GTS5:PALB2-related cancer predisposition syndrome (PALB2): Difference between revisions
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[[GTS5:Table_of_Contents|Genetic Tumour Syndromes (Who Classification, 5th ed.)]] | |||
==Primary Author(s)*== | |||
Parisa Kargaran, Ph.D. | |||
Hieu Nguyen, Ph.D., FACMG | |||
==WHO Classification of Disease== | |||
{| class="wikitable" | |||
!Structure | |||
!Disease | |||
|- | |||
|Book | |||
|Genetic Tumour Syndromes (5th ed.) | |||
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|Category | |||
|DNA repair and genomic stability | |||
|- | |||
|Family | |||
|Homologous recombination | |||
|- | |||
|Type | |||
|PALB2-related cancer predisposition syndrome (PALB2) | |||
|- | |||
|Subtype(s) | |||
|N/A | |||
|} | |||
==Related Terminology== | |||
{| class="wikitable" | |||
|+ | |||
| | |||
|Acceptable | |||
| | |||
|DNA double-strand break repair; homologous recombination repair; pancreatic cancer 3; Fanconi anaemia, complementation group N | |||
|- | |||
| | |||
|Primary Name | |||
| | |||
|Partner and localizer of BRCA2 (PALB2) | |||
|- | |||
| | |||
|Synonyms | |||
| | |||
|FANCN (Fanconi anemia when homozygous), FLJ21816 | |||
|- | |||
| | |||
|Not Recommended | |||
| | |||
|N/A | |||
|} | |||
==Definition/Description of Disease== | |||
=== ''PALB2'' – Gene Function and Clinical Relevance === | |||
==== Gene Function ==== | |||
The ''PALB2'' gene is located at chromosome 16p12.2 and contains 13 exons, encoding a 1,186 amino acid protein. The PALB2 protein (Partner and Localizer of BRCA2) is a key component of the homologous recombination (HR) DNA repair pathway, where it directly interacts with BRCA2 to facilitate the accurate repair of DNA double-strand breaks. Through its role in DNA damage repair, ''PALB2'' functions as a tumor suppressor gene that maintains genomic integrity.<ref name=":0" /><ref name=":1" /> | |||
[[File:PALB2.png|none|thumb|945x945px|[https://BioRender.com ''PALB2''<nowiki> gene diagram showing DNA (top), RNA (MANE transcript ID NM_24675, middle), and protein (lower).The WD40 functional domain is highlighted in green. Images from St Jude Protein Paint [url: https://proteinpaint.stjude.org/] and edited using BioRender software [url: https://BioRender.com].</nowiki>]]] | |||
==== Clinical Phenotypes by Zygosity ==== | |||
===== Heterozygous State (Monoallelic Pathogenic Variants) ===== | |||
Germline heterozygous pathogenic variants in ''PALB2'' confer susceptibility to hereditary cancer syndromes with high penetrance; only ''BRCA1'' and ''BRCA2'' germline pathogenic variants confer a higher overall risk of breast cancer<ref>{{Cite journal|last=Breast Cancer Association Consortium|last2=Dorling|first2=Leila|last3=Carvalho|first3=Sara|last4=Allen|first4=Jamie|last5=González-Neira|first5=Anna|last6=Luccarini|first6=Craig|last7=Wahlström|first7=Cecilia|last8=Pooley|first8=Karen A.|last9=Parsons|first9=Michael T.|date=2021-02-04|title=Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women|url=https://pubmed.ncbi.nlm.nih.gov/33471991|journal=The New England Journal of Medicine|volume=384|issue=5|pages=428–439|doi=10.1056/NEJMoa1913948|issn=1533-4406|pmc=7611105|pmid=33471991}}</ref>. The most frequently associated malignancies include breast, pancreatic, and ovarian cancers<ref name=":3" /><ref name=":5" />. Germline ''PALB2'' pathogenic variants have also been reported in individuals with prostate, gastric, and colorectal cancers, though penetrance for these cancers is less well established<ref name=":22">Slavin TP, et al. The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk. NPJ Breast Cancer. 2017;3:22.</ref>. | |||
===== Cancer risk estimates for heterozygous carriers: ===== | |||
* Lifetime breast cancer risk (females): ~35–60% | |||
* Relative risk: ~5-fold compared with the general population | |||
* Tumor phenotype: Both estrogen receptor positive and estrogen receptor negative breast cancers. Enrichment of triple-negative breast cancer among ''PALB2''-associated breast cancers<ref name=":3" /><ref name=":15" /> | |||
===== Biallelic State (Compound Heterozygous or Homozygous Pathogenic Variants) ===== | |||
Biallelic pathogenic variants in ''PALB2'' result in Fanconi anemia subtype N (FANCN), a severe genomic instability disorder characterized by growth retardation, congenital malformations, skeletal abnormalities, hearing loss, intellectual disability, progressive bone marrow failure, anemia, and increased susceptibility to pediatric cancers, particularly acute leukemia in early childhood<ref name=":13" /><ref name=":15" /><ref name=":23">Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res. 2010;70(19):7353–7359</ref>. | |||
