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

== ''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. ''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" />

=== Clinical Phenotypes by Zygosity ===

==== Heterozygous State (Monoallelic Pathogenic Variants) ====

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>.

==== Cancer risk estimates for heterozygous carriers: ====

* Tumor phenotype: 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) ====

==== Incidence ====

==== Summary of Cancer Risks in Heterozygous Carriers ====

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 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: ===

=== Differential Diagnosis: ===

|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" />

 

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>. 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" />.

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 BRCA1/2<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" />.

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# <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 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.

 

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