Compendium of Cancer Genome Aberrations

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

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- In the compound heterozygous or homozygous state, biallelic pathogenic variants in PALB2 cause Fanconi anemia (FA) subtype N (Complementation Group N - FANCN), which is a severe genomic instability condition characterized by growth retardation, congenital malformations, skeletal abnormalities, hearing loss, intellectual disability, progressive bone marrow failure, anemia, and pediatric cancer susceptibility (acute leukemia in early childhood).  
- In the compound heterozygous or homozygous state, biallelic pathogenic variants in PALB2 cause Fanconi anemia (FA) subtype N (Complementation Group N - FANCN), which is a severe genomic instability condition characterized by growth retardation, congenital malformations, skeletal abnormalities, hearing loss, intellectual disability, progressive bone marrow failure, anemia, and pediatric cancer susceptibility (acute leukemia in early childhood).  


'''PALB2 Related Cancer Predisposition Syndrome:'''
'''PALB2 Related Cancer Predisposition Syndrome:'''


PALB2 related cancer predisposition syndrome is an autosomal dominant hereditary cancer susceptibility syndrome caused by heterozygous pathogenic or likely pathogenic germline variants in ''PALB2'' (Partner of BRCA2), a tumor suppressor gene that encodes a critical mediator of homologous recombination mediated DNA double strand break repair through its interaction with BRCA2<ref name=":0">Xia B, et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006;22:719–729.</ref><ref name=":1">Sy SMH, Huen MSY, Chen J. PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proc Natl Acad Sci USA. 2009;106:7155–7160.</ref>. The syndrome is primarily associated with a substantially increased lifetime risk of breast cancer, with cumulative risk estimates approaching those observed in ''BRCA2'' carriers in some families<ref name=":2">Antoniou AC, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371:497–506.</ref><ref name=":3">Yang X, et al. Cancer risks associated with germline PALB2 pathogenic variants: an international study of 524 families. J Clin Oncol. 2020;38:674–685.</ref>. In addition to breast cancer, germline PALB2 pathogenic variants are associated with an increased risk of pancreatic cancer and, to a lesser extent, ovarian cancer and other solid tumors<ref name=":3" /><ref name=":4">Couch FJ, et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol. 2017;3:1190–1196.</ref><ref name=":5">Hu C, et al. Prevalence of pathogenic mutations in cancer predisposition genes among pancreatic cancer patients. JAMA. 2018;319:2401–2409.</ref>.  
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 [4,6]. 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 [5,7]. An increased risk of male breast cancer has also been reported relative to the general population [6].
 
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 [8,9]. Associations with ovarian cancer have been described, although penetrance appears lower than that observed for BRCA1 and BRCA2 [4,6].


==Epidemiology/Prevalence==
- Incidence: 0.1%  
- Incidence: 0.1%  


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<ref name=":0" />Xia B, et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006;22:719–729.
<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=":1" />Sy SMH, Huen MSY, Chen J. PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proc Natl Acad Sci USA. 2009;106:7155–7160.
<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 name=":2" />Antoniou AC, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371:497–506.
<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 name=":3" />Yang X, et al. Cancer risks associated with germline PALB2 pathogenic variants: an international study of 524 families. J Clin Oncol. 2020;38:674–685.
<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 name=":4" />Couch FJ, et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol. 2017;3:1190–1196.
<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 name=":5" />Hu C, et al. Prevalence of pathogenic mutations in cancer predisposition genes among pancreatic cancer patients. JAMA. 2018;319:2401–2409.
<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.


==Notes==
==Notes==
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