GTS5:PALB2-related cancer predisposition syndrome (PALB2): Difference between revisions
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=== Clinical Phenotypes by Zygosity === | === 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>. | 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: ==== | |||
* Lifetime breast cancer risk (females): ~35–60% | * Lifetime breast cancer risk (females): ~35–60% | ||
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* Tumor phenotype: Enrichment of triple-negative breast cancer among PALB2-associated breast cancers<ref name=":3" /><ref name=":15" /> | * 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) ==== | |||
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>Tischkowitz M, Xia B. PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res. 2010;70(19):7353–7359</ref>. | 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>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" />. | 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: | Heterozygous pathogenic variants in PALB2 are associated with: | ||
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=== PALB2 Related Cancer Predisposition Syndrome: === | === 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" />. | ''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" />. | 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" />. | ||