HEREDITARY OVARIAN CANCER

Hereditary Ovarian Cancer — approximately 20-25% of ovarian cancers have hereditary causes, the highest proportion of any common cancer, and PARP inhibitors have transformed outcomes for BRCA-positive patients.

Whole genome sequencing evaluates all ovarian cancer predisposition genes — BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, MLH1, MSH2, MSH6, PALB2 — providing comprehensive genetic assessment for treatment selection and family cancer prevention.

BRCA1
BRCA2
RAD51C
RAD51D
BRIP1
MLH1
MSH2

About this condition

Ovarian Cancer — Hereditary

Ovarian cancer has the highest hereditary fraction of any common cancer — approximately 20-25% of epithelial ovarian cancers (EOC) have identifiable germline pathogenic variants. BRCA1 (~39-46% lifetime ovarian cancer risk) and BRCA2 (~11-18% lifetime risk) are the most common, accounting for approximately 15% of all EOC. Additional genes include RAD51C (~5-10% lifetime risk), RAD51D (~5-13% lifetime risk), BRIP1 (~5-6% lifetime risk), and Lynch syndrome genes MLH1/MSH2/MSH6 (3-14% lifetime risk, particularly endometrioid and clear cell subtypes). Emerging evidence supports PALB2 as a moderate ovarian cancer risk gene.

PARP inhibitors have transformed hereditary ovarian cancer treatment. Olaparib, niraparib, and rucaparib are FDA-approved for BRCA-mutated ovarian cancer in various settings (maintenance after platinum chemotherapy, recurrent disease). The SOLO-1 trial demonstrated that olaparib maintenance after first-line platinum chemotherapy in germline BRCA-mutated advanced ovarian cancer reduced the risk of progression by 70% — a paradigm-shifting result. RAD51C and RAD51D variants also confer homologous recombination deficiency (HRD) and sensitivity to PARP inhibitors, though specific approvals for these genes are evolving.

Risk-reducing salpingo-oophorectomy (RRSO) is the most effective prevention strategy for hereditary ovarian cancer. RRSO reduces ovarian cancer risk by approximately 80% in BRCA1/2 carriers and is recommended between ages 35-40 for BRCA1 and 40-45 for BRCA2 — after completion of childbearing. Currently, no effective ovarian cancer screening strategy exists for the general population (CA-125 and transvaginal ultrasound have insufficient sensitivity/specificity for population screening). This makes genetic identification of high-risk individuals particularly critical — RRSO is the primary prevention tool, and it requires knowing who should receive it.

There is NO effective population screening for ovarian cancer. Unlike breast cancer (mammography) and colon cancer (colonoscopy), ovarian cancer prevention relies on identifying genetic high-risk individuals and offering risk-reducing surgery. Genetic testing is the prevention strategy.

Gene locus: BRCA1 (17q21.31), BRCA2 (13q13.1), RAD51C (17q22), RAD51D (17q12), BRIP1 (17q23.2), MLH1 (3p21.3), MSH2 (2p21)

Ovarian cancer prevention depends on genetic identification — there is no effective screening test. RRSO reduces risk by ~80% but requires knowing who carries a high-risk variant. Genetic testing IS the prevention program.

PARP inhibitor eligibility requires germline BRCA confirmation — and RAD51C/D are emerging as additional PARP-sensitive genes

PARP inhibitor maintenance after platinum chemotherapy has become standard of care for germline BRCA-mutated ovarian cancer based on landmark trials (SOLO-1, PRIMA, ARIEL3). Germline testing is now recommended for ALL ovarian cancer patients at diagnosis — not just those with family history — because 15-20% will carry actionable variants. RAD51C and RAD51D variants also confer HRD and emerging evidence supports PARP inhibitor sensitivity. WGS evaluates all HRD genes simultaneously.

BRCA1 vs. BRCA2 have different optimal RRSO timing — molecular identification of the specific gene determines the surgical window

BRCA1 carries higher ovarian cancer risk with earlier median onset — RRSO is recommended by age 35-40. BRCA2 carries lower risk with later onset — RRSO can be deferred to 40-45, preserving natural menopause and cardiovascular/bone health longer. For RAD51C and RAD51D, RRSO timing recommendations are still being refined but generally align with BRCA2 timing. Without molecular identification of the specific gene, RRSO timing cannot be optimized.

Hereditary Ovarian Cancer — approximately 20-25% of ovarian cancers have hereditary causes, the highest proportion of any common cancer, and PARP inhibitors have transformed outcomes for BRCA-positive patients.

Ovarian Cancer — Hereditary

Ovarian cancer prevention depends on genetic identification — there is no effective screening test. RRSO reduces risk by ~80% but requires knowing who carries a high-risk variant. Genetic testing IS the prevention program.

PARP inhibitor eligibility requires germline BRCA confirmation — and RAD51C/D are emerging as additional PARP-sensitive genes

BRCA1 vs. BRCA2 have different optimal RRSO timing — molecular identification of the specific gene determines the surgical window

Others in Hereditary Cancer

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