
|Chromosomal instability contributes to genomic heterogeneity and tumor evolution in breast tumors.
|
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|Aneuploidy
Microsatellite instability - hypermutated
|Abnormal chromosome numbers caused by chromosomal missegregation during cell division
|
|Common (>20%)
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|P
|<span class="blue-text">EXAMPLE:</span> P, T
|No
|
|Aneuploidy is frequently observed in breast tumors and is associated with tumor progression.
|
|-
|-
|
|Homologous recombination deficiency
|
|Homologous recombination deficiency
|
|Rare (<5%)
|
|P, T
|
|Yes
|
|HR deficiency may influence response to PARP inhibitor therapy in breast cancer; however, PARP inhibitor therapy is not applicable to in situ disease.
|}
|}
==Gene Mutations (SNV/INDEL)==
==Gene Mutations (SNV/INDEL)==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.'') </span>
Breast tumors including ductal carcinoma in situ frequently harbor recurrent somatic mutations affecting pathways involved in cell proliferation, transcriptional regulation, and genomic stability. Commonly mutated genes include PIK3CA, TP53, and GATA3, among others<ref>{{Cite journal|last=Kader|first=Tanjina|last2=Elder|first2=Kenneth|last3=Zethoven|first3=Magnus|last4=Semple|first4=Timothy|last5=Hill|first5=Prue|last6=Goode|first6=David L.|last7=Thio|first7=Niko|last8=Cheasley|first8=Dane|last9=Rowley|first9=Simone M.|date=2020|title=The genetic architecture of breast papillary lesions as a predictor of progression to carcinoma|url=https://pubmed.ncbi.nlm.nih.gov/32195332|journal=NPJ breast cancer|volume=6|pages=9|doi=10.1038/s41523-020-0150-6|issn=2374-4677|pmc=7067788|pmid=32195332}}</ref>. The mutational profile of papillary DCIS largely overlaps with other luminal-type breast neoplasms. Intraductal papilloma (IDP) is a non-obligate precursor of papillary DCIS with a high frequency of ''PIK3CA'' and ''AKT1'' mutations observed; the majority of synchronous DCIS in cases of IDP exhibit non-papillary morphology.<ref>{{Cite journal|last=Kader|first=Tanjina|last2=Elder|first2=Kenneth|last3=Zethoven|first3=Magnus|last4=Semple|first4=Timothy|last5=Hill|first5=Prue|last6=Goode|first6=David L.|last7=Thio|first7=Niko|last8=Cheasley|first8=Dane|last9=Rowley|first9=Simone M.|date=2020|title=The genetic architecture of breast papillary lesions as a predictor of progression to carcinoma|url=https://pubmed.ncbi.nlm.nih.gov/32195332|journal=NPJ breast cancer|volume=6|pages=9|doi=10.1038/s41523-020-0150-6|issn=2374-4677|pmc=7067788|pmid=32195332}}</ref><ref>{{Cite journal|last=Troxell|first=Megan L.|last2=Levine|first2=Judith|last3=Beadling|first3=Carol|last4=Warrick|first4=Andrea|last5=Dunlap|first5=Jennifer|last6=Presnell|first6=Ajia|last7=Patterson|first7=Janice|last8=Shukla|first8=Arielle|last9=Olson|first9=Neal R.|date=2010-01|title=High prevalence of PIK3CA/AKT pathway mutations in papillary neoplasms of the breast|url=https://pubmed.ncbi.nlm.nih.gov/19898424|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=23|issue=1|pages=27–37|doi=10.1038/modpathol.2009.142|issn=1530-0285|pmid=19898424}}</ref>  
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
|''PIK3CA''
 
