BRCA1 (chromosome 17q) and BRCA2 (chromosome 13q) are tumour suppressor genes involved in transcriptional regulation and DNA repair (specifically homologous recombination repair of double-strand DNA breaks). ^[2]

BRCA genes are involved in transcriptional regulation and DNA repair; defective DNA repair may lead to excessive chromosomal damage, may increase radiosensitivity and may make cells more sensitive to chemotherapy. ^[2]

Why does losing BRCA function cause cancer?

• Normally, when your DNA gets a double-strand break (DSB), the BRCA1/BRCA2 proteins help recruit RAD51 to the break site for homologous recombination (HR) — the highest-fidelity repair mechanism.
• If BRCA is non-functional, cells must use error-prone repair pathways (e.g., non-homologous end joining, NHEJ), leading to accumulating genomic instability → progressive mutations in other genes → cancer.
• This follows Knudson's two-hit hypothesis: one allele is inherited as a germline mutation (first hit), and the second allele is lost somatically (second hit / loss of heterozygosity), resulting in complete loss of function.

BRCA mutations are autosomal dominant hereditary syndromes ^[2]

This means:

• 50% chance of passing the mutation to each offspring
• Both males and females can carry and transmit the mutation
• Penetrance is incomplete (not everyone with the mutation develops cancer, but their risk is vastly elevated above the general population)

BRCA gene mutations account for 30–70% of patients with hereditary breast/ovarian cancer and 5–10% of all breast and ovarian cancers ^[2]

This means the vast majority (90–95%) of breast/ovarian cancers are sporadic, not hereditary. But among the hereditary subset, BRCA1/2 are the dominant genes.

Three clinical syndrome presentations:

• Breast and ovarian cancer syndrome
• Site-specific breast cancer syndrome
• Site-specific ovarian cancer syndrome ^[2]

BRCA1 mutation carriers: 85% lifetime risk of breast cancer, 35–60% ovarian/fallopian tube/primary peritoneal cancer ^[2]

BRCA2 mutation carriers: 85% lifetime risk of breast cancer, 10–27% ovarian cancer, 6% male breast cancer ^[2]

The quoted figures above are the lecture-era estimates. For current counselling, use contemporary ranges rather than treating 85% as a universal individual prediction ^[12]:

The slide's larger “possible/definite” organ table should be read as a historical association map, not a screening checklist. Pancreatic and prostate risks are established, especially for BRCA2. Associations with melanoma, stomach cancer and uterine serous carcinoma remain uncertain; cervical, biliary, colorectal, head-and-neck and oesophageal screening should not be added merely because they appear in that slide ^[12].

Both are large genes, encoding exceptionally large, highly charged proteins. No mutational hot-spots, although more than half of all mutations found in large exon 11. Up to 85% of BRCA1 mutations result in truncated protein. ^[2]

Why does this matter clinically?

• No hotspot → you cannot use a simple targeted assay; you need to sequence the entire gene (full gene sequencing)
• Truncating mutations (frameshift, nonsense) → produce a non-functional, truncated protein → clear pathogenicity
• Methods needed: Direct DNA sequencing, Next-generation sequencing (NGS), and MLPA analysis for detecting large genomic deletions and duplications that standard sequencing would miss ^[2]

"Mutation" = disease-causing change; "Polymorphism" = non-disease-causing change found at frequency ≥1%. Use term "sequence variation" to prevent confusion. ^[2]

The term "mutation" is used to mean disease causing change — "Deleterious mutation" — now called Germline Pathogenic Variant (GPV) ^[2]

This modern terminology shift matters: in clinical reports you'll see "germline pathogenic variant" rather than "mutation." A Variant of Unknown Significance (VUS) is a change whose clinical importance is unclear — this creates major counselling challenges.

Breast cancer diagnosed at an early age; Bilateral breast cancer; History of both breast and ovarian cancer; Presence of breast cancer in one or more male family members; Multiple cases of breast cancer in family; Both breast and ovarian cancer in family; Two or more primary types of BRCA1 or BRCA2 related cancers in a single family member ^[2]

Factors considered when assessing risk:

Number of affected relatives; Relationship of affected relatives; Age at diagnosis of breast cancer; Presence of ovarian cancer in family; Presence of associated malignancies ^[2]

Lecture-era threshold for testing:

3 or more members of direct lineage with breast and/or ovarian cancer ^[2]

Expanded indication (regardless of family history):

Patients with TNBC (triple-negative breast cancer) and/or high grade serous ovarian carcinoma regardless of family history ^[2]

Reading the pedigrees shown in the lecture

The pedigree slides are not decorative: they show how number of affected relatives, age at diagnosis, cancer type, and the branch of the family change the pre-test probability.

