Frontiers in oncology · 2026
Challenging the extended phenotype: HRD-negative salivary gland carcinoma in a BRCA1 founder-variant carrier, case report and literature review.
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Torres William, Vargas Elizabeth, Ballen Diego-Felipe, Tapiero-Rodriguez Sandra M, Cadena Enrique, Parra-Medina Rafael, Riaño-Moreno Julian C
Аннотация
BACKGROUND: Pathogenic BRCA1 variants are established in hereditary breast and ovarian cancer (HBOC) and associated with pancreatic, prostate, and gastric cancers. Salivary gland tumors (SGTs) have been reported in BRCA1/2 carriers and suggested as part of an extended HBOC phenotype based on epidemiological associations. However, functional evidence is lacking, and homologous recombination deficiency (HRD)-the hallmark of BRCA-driven cancers-has not been systematically assessed in BRCA1-associated SGTs.
CASE PRESENTATION: We report a Colombian family segregating the BRCA1 c.3331_3334delCAAG (p.Gln1111Asnfs*5) founder variant with phenotypic variability across four generations: gastric (31%), breast (37.5%), colorectal (19%), and thyroid cancers (12.5%). The proband, a 61-year-old woman, developed high-grade mucoepidermoid carcinoma of the parotid gland. Germline testing confirmed the familial BRCA1 variant. Tumor profiling revealed the same BRCA1 variant (VAF 56%) plus a pathogenic TP53 mutation (c.730G>T, p.Gly244Cys; VAF 32%), without BRCA1 loss of heterozygosity. HRD testing using shallow whole genome sequencing showed preserved homologous recombination function (Genomic Instability Score: 0.01, LGA: 11.40, LPC: 0), all below HRD-positive thresholds.
CONCLUSION: This represents the first SGT in a BRCA1 carrier evaluated with HRD testing. The absence of HRD argues against BRCA1-driven tumorigenesis despite clear familial segregation. These findings challenge the presumed causal relationship between BRCA1 variants and SGT development. Clinical implications are direct: SGTs in BRCA1 carriers should not be assumed eligible for PARP inhibitor therapy without HRD confirmation, and enhanced surveillance appears unwarranted. This case underscores that co-occurrence does not establish causation and highlights the critical importance of functional validation before expanding hereditary cancer spectra.
CASE PRESENTATION: We report a Colombian family segregating the BRCA1 c.3331_3334delCAAG (p.Gln1111Asnfs*5) founder variant with phenotypic variability across four generations: gastric (31%), breast (37.5%), colorectal (19%), and thyroid cancers (12.5%). The proband, a 61-year-old woman, developed high-grade mucoepidermoid carcinoma of the parotid gland. Germline testing confirmed the familial BRCA1 variant. Tumor profiling revealed the same BRCA1 variant (VAF 56%) plus a pathogenic TP53 mutation (c.730G>T, p.Gly244Cys; VAF 32%), without BRCA1 loss of heterozygosity. HRD testing using shallow whole genome sequencing showed preserved homologous recombination function (Genomic Instability Score: 0.01, LGA: 11.40, LPC: 0), all below HRD-positive thresholds.
CONCLUSION: This represents the first SGT in a BRCA1 carrier evaluated with HRD testing. The absence of HRD argues against BRCA1-driven tumorigenesis despite clear familial segregation. These findings challenge the presumed causal relationship between BRCA1 variants and SGT development. Clinical implications are direct: SGTs in BRCA1 carriers should not be assumed eligible for PARP inhibitor therapy without HRD confirmation, and enhanced surveillance appears unwarranted. This case underscores that co-occurrence does not establish causation and highlights the critical importance of functional validation before expanding hereditary cancer spectra.