GTS5:PALB2-related cancer predisposition syndrome (PALB2): Difference between revisions

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 !Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
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-|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations
+|PALB2; Loss of function germline variants (frameshift, nonsense, splice site, deletions)
-|<span class="blue-text">EXAMPLE:</span> MAPK signaling
+|Homologous recombination (HR) DNA double-strand break repair
-|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
+|Disruption of PALB2-mediated BRCA1–BRCA2 complex formation leads to impaired RAD51 recruitment, defective high fidelity DNA repair, homologous recombination deficiency, and genomic instability, promoting tumor initiation and progression<ref name=":0" /><ref name=":1" /><ref name=":2" />
 |-
-|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations
+|PALB2; Biallelic inactivation (germline + somatic second hit)
-|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
+|DNA damage response and genome stability maintenance
-|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
+|Complete loss of PALB2 function results in profound HR deficiency (“BRCAness”), accumulation of chromosomal aberrations, and increased sensitivity to DNA-damaging agents and PARP inhibition<ref name=":2" /><ref name=":3" /><ref name=":4" /><ref name=":5" />
 |-
-|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
+|PALB2; Biallelic germline variants
-|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
+|Fanconi anemia (FA) pathway / interstrand crosslink repair
-|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
+|ailure of FA pathway coordination causes Fanconi anemia complementation group N, characterized by bone marrow failure, developmental abnormalities, and early-onset malignancies<ref name=":2" /><ref>Reid S, et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype N. Nat Genet. 2007.</ref>
 |-
-|
+|PALB2; Reversion mutations (therapy-associated)
-|
+|Restoration of homologous recombination repair
-|
+|Secondary somatic mutations restore PALB2 reading frame or function, reactivating HR repair and leading to resistance to PARP inhibitors and platinum-based chemotherapy<ref name=":10" /><ref name=":11" />
 |}
 ==Genetic Diagnostic Testing Methods==