This table is directly from the WHO Classification of Tumours, 5th Edition, as presented on the lecture slide ^[2]:

These three categories overlap but are NOT synonymous ^[2]:

Triple Negative ≠ Basal-like ≠ BRCA1

Basal-like tumours have a distinct genomic expression and protein profile, distinct morphology, and are often but not invariably Triple Negative (ER, PR, HER2 −ve). Found in 80–90% of BRCA1 mutation breast cancers and 15% of breast cancers with no family history. ^[2]

Histological features of basal-like breast cancer ^[2]:

• Grade 3 invasive carcinoma or metaplastic carcinoma
• Geographic necrosis
• Pushing borders of invasion
• Stromal lymphocytic response
• High mitotic count
• IHC: CK5/6 positive, ER negative, HER2 negative, p63 negative

Clinical behaviour of basal-like tumours ^[2]:

• Younger patients
• Frequently "interval cancers" with rapid progression (important: annual mammography may miss them)
• Heterogeneous — not all uniformly poor prognosis
• Visceral metastases to brain and lung, rather than lymph node (unlike luminal-type which metastasises to bone)
• Pathological complete response (pCR) to neoadjuvant chemotherapy (paradox: bad biology but good chemosensitivity)
• Not associated with locoregional relapse after conservative treatment

High grade serous adenocarcinoma — ovarian, tubal and peritoneal. Prophylactic oophorectomy in BRCA mutation carriers revealed high number of tubal neoplasms. Distal fallopian tube is an important source of pelvic serous cancer. ^[2]

Clinical implications:

• Recommendation to include removal of entire tubes at oophorectomy with thorough microscopic evaluation
• Visualisation of peritoneal surfaces with pelvic washings should be performed ^[2]

Why is this important? The paradigm has shifted: many "ovarian" high-grade serous carcinomas actually originate in the fimbriated end of the fallopian tube (serous tubal intraepithelial carcinoma, STIC). This is why prophylactic surgery must include the tubes, and pathology must section them thoroughly.

Families identified to have high risk should always start with "Index" testing — family member with diagnosis of breast or ovarian cancer. Once the germline mutation is identified for the index patient, then "carrier testing" can be offered to unaffected family members. ^[2]

Negative result useful only if a BRCA mutation has been identified in an affected first degree relative. ^[2]

Why index testing first?

Testing an affected relative first gives the highest chance of finding the familial cause and makes a later negative result in an unaffected relative interpretable. If no affected relative is available, however, an unaffected person with a sufficiently suggestive history may still undergo an appropriate multigene germline test after counselling; a negative result is then usually uninformative rather than reassuring ^[12].

If no mutation can be found in any of the index patients, then BRCA testing should not be offered to unaffected relatives. ^[2]

That final sentence records the slide-era teaching, not an absolute current prohibition. Modern testing access, multigene panels and treatment implications have broadened testing, but the interpretive limitation of an unaffected-first negative result remains.

12% of high risk families may have genomic rearrangements (these would be missed by standard sequencing → need MLPA) ^[2]

13% reported VUS — associated harm unknown ^[2]

Both percentages are historical assay/cohort figures, not values to memorise for present-day counselling. Current multigene panels produce laboratory- and ancestry-dependent VUS rates. Most BRCA VUS are later downgraded to benign/likely benign; until reclassified, they are non-actionable ^[12].

Allelic heterogeneity: Different mutations within the same gene can confer different age-specific risks of breast/ovarian cancer ^[2]. This is why penetrance figures are given as ranges.

Penetrance — the probability of developing breast or ovarian cancer with a BRCA mutation. Incidence of diagnosis: Breast cancer 46% (BRCA1), 52% (BRCA2); Ovarian cancer 12% (BRCA1), 6% (BRCA2) ^[2]

These figures are another historical cohort snapshot, not a competing set of current lifetime estimates. Penetrance varies by attained age, variant, family history and modifiers; use a validated contemporary source and an individualised risk tool for counselling ^[12].

1. Interpretation of result; 2. Cancer risks; 3. Interventions offered; 4. Treatment response ^[2]

Mammography: Poor sensitivity 40% — no evidence of benefit for BRCA mutation carriers. Interval cancers — annual mammography may miss aggressive cancers. ^[2]

MRI: Higher sensitivity 81%, reduced specificity, PPV 53%. ^[2]

Transvaginal ultrasound for early detection of ovarian cancer: High false positive results. ^[2]

Combination of MRI, mammography, ultrasonography: 95% sensitivity. Effect on morbidity and mortality unclear. ^[2]

Why is mammography alone insufficient? BRCA1 cancers are often high-grade, rapidly growing "interval cancers" that arise between annual screens. The dense breast tissue in younger women also reduces mammographic sensitivity. MRI is far more sensitive but less specific (more false positives → more biopsies).

Current practice uses MRI in addition to mammography, according to age and the local high-risk protocol; ultrasound is not a routine substitute for either ^[12]. The slide's 40%, 81% and 95% sensitivity values are study-specific historical figures rather than universal test characteristics.

