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

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 - Lifetime risk of breast cancer in females is 35-60% (relative risk ~ 5-fold). The incidence of triple negative breast cancer is enriched in those with PALB2-related breast cancer.
-'''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" />.
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 The diagnosis of ''PALB2'' related cancer predisposition syndrome is established by identifying a germline pathogenic or likely pathogenic variant in ''PALB2'' using validated molecular genetic testing methods, including multigene hereditary cancer panels, genome sequencing, or targeted familial testing<ref name=":4" /><ref name=":5" />. Testing is typically pursued in individuals with early onset breast cancer, multiple primary malignancies, a personal or family history suggestive of hereditary breast and/or pancreatic cancer, or tumor genomic findings consistent with homologous recombination deficiency that prompt germline evaluation<ref name=":4" /><ref name=":7" />. Once a pathogenic variant is identified, cascade testing of at-risk relatives is recommended<ref name=":5" /><ref name=":8" />.
-'''Differential Diagnosis:'''
+=== Differential Diagnosis: ===
 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.
-'''Disease Context within WHO Classification:'''
+=== Disease Context within WHO Classification: ===
 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>.
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 ==Additional Information==
-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" /> (Reid et al., 2007). 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 (Park et al., 2021; Mateo et al., 2019). 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 (NCCN, 2024).
+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" />.
 ==Links==
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 <ref name=":19" />Richards S, et al. Standards and guidelines for the interpretation of sequence variants. Genet Med. 2015;17(5):405–424.
+<ref name=":20" />Park JY, et al. Efficacy of PARP inhibitors in PALB2-mutated cancers. Clin Cancer Res. 2021;27(15):4231–4240.
+<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.
 ==Notes==