|Activating mutations
<br />
|Oncogene
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|Common
|<span class="blue-text">EXAMPLE:</span> Oncogene
|T
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|Yes (NCCN)
|<span class="blue-text">EXAMPLE:</span> T
|Activates PI3K–AKT signaling pathway leading to increased cell growth and survival. Targeted therapy is reserved for invasive disease.
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|-
|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
|''AKT1''
|Activating mutations
|Oncogene
|Recurrent
|T
|Yes (NCCN)
|Activates PI3K–AKT signaling pathway leading to increased cell growth and survival. Targeted therapy is reserved for invasive disease.
|-
|''TP53''
|Inactivating mutations
|TSG
|Recurrent
|P
|Yes
|Associated with genomic instability and aggressive tumor behavior. In papillary lesions, ''TP53'' mutation is associated with malignancy.<ref>{{Cite journal|last=Di Cristofano|first=Claudio|last2=Mrad|first2=Karima|last3=Zavaglia|first3=Katia|last4=Bertacca|first4=Gloria|last5=Aretini|first5=Paolo|last6=Cipollini|first6=Giovanna|last7=Bevilacqua|first7=Generoso|last8=Ben Romdhane|first8=Kaled|last9=Cavazzana|first9=Andrea|date=2005-03|title=Papillary lesions of the breast: a molecular progression?|url=https://pubmed.ncbi.nlm.nih.gov/15770529|journal=Breast Cancer Research and Treatment|volume=90|issue=1|pages=71–76|doi=10.1007/s10549-004-3003-3|issn=0167-6806|pmid=15770529}}</ref>
|-
|''GATA3''
|Inactivating mutations
|Other
|Recurrent
|P
|No
|Transcription factor regulating luminal cell differentiation in breast epithelium.<ref>{{Cite journal|last=Medford|first=Arielle J.|last2=Velimirovic|first2=Marko|last3=Gefen|first3=Yifat|last4=Niemierko|first4=Andrzej|last5=Gerratana|first5=Lorenzo|last6=Davis|first6=Andrew A.|last7=Clifton|first7=Katherine|last8=Keenan|first8=Jennifer|last9=Podany|first9=Emily|date=2025-08|title=Genomic and proteomic profiling of GATA3 mutant metastatic hormone receptor-positive breast cancer and impact on clinical outcomes|url=https://pubmed.ncbi.nlm.nih.gov/40439821|journal=Breast Cancer Research and Treatment|volume=212|issue=3|pages=437–447|doi=10.1007/s10549-025-07710-w|issn=1573-7217|pmc=12209021|pmid=40439821}}</ref>
|-
|''ERBB2''
|Activating mutations, amplification
|Oncogene
|Recurrent
|D, P, T
|Yes (NCCN)
|Drives HER2 signaling and may guide targeted therapy decisions. In papillary lesions, ''ERBB2'' amplification is primarily associated with solid papillary carcinoma and encapsulated papillary carcinoma with apocrine features and is a marker of high risk and chemotherapy benefit.<ref name=":0" />
|-
|''MAP3K1''
|Inactivating mutations
|TSG
|Recurrent
|P
|No
|Implicated in MAPK signaling and luminal breast cancer development.
|-
|''CDH1''
|Inactivating mutations
|TSG
|Rare
|P
|Yes
|Loss of E-cadherin disrupts cell adhesion and promotes tumor progression.
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
<br />
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|<span class="blue-text">EXAMPLE:</span> P
|
|
|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
|
|-
|
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
|
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|
|
|
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|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], 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 [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
==Epigenomic Alterations==
==Epigenomic Alterations==
Put your text here
Epigenetic changes in breast tumor development include alterations in DNA methylation and chromatin remodeling. Hyper-methylation of tumor suppressor gene promoters, such as RASSF1A, CDH1, and BRCA1, in breast tumor samples has been documented and is believed to lead to gene silencing. Abnormalities in histone modification and chromatin remodeling are also known to affect gene expression patterns controlling cell proliferation and differentiation.
 
