GTS5:PALB2-related cancer predisposition syndrome (PALB2): Difference between revisions
| [unchecked revision] | [unchecked revision] |
No edit summary |
No edit summary |
||
| Line 106: | Line 106: | ||
!Notes | !Notes | ||
|- | |- | ||
|PALB2||Biallelic inactivation (second hit): loss of heterozygosity (LOH), somatic truncating mutation, focal or whole-gene deletion, copy-neutral LOH||Somatic inactivation of the remaining wild-type PALB2 allele in tumors from germline carriers leads to complete loss of PALB2 function, resulting in homologous recombination deficiency, impaired RAD51 loading, and genomic instability||Not inherited; somatic event occurring in tumors of germline carriers; contributes to tumor initiation and progression | |''PALB2''||Biallelic inactivation (second hit): loss of heterozygosity (LOH), somatic truncating mutation, focal or whole-gene deletion, copy-neutral LOH||Somatic inactivation of the remaining wild-type PALB2 allele in tumors from germline carriers leads to complete loss of PALB2 function, resulting in homologous recombination deficiency, impaired RAD51 loading, and genomic instability||Not inherited; somatic event occurring in tumors of germline carriers; contributes to tumor initiation and progression | ||
|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 | |''PALB2'' | ||
|Somatic loss of function variants (frameshift, nonsense, splice site) in sporadic tumors | |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 PALB2 loss disrupts HR DNA repair independently of germline status, resulting in HR-deficient tumor phenotypes. | ||
| Line 115: | Line 115: | ||
|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=":7" />. Tumors may demonstrate “BRCAness” features and potential responsiveness to HR-directed therapies<ref name=":2" /><ref name=":7" />. | |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=":7" />. Tumors may demonstrate “BRCAness” features and potential responsiveness to HR-directed therapies<ref name=":2" /><ref name=":7" />. | ||
|- | |- | ||
|PALB2 | |''PALB2'' | ||
|Reversion mutations (therapy associated) | |Reversion mutations (therapy associated) | ||
|Secondary somatic mutations restore the open reading frame or functional domains of PALB2, partially or fully rescuing homologous recombination activity | |Secondary somatic mutations restore the open reading frame or functional domains of PALB2, partially or fully rescuing homologous recombination activity | ||
| Line 127: | Line 127: | ||
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome | !Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome | ||
|- | |- | ||
|PALB2; Loss of function germline variants (frameshift, nonsense, splice site, deletions) | |''PALB2;'' Loss of function germline variants (frameshift, nonsense, splice site, deletions) | ||
|Homologous recombination (HR) DNA double-strand break repair | |Homologous recombination (HR) DNA double-strand break repair | ||
|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" /> | |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" /> | ||
|- | |- | ||
|PALB2; Biallelic inactivation (germline + somatic second hit) | |''PALB2''; Biallelic inactivation (germline + somatic second hit) | ||
|DNA damage response and genome stability maintenance | |DNA damage response and genome stability maintenance | ||
|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" /> | |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" /> | ||
|- | |- | ||
|PALB2; Biallelic germline variants | |''PALB2''; Biallelic germline variants | ||
|Fanconi anemia (FA) pathway / interstrand crosslink repair | |Fanconi anemia (FA) pathway / interstrand crosslink repair | ||
|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 name=":13">Reid S, et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype N. Nat Genet. 2007.</ref> | |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 name=":13">Reid S, et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype N. Nat Genet. 2007.</ref> | ||
|- | |- | ||
|PALB2; Reversion mutations (therapy-associated) | |''PALB2''; Reversion mutations (therapy-associated) | ||
|Restoration of homologous recombination repair | |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" /> | |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" /> | ||
| Line 145: | Line 145: | ||
==Genetic Diagnostic Testing Methods== | ==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> | Put your text here <span style="color:#0070C0">(''Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.'')</span> | ||
Recommended testing approaches for ''PALB2'' include comprehensive germline sequencing with concurrent copy number analysis. | |||
Next generation sequencing (NGS) based multigene hereditary cancer panels or targeted PALB2 sequencing are the primary diagnostic methods to identify clinically significant variants, including pathogenic single-nucleotide variants (SNVs), small insertions/deletions (indels), and canonical splice-site alterations<ref name=":14">Antoniou AC, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371(6):497–506.</ref><ref name=":15">Tischkowitz M, et al. Management of PALB2-associated breast cancer risk. Lancet Oncol. 2017;18(2):e75–e86</ref>. | |||
Because exonic and whole-gene deletions or duplications represent a clinically relevant subset of pathogenic PALB2 variants, copy-number variant (CNV) analysis should be performed as part of routine testing. CNV detection may be achieved using NGS read-depth algorithms, multiplex ligation-dependent probe amplification (MLPA), or chromosomal microarray (CMA) when appropriate (Slavin et al., 2017; NCCN, 2024). | |||
For individuals with a strong personal or family history suggestive of hereditary breast, ovarian, or pancreatic cancer and negative standard testing, RNA analysis may be considered to clarify the functional impact of suspected splice-altering variants or deep intronic changes (Southey et al., 2016). | |||
When PALB2 variants are identified through tumor-only genomic testing, paired germline testing is recommended to distinguish germline pathogenic variants from somatic alterations and to inform clinical management, cascade testing, and cancer risk assessment for at-risk relatives (ACMG/AMP, 2015; NCCN, 2024). | |||
==Additional Information== | ==Additional Information== | ||
Put your text here | Put your text here | ||
| Line 179: | Line 190: | ||
<ref name=":13" />Reid S, et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype N. Nat Genet. 2007. | <ref name=":13" />Reid S, et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype N. Nat Genet. 2007. | ||
<ref name=":14" />Antoniou AC, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371(6):497–506. | |||
<ref name=":15" />Tischkowitz M, et al. Management of PALB2-associated breast cancer risk. Lancet Oncol. 2017;18(2):e75–e86. | |||
==Notes== | ==Notes== | ||