GTS5:PALB2-related cancer predisposition syndrome (PALB2): 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)*== | ||
Hieu Nguyen, | Hieu Nguyen, Ph.D., FACMG | ||
Parisa Kargaran, | Parisa Kargaran, Ph.D. | ||
==WHO Classification of Disease== | ==WHO Classification of Disease== | ||
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|Tumor development in PALB2 associated cancers typically follows a two hit model, analogous to BRCA1/2, with somatic loss of the wild-type allele frequently observed in breast and pancreatic tumors <ref name=":0" /><ref name=":1" /><ref name=":2" />. Biallelic loss is associated with HR-deficient genomic signatures and therapeutic sensitivity to DNA-damaging agents and PARP inhibitors<ref name=":2" /><ref name=":3" /><ref name=":4" /> | |Tumor development in PALB2 associated cancers typically follows a two hit model, analogous to BRCA1/2, with somatic loss of the wild-type allele frequently observed in breast and pancreatic tumors <ref name=":0" /><ref name=":1" /><ref name=":2" />. Biallelic loss is associated with HR-deficient genomic signatures and therapeutic sensitivity to DNA-damaging agents and PARP inhibitors<ref name=":2" /><ref name=":3" /><ref name=":4" /> | ||
|- | |- | ||
|< | |PALB2 | ||
|Somatic loss of function variants (frameshift, nonsense, splice site) in sporadic tumors | |||
|Somatic PALB2 loss disrupts HR DNA repair independently of germline status, resulting in HR-deficient tumor phenotypes. | |||
|Somatic, non-heritable; variable expressivity depending on tumor type and co-occurring alterations | |||
|Somatic PALB2 alterations are less frequent than BRCA1/2 alterations but have been identified in breast, pancreatic, and other solid tumors<ref name=":3" /><ref name=":5" />. Tumors may demonstrate “BRCAness” features and potential responsiveness to HR-directed therapies<ref name=":2" /><ref name=":5" />. | |||
|- | |- | ||
| | |PALB2 | ||
| | |Reversion mutations (therapy associated) | ||
| | |Secondary somatic mutations restore the open reading frame or functional domains of PALB2, partially or fully rescuing homologous recombination activity | ||
| | |Acquired somatic resistance mechanism; observed after selective therapeutic pressure | ||
| | |Reversion mutations have been reported in PALB2 deficient tumors following treatment with PARP inhibitors or platinum based chemotherapy, leading to restoration of HR repair and acquired therapeutic resistance, similar to mechanisms described for BRCA1/2<ref name=":6" /><ref name=":7" /><ref name=":8" />. | ||
|} | |} | ||
==Genes and Main Pathways Involved== | ==Genes and Main Pathways Involved== | ||