===== Incidence ===== | |||
The estimated population frequency of pathogenic ''PALB2'' variants is approximately 0.1% <ref name=":15" /><ref name=":5" />. | |||
===== Summary of Cancer Risks in Heterozygous Carriers ===== | |||
Heterozygous pathogenic variants in ''PALB2'' are associated with: | |||
* Breast cancer risk: ~33–53%, with some studies estimating risks up to 60% | |||
* Pancreatic cancer risk: Increased relative to the general population | |||
* Ovarian cancer risk: Moderately increased | |||
* Breast cancer subtype: Enrichment of triple-negative breast cancer<ref name=":3" /><ref name=":8" /> | |||
=== ''PALB2'' Related Cancer Predisposition Syndrome: === | |||
''PALB2'' encodes a key tumor suppressor protein that plays a central role in the homologous recombination (HR) DNA double strand break repair pathway, acting as a molecular scaffold that physically and functionally connects BRCA1 and BRCA2 <ref name=":0">Xia B, Sheng Q, Nakanishi K, et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Molecular Cell. 2006;22(6):719–729.</ref><ref name=":1">Sy SMH, Huen MSY, Chen J. PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proceedings of the National Academy of Sciences USA. 2009;106(17):7155–7160.</ref><ref name=":2">Park JY, Zhang F, Andreassen PR. PALB2: the hub of a network of tumor suppressors involved in DNA damage responses. Biochimica et Biophysica Acta. 2014;1846(1):263–275.</ref>. Loss of ''PALB2'' function results in homologous recombination deficiency, leading to impaired RAD51 recruitment to sites of DNA damage, defective high fidelity DNA repair, and genomic instability molecular mechanisms shared with BRCA associated cancers <ref name=":0" /><ref name=":1" /><ref name=":2" />. | |||
Clinically, individuals with pathogenic ''PALB2'' variants exhibit moderate to high penetrance for breast cancer, with cumulative lifetime risk estimates ranging from approximately 35–60%, depending on family history and modifying factors<ref name=":3">Antoniou AC, Casadei S, Heikkinen T, et al. Breast-cancer risk in families with mutations in PALB2. New England Journal of Medicine. 2014;371(6):497–506.</ref><ref name=":4">Couch FJ, Shimelis H, Hu C, et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncology. 2017;3(9):1190–1196.</ref><ref name=":5">Yang X, Leslie G, Doroszuk A, et al. Cancer risks associated with germline PALB2 pathogenic variants: an international study of 524 families. Journal of Clinical Oncology. 2020;38(7):674–685.</ref>. In some families, breast cancer risks approach those observed in ''BRCA2'' carriers<ref name=":3" /><ref name=":5" />. ''PALB2'' associated breast cancers may present at younger ages than sporadic cases and encompass a range of histologic and molecular subtypes, including triple negative and hormone receptor positive tumors<ref name=":4" /><ref name=":6">Heikkinen T, Kärkkäinen H, Aaltonen K, et al. The breast cancer susceptibility mutation PALB2 1592delT is associated with an aggressive tumor phenotype. Cancer Research. 2009;69(3):862–868.</ref>. An increased risk of male breast cancer has also been reported relative to the general population <ref name=":5" />. | |||
Beyond breast cancer, germline ''PALB2'' pathogenic variants are also associated with an increased risk of pancreatic ductal adenocarcinoma, and ''PALB2'' is recognized as a clinically actionable pancreatic cancer susceptibility gene in multiple professional guidelines and consensus statements <ref name=":7">Hu C, Hart SN, Polley EC, et al. Prevalence of pathogenic mutations in cancer predisposition genes among pancreatic cancer patients. JAMA. 2018;319(23):2401–2409.</ref><ref name=":8">National Comprehensive Cancer Network (NCCN). Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Current version.</ref>. Associations with ovarian cancer have been described, although penetrance appears lower than that observed for ''BRCA1'' and ''BRCA2'' <ref name=":3" /><ref name=":5" />. | |||
==== Diagnostic Criteria: ==== | |||
The diagnosis of ''PALB2'' related cancer predisposition syndrome is established by identifying a germline pathogenic or likely pathogenic variant in ''PALB2'' using validated molecular genetic testing methods, including multigene hereditary cancer panels, genome sequencing, or targeted familial testing<ref name=":4" /><ref name=":5" />. Testing is typically pursued in individuals with early onset breast cancer, multiple primary malignancies, a personal or family history suggestive of hereditary breast and/or pancreatic cancer, or tumor genomic findings consistent with homologous recombination deficiency that prompt germline evaluation<ref name=":4" /><ref name=":7" />. Once a pathogenic variant is identified, cascade testing of at-risk relatives is recommended<ref name=":5" /><ref name=":8" />. | |||