==Genes and Main Pathways Involved==
==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>
Overexpression of MET may be a key factor in papillary differentiation.<ref>{{Cite journal|last=Ruco|first=L. P.|last2=Stoppacciaro|first2=A.|last3=Ballarini|first3=F.|last4=Prat|first4=M.|last5=Scarpino|first5=S.|date=2001-05|title=Met protein and hepatocyte growth factor (HGF) in papillary carcinoma of the thyroid: evidence for a pathogenetic role in tumourigenesis|url=https://pubmed.ncbi.nlm.nih.gov/11329134|journal=The Journal of Pathology|volume=194|issue=1|pages=4–8|doi=10.1002/path.847|issn=0022-3417|pmid=11329134}}</ref><ref>{{Cite journal|last=Nusrat|first=A.|last2=Parkos|first2=C. A.|last3=Bacarra|first3=A. E.|last4=Godowski|first4=P. J.|last5=Delp-Archer|first5=C.|last6=Rosen|first6=E. M.|last7=Madara|first7=J. L.|date=1994-05|title=Hepatocyte growth factor/scatter factor effects on epithelia. Regulation of intercellular junctions in transformed and nontransformed cell lines, basolateral polarization of c-met receptor in transformed and natural intestinal epithelia, and induction of rapid wound repair in a transformed model epithelium|url=https://pubmed.ncbi.nlm.nih.gov/8182137|journal=The Journal of Clinical Investigation|volume=93|issue=5|pages=2056–2065|doi=10.1172/JCI117200|issn=0021-9738|pmc=294323|pmid=8182137}}</ref>  
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations
|''PIK3CA'', ''AKT1''; activating mutations / PTEN inactivating mutations
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|PI3K-AKT-mTOR signaling
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|Increased cell proliferation and survival
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations
|''MET''; c-Met overexpression
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|HGF/c-Met
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|Cell motility, epithelial-to-mesenchymal transition
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
|''TP53''; inactivating mutations
|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
|DNA damage response
|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
|Genomic instability and tumor progression
|-
|-
|
|''ERBB2''; amplification or activating mutations
|
|MAPK/PI3K signaling pathways
|
|Enhanced growth signaling and tumorigenesis
|-
|''GATA3''; inactivating mutations
|Estrogen signaling pathways
|Altered luminal epithelial cell differentiation
|-
|''FOXA1''; activating mutations
|Estrogen signaling pathways
|Maintains papillary phenotype
|-
|''VEGFA''; VEGF overexpression
|VEGF signaling pathway
|Angiogenesis, promotes cancer cell survival, proliferation, and migration
|}
|}
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==
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Genetic alterations in breast cancers can be identified through various molecular diagnostic methods. Next-generation sequencing (NGS) panel tests may be used to identify somatic mutations. Immunohistochemistry and in situ hybridization (ISH) are used to identify overexpression and amplification of the ERBB2 (HER2) gene, respectively. In addition, various PCR tests and comparative genomic hybridization (CGH) may be used to identify particular mutations and copy number variations.
 
==Familial Forms==
==Familial Forms==
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While the majority of breast tumors are considered to be sporadic, some cases are linked with hereditary cancer syndromes. Germline mutations in BRCA1 and BRCA2, PALB2, and CHEK2 are the most common genes associated with a hereditary predisposition to breast cancer. Additional susceptibility genes include TP53, which causes Li-Fraumeni syndrome, and PTEN, which causes Cowden syndrome.
 
==Additional Information==
==Additional Information==
Put your text here
Breast tumors are a diverse group of neoplastic disorders that vary in their molecular and histopathologic characteristics. Recent advances in genomic profiling have significantly enhanced our current understanding of tumor biology and have paved the way to develop novel therapeutic strategies. Molecular classification and genetic testing are assuming a significant role in diagnosis, prognosis, and treatment of breast cancer.
 
==Links==
==Links==
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WHO Classification of Tumours – Breast Tumours: <nowiki>https://publications.iarc.fr/581</nowiki>
 
cBioPortal for Cancer Genomics: <nowiki>https://www.cbioportal.org/</nowiki>
 
COSMIC – Catalogue of Somatic Mutations in Cancer: <nowiki>https://cancer.sanger.ac.uk/cosmic</nowiki>
 
The Cancer Genome Atlas (TCGA) Breast Cancer Dataset: <nowiki>https://www.cancer.gov/tcga</nowiki>
 
==References==
==References==
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<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 [[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.  
<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.  
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