A 35-year-old woman with a family history of early-onset breast cancer (mother diagnosed at age 38) undergoes genetic counseling. Pedigree analysis suggests autosomal dominant inheritance. Which investigation is most appropriate to confirm a germline BRCA1/BRCA2 mutation?
A. Whole-genome sequencing (WGS) with constitutional DNA analysis
B. Karyotyping of peripheral blood lymphocytes
C. Comparative genomic hybridization (CGH) of tumor tissue
D. Immunohistochemistry for BRCA1 protein in breast tissue biopsy
Explanation
Germline Mutation Detection in Hereditary Cancer Syndromes
Key Point
Whole-genome sequencing (or targeted NGS of BRCA1/BRCA2) of constitutional (blood) DNA is the gold standard for identifying germline mutations that confer hereditary cancer predisposition.
Rationale for WGS / Targeted Sequencing
1.
Detects all mutation types: Point mutations, insertions, deletions, large rearrangements, and copy number changes in BRCA1/BRCA2
2.
Constitutional DNA: Analyzes germline DNA from blood, not somatic tumor DNA
3.
High sensitivity and specificity: >99% for pathogenic variants
4.
Clinical utility: Results guide surveillance, prophylactic surgery, and family screening
5.
Actionable: Identifies BRCA1/BRCA2 carriers eligible for PARP inhibitors (olaparib, rucaparib) and platinum-based chemotherapy
Why Other Investigations Fail
Table
Investigation
Problem
IHC for BRCA1
Detects protein expression in tumor, not germline mutations; loss of BRCA1 expression is indirect and non-specific
CGH
Analyzes somatic tumor DNA; cannot identify germline mutations; designed for copy number changes, not point mutations
BRCA1/BRCA2 mutations account for ~5–10% of breast cancers and confer 45–87% lifetime risk of breast cancer. Genetic testing is recommended for:
Personal history of breast cancer <45 years
Family history of early-onset breast or ovarian cancer
Ashkenazi Jewish ancestry
Male breast cancer
Mnemonic: BRCA — Breast cancer susceptibility genes (BRCA1, BRCA2) encode DNA repair proteins; mutations impair homologous recombination repair.
Clinical Pearl
BRCA1/BRCA2 carriers benefit from enhanced surveillance, risk-reducing surgery (mastectomy, oophorectomy), and PARP inhibitor therapy in metastatic disease.
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