==== Differential Diagnosis: ==== | |||
The differential diagnosis includes other hereditary cancer predisposition syndromes involving defects in DNA damage response or homologous recombination repair pathways, particularly BRCA1 and BRCA2 related hereditary breast and ovarian cancer syndrome, CHEK2 associated cancer susceptibility, ATM associated hereditary cancer predisposition, and TP53 related Li-Fraumeni syndrome, especially in individuals with very early onset disease or multiple primary malignancies<ref name=":3" /><ref name=":4" /><ref name=":5" />. Distinction among these conditions relies on germline genetic testing, tumor characteristics, and family history patterns. | |||
=== Disease Context within WHO Classification: === | |||
Within the WHO Classification of Tumours, ''PALB2'' related cancer predisposition syndrome is classified as a hereditary cancer susceptibility condition involving genes responsible for DNA repair and genome stability. ''PALB2'' is discussed across WHO tumor classification volumes addressing breast, pancreatic, and gynecologic malignancies, where it is grouped with other high and moderate penetrance homologous recombination repair genes<ref name=":9">International Agency for Research on Cancer (IARC). WHO Classification of Tumours. Genetic tumour syndromes and DNA repair–related cancer susceptibility.</ref>. | |||
''PALB2'' associated cancers are classified according to tumor site and histopathology, rather than as a distinct morphologic entity. However, identification of the underlying genetic etiology has important implications for risk assessment, surveillance strategies, therapeutic decision making (including sensitivity to DNA damaging agents and PARP inhibitors), and familial counseling<ref name=":2" /><ref name=":5" /><ref name=":8" />. | |||
==Genetic Abnormalities: Germline== | |||
{| class="wikitable sortable" | |||
|- | |||
!Gene!!Genetic Variant or Variant Type!!Molecular Pathogenesis!!Inheritance, Penetrance, Expressivity | |||
!Notes | |||
|- | |||
|''PALB2''||SNVs (frameshift, nonsense, canonical splice site, missense with loss of function, synonymous variants affecting splicing); CNVs (inactivating deletions or duplications).||Loss of function variants disrupt ''PALB2'' mediated homologous recombination DNA repair through impaired BRCA1 BRCA2 interaction and defective RAD51 recruitment, resulting in homologous recombination deficiency and genomic instability.||Autosomal dominant cancer predisposition with moderate to high penetrance for breast cancer (~35-60%, modified by family history); Autosomal recessive inheritance causes Fanconi anemia, complementation group N (FA-N) with high penetrance. | |||
|Germline pathogenic variants are predominantly loss-of-function (frameshift, nonsense, splice site)<ref name=":0" /><ref name=":1" /><ref name=":2" />. Several founder mutations have been reported, including c.1592delT in Finnish populations and recurrent truncating variants in European ancestry cohorts<ref name=":3" /><ref name=":6" />. Missense variants are less common and require functional and/or segregation evidence for classification<ref name=":2" /><ref name=":4" />. CNVs involving partial or whole-gene deletions account for a minority of pathogenic alleles but are clinically significant<ref name=":4" /><ref name=":5" />. Biallelic pathogenic variants cause Fanconi anemia subtype N, characterized by childhood onset bone marrow failure, developmental anomalies, and early onset malignancies<ref name=":2" />. ''PALB2'' associated tumors share molecular features with BRCA-associated cancers and may demonstrate sensitivity to DNA damaging agents and PARP inhibitors<ref name=":2" /><ref name=":5" /><ref name=":8" />. | |||
|} | |||
==Genetic Abnormalities: Somatic== | |||
{| class="wikitable sortable" | |||
|- | |||
!Gene!!Genetic Variant or Variant Type!!Molecular Pathogenesis!!Inheritance, Penetrance, Expressivity | |||
!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 | |||
|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=":7" />. Tumors may demonstrate “BRCAness” features and potential responsiveness to HR-directed therapies<ref name=":2" /><ref name=":7" />. | |||
|- | |||
|''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'' and ''BRCA2''<ref name=":10">Goodall J, et al. Circulating tumor DNA to identify reversion mutations associated with acquired resistance to PARP inhibitors. J Clin Oncol. 2017.</ref><ref name=":11">Quigley D, et al. Analysis of circulating tumor DNA identifies reversion mutations associated with therapeutic resistance. Sci Transl Med. 2017.</ref><ref name=":12">Edwards SL, et al. Resistance to therapy caused by intragenic deletion in BRCA2; analogous mechanisms in PALB2-deficient tumors. Nature. 2008.</ref> | |||
