GTS5:BRCA-related cancer predisposition syndrome (BRCA1, BRCA2): Difference between revisions
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|''BRCA1''|| | |''BRCA1''||'''SNVs''' (frameshift, nonsense, pathogenic missense, canonical splice-site, synonymous splice-altering variants); '''CNVs''' (inactivating multi-exon deletions or duplications)||Multiple variant types lead to loss of BRCA1 function, resulting in impaired homologous recombination–mediated DNA double-strand break repair, defective DNA damage response, and genomic instability||Autosomal dominant cancer predisposition with incomplete penetrance and variable expressivity; rare biallelic pathogenic variants associated with Fanconi anemia–like phenotypes | ||
~ | |Heterozygous pathogenic variants confer increased lifetime risk of female and male breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer. Estimated lifetime breast cancer risk ~60–80% and ovarian cancer risk ~35–45% in women [1,2]. Founder mutations reported in multiple populations, including c.68_69delAG (185delAG) and c.5266dupC (5382insC) [1,5]. Large genomic rearrangements represent a clinically significant subset of pathogenic BRCA1 variants and require copy-number–sensitive testing methods [4]. Molecular pathogenesis reflects failure of homologous recombination repair [3]. | ||
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|''BRCA2'' | |''BRCA2'' | ||
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| | |''BRCA1''||'''Biallelic inactivation (second hit)''' including somatic SNVs/indels, copy-neutral LOH, focal or arm-level deletion, promoter hypermethylation, or complex structural rearrangements||In individuals with a germline pathogenic '''BRCA1''' variant, tumor development follows a '''two-hit mechanism'''. Somatic loss of the remaining wild-type allele results in complete BRCA1 deficiency, impaired homologous recombination DNA repair, genomic instability, and carcinogenesis||'''Somatic, tumor-specific event'''; not inherited. Results in a '''homologous recombination–deficient (HRD)''' tumor phenotype | ||
| | |Common in '''BRCA1-associated breast and ovarian cancers'''. Biallelic loss is associated with increased sensitivity to '''platinum chemotherapy and PARP inhibitors''' '''[1,2]'''. '''Promoter hypermethylation''' represents a frequent non-sequence–based second hit in BRCA1-driven tumors '''[3]'''. | ||
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|''BRCA1'' | |||
|'''Somatic reversion mutations''' (frameshift correction, splice rescue, deletion of pathogenic allele restoring open reading frame) | |||
|Under selective pressure from '''PARP inhibitors or platinum therapy''', secondary somatic mutations may restore BRCA1 function, re-establish homologous recombination, and confer '''therapeutic resistance''' | |||
|'''Acquired resistance mechanism'''; tumor-specific; not inherited | |||
|Documented in '''ovarian and breast cancers''' and associated with '''acquired resistance to PARP inhibitors and platinum agents''' and disease progression '''[4,5]''' | |||
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| | |''BRCA2'' | ||
| | |'''Biallelic inactivation (second hit)''' including somatic SNVs/indels, copy-neutral LOH, focal or whole-arm deletion, or complex structural rearrangements | ||
| | |In individuals with a germline pathogenic '''BRCA2''' variant, tumorigenesis follows a '''two-hit mechanism'''. Somatic loss of the remaining wild-type allele leads to complete loss of BRCA2 function, defective homologous recombination repair, genomic instability, and tumor development | ||
| | |Somatic event occurs '''in tumor tissue only'''; not inherited. Tumor phenotype shows '''homologous recombination deficiency (HRD)''' | ||
| | |Common mechanism in BRCA2-associated breast, ovarian, pancreatic, and prostate cancers. Presence of biallelic loss predicts '''sensitivity to platinum chemotherapy and PARP inhibitors''' | ||
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| | |''BRCA2'' | ||
| | |'''Somatic reversion mutations''' (frameshift/nonsense “correction,” splice rescue, or deletion of pathogenic allele restoring reading frame) | ||
| | |Under selective pressure from '''PARP inhibitors or platinum therapy''', secondary somatic mutations can restore partial or full BRCA2 function, re-establish homologous recombination, and confer '''therapy resistance''' | ||
| | |Acquired, tumor-specific resistance mechanism; not inherited | ||
| | |Well-described in ovarian, breast, pancreatic, and prostate cancers. Associated with '''acquired resistance to PARP inhibitors and platinum agents''' and disease progression | ||
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==Genes and Main Pathways Involved== | ==Genes and Main Pathways Involved== | ||