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

== PALB2 – Gene Function and Clinical Relevance ==

The PALB2 gene is located at chromosome 16p12.2 and contains 13 exons, encoding a 1,186 amino acid protein. PALB2 (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 that maintains genomic integrity<ref name=":0" /><ref name=":1" />

Germline heterozygous pathogenic variants in PALB2 confer susceptibility to hereditary cancer syndromes with incomplete penetrance. 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>.

* Tumor phenotype: Enrichment of triple-negative breast cancer among PALB2-associated breast cancers<ref name=":3" /><ref name=":15" />

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>.

The estimated population frequency of pathogenic PALB2 variants is approximately 0.1% <ref name=":15" /><ref name=":5" />.

Heterozygous pathogenic variants in PALB2 are associated with:

=== 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" />.  

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" />.  

|''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" />.

|''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" />

|Somatic PALB2 loss disrupts HR DNA repair independently of germline status, resulting in HR-deficient tumor phenotypes.

|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" />.

|Secondary somatic mutations restore the open reading frame or functional domains of PALB2, partially or fully rescuing homologous recombination activity

|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=":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>

|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" />

|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" />

|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" />