|} | |||
==Genes and Main Pathways Involved== | |||
{| class="wikitable sortable" | |||
|- | |||
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome | |||
|- | |||
|''PALB2;'' Loss of function germline variants (frameshift, nonsense, splice site, deletions) | |||
|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" /> | |||
|- | |||
|''PALB2''; Biallelic inactivation (germline + somatic second hit) | |||
|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" /> | |||
|- | |||
|''PALB2''; Biallelic germline variants | |||
|Fanconi anemia (FA) pathway / interstrand crosslink repair | |||
|Failure 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) | |||
|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== | |||
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<ref name=":16">lavin TP, et al. The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk. NPJ Breast Cancer. 2017;3:22.</ref><ref name=":17">National Comprehensive Cancer Network (NCCN). Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2024</ref>. 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<ref name=":18">Southey MC, et al. PALB2 splice variants and breast cancer risk. Breast Cancer Res. 2016;18:14.</ref>. Almost 90% of ''PALB2'' variants identified in tumor-only NGS testing of breast cancers are germline<ref>{{Cite journal|last=Kuzbari|first=Z.|last2=Bandlamudi|first2=C.|last3=Loveday|first3=C.|last4=Garrett|first4=A.|last5=Mehine|first5=M.|last6=George|first6=A.|last7=Hanson|first7=H.|last8=Snape|first8=K.|last9=Kulkarni|first9=A.|date=2023-03|title=Germline-focused analysis of tumour-detected variants in 49,264 cancer patients: ESMO Precision Medicine Working Group recommendations|url=https://pubmed.ncbi.nlm.nih.gov/36529447|journal=Annals of Oncology: Official Journal of the European Society for Medical Oncology|volume=34|issue=3|pages=215–227|doi=10.1016/j.annonc.2022.12.003|issn=1569-8041|pmid=36529447}}</ref>. Therefore, 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<ref name=":19">Richards S, et al. Standards and guidelines for the interpretation of sequence variants. Genet Med. 2015;17(5):405–424</ref><ref name=":17" />. | |||
==Additional Information== | |||
Pathogenic variants in ''PALB2'' are associated with hereditary breast cancer susceptibility and confer a moderate to high lifetime risk of breast cancer, with risk estimates approaching those observed for ''BRCA2'' in some families<ref name=":14" /><ref name=":15" />. Female carriers have an estimated 35–58% lifetime risk of breast cancer by age 70, with risk modified by family history and other genetic or environmental factors. ''PALB2'' pathogenic variants are also associated with an increased risk of pancreatic cancer, and emerging evidence suggests a possible association with ovarian cancer, although penetrance for non-breast cancers remains lower and less well defined compared with ''BRCA1'' and ''BRCA2''<ref name=":5" /><ref name=":17" />. Biallelic pathogenic variants in ''PALB2'' cause Fanconi anemia subtype N, characterized by congenital anomalies, bone marrow failure, and childhood cancer predisposition, highlighting the gene’s essential role in DNA repair<ref name=":13" />. From a molecular standpoint, ''PALB2'' encodes a critical partner of ''BRCA1'' and ''BRCA2'' within the homologous recombination (HR) DNA repair pathway. Loss of function variants result in homologous recombination deficiency (HRD), which has therapeutic relevance, as tumors harboring germline or somatic ''PALB2'' pathogenic variants may demonstrate sensitivity to PARP inhibitors and platinum based chemotherapy<ref name=":20">Park JY, et al. Efficacy of PARP inhibitors in PALB2-mutated cancers. Clin Cancer Res. 2021;27(15):4231–4240.</ref><ref name=":21">Mateo J, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2019;373(18):1697–1708.</ref>. Identification of a pathogenic ''PALB2'' variant has important clinical management implications, including enhanced breast cancer surveillance (e.g., annual breast MRI), consideration of risk reducing strategies, and cascade testing for at risk relatives, in accordance with established professional guidelines<ref name=":17" />. | |||
==Links== | |||
https://www.ncbi.nlm.nih.gov/clinvar/?term=%22PALB2%22%5BGENE%5D&redir=gene | |||
==References== | |||
[[Category:GTS5]][[Category:DISEASE]] | |||
<references /> | |||
==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): | |||