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

''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 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" />.

 

 

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.

 

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>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" />.