For ovarian cancer, no effective screening exists: transvaginal ultrasound and CA-125 have not detected cancers early enough to improve long-term survival. They do not replace timely risk-reducing salpingo-oophorectomy ^[12].

Selective estrogen modulators (SERMs) e.g. Tamoxifen, Raloxifene. Side effects: DVT, pulmonary emboli, endometrial cancer. Reduces relative risk for ER+ breast cancer BUT most breast cancers associated with BRCA1 mutations are ER−ve hence not prevented by Tamoxifen. ^[2]

Tamoxifen blocks estrogen-receptor signalling, so any preventive effect should be concentrated in ER-positive disease. Evidence for primary prevention specifically in BRCA carriers remains uncertain; observational data suggest possible contralateral-breast benefit in BRCA1/2 carriers and reduction of ER-positive breast cancer in BRCA2 carriers ^[12]. Counsel about thromboembolism and endometrial effects rather than treating receptor phenotype as a categorical rule.

Prophylactic bilateral mastectomy: 90% reduction in risk for breast cancer, but only 30% uptake. ^[2]

Prophylactic bilateral salpingo-oophorectomy (BSO): 85% reduction in ovarian cancer risk; 50% reduction in breast cancer risk and breast cancer survival in premenopausal women. ^[2]

Recommendation: Women with BRCA mutations should be offered risk-reducing salpingo-oophorectomy by age 40 years or when childbearing is complete. ^[2]

These are lecture-era estimates. Current NCI material estimates that bilateral risk-reducing mastectomy lowers breast-cancer risk by at least 95% in BRCA1/2 carriers but does not eliminate risk ^[13]. Risk-reducing salpingo-oophorectomy removes both tubes and ovaries; it substantially reduces tubo-ovarian cancer risk but leaves a small primary-peritoneal risk. The claimed 50% breast-risk reduction after oophorectomy should not be presented as settled: study results conflict ^[13].

Timing is gene- and family-specific after completion of childbearing. NICE recommends no earlier than age 35 for BRCA1 and 40 for BRCA2, with timing individualised to family age of onset and multidisciplinary counselling ^[16]. Discuss surgical menopause, fertility, menopausal management and residual risk. Salpingectomy with delayed oophorectomy remains under study and is not yet an equivalent cancer-prevention substitute ^[12].

Defective DNA repair results in better response to radiation and chemotherapeutic agents ^[2]

Sensitivity to DNA cross-linking agents: carboplatin, cisplatin, mitomycin C ^[2]

BRCA carriers more likely to achieve pCR (pathological complete response) to neoadjuvant chemotherapy. Platinum-based chemotherapy effective in BRCA1 carriers. ^[2]

First-principles explanation: platinum agents create DNA adducts and crosslinks that challenge homologous-recombination repair. BRCA-deficient tumour cells may therefore be sensitive to platinum therapy. Clinical use still depends on cancer site, stage, prior therapy and the relevant guideline; germline BRCA status is neither a universal chemotherapy indication nor a blanket reason to alter standard radiotherapy ^[12].

If no chemotherapy for small sized, lymph node−ve BRCA carriers → worse prognosis, more significant risk of micrometastases ^[2]

This slide statement should not drive present-day treatment. A small node-negative cancer is managed according to its stage, receptor subtype, pathology and validated treatment biomarkers; do not prescribe chemotherapy merely because the patient carries BRCA1/2.

Synthetic lethality restricted to tumour cells — Poly-ADP ribose polymerase (PARP) inhibitor ^[2]

Mechanism from first principles:

1. BRCA1/2 loss produces homologous-recombination deficiency.
2. PARP1 normally detects single-strand DNA lesions and helps coordinate their repair; several PARP inhibitors also trap PARP on DNA.
3. Unrepaired lesions and trapped complexes stall or collapse replication forks, creating lesions that require homologous recombination.
4. A BRCA-deficient tumour cell cannot rescue that damage, so the combined defects are lethal—synthetic lethality.
5. Selectivity is relative, not absolute: normal tissues can still be injured, and PARP inhibitors have clinically important toxicities. Their use is restricted to eligible tumour types and treatment settings ^[12].

^[3][4][5]

Per the 2021 SAQ ^[6] and AOS Pathology ^[7]:

• BRCA1/BRCA2 germline mutation testing in high-grade serous ovarian CA → determines eligibility for PARP inhibitors and identifies families for screening
• MMR/MSI testing in endometrial cancer → Lynch syndrome screening + immunotherapy eligibility
• These require genetic counselling and informed consent (for germline tests) — distinguishing feature from somatic-only tests ^[7]

HER2 IHC score 3+ = positive → start trastuzumab. IHC 2+ = equivocal → reflex FISH testing. This is relevant because BRCA-associated breast cancers are typically HER2-negative (both BRCA1 and BRCA2), so trastuzumab is generally NOT part of their treatment regimen. ^[8]

The slide's assay sensitivities, VUS rate and rearrangement percentage are useful historical examples, not stable universal constants.