Genetic Testing For Hereditary Cancer Syndromes

The hereditary nature of cancer: penetrance framework

• High-penetrance genes (>100 identified): Mendelian, large individual risk (e.g., BRCA1/2, TP53, MMR genes). Account for only a small fraction of all cancers; e.g., only ~10% of familial breast cancer is explained by high-penetrance variants.
• Moderate-penetrance genes: relative risk ~2 to 5 (e.g., CHEK2, ATM; PALB2 breast risk ~40 to 60% is now considered high penetrance). Now routinely on multigene panels, but clinical validity and utility are not fully defined and management may be uncertain.
• Low-penetrance loci (SNPs): GWAS-identified, relative risk ~1.1 to 1.5, largely from European-ancestry cohorts. Individual testing not routine; aggregated into polygenic risk scores (PRS), whose clinical utility (improved outcomes) and cross-ancestry transferability remain unproven prospectively, although predictive validity has been shown for some (e.g., 313-SNP breast PRS).
• Clinical validity (accuracy of predicting cancer) and clinical utility (does the result improve outcomes) should both be weighed before testing.

When to test (general indications / red flags)

• Young age at diagnosis (breast <50, CRC <50, ovarian any age, pancreatic any age, metastatic prostate).
• Multiple primary cancers in one person, or bilateral disease.
• Strong family history (≥2 relatives with same/related cancer on the same side; similar cancers across ≥3 generations).
• Specific high-risk histologies: TNBC (any age), medullary thyroid (RET), pheochromocytoma/paraganglioma, ovarian, pancreatic.
• Founder population: Ashkenazi Jewish (BRCA1 c.68_69delAG [185delAG], c.5266dupC [5382insC]; BRCA2 c.5946delT [6174delT]), prevalence ~1 in 40.
• Universal germline testing recommended for: ovarian/fallopian/primary peritoneal (any age), pancreatic, metastatic prostate, TNBC, early-onset CRC, MDS before age 40, RCC with young onset, bilateral/multifocal tumors, family history, or syndromic histology (e.g., FH-deficient, SDH-deficient), MTC (RET), paraganglioma/pheo.
• Universal tumor MMR/MSI on all CRC and endometrial cancers.
• Note: targeted NGS studies show ~13 to 17.5% of advanced-cancer patients carry an actionable germline variant, and roughly half would be missed by guideline-based criteria alone.

Genetic counseling

• Definition (NSGC): helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease.
• Pretest counseling: collect a 3-generation maternal and paternal family history; risk assessment; discuss likely outcomes and implications; select test/lab; informed consent (required by some states, e.g., New York). Blood is preferred (allows RNA and copy-number/large-rearrangement analysis); saliva/blood are unreliable in hematologic malignancy or post-allogeneic transplant (use cultured fibroblasts from skin punch).
• Posttest counseling: disclose/interpret results; review screening, risk reduction, and therapeutic implications; arrange cascade testing of relatives; provide support. A negative result may be uninformative (phenocopy possible); manage by personal/family history when appropriate.
• Timing in the oncology course: peridiagnostic (may alter surgical extent), during treatment (guides PARP-i, IO, belzutifan), and in survivorship (second-primary surveillance). Reconsider testing every ~5 yr; anyone tested before ~2013 likely predates NGS multigene panels and should be retested if negative with strong history.
• Ethical principles: autonomy, nonmaleficence, equity, and duty to warn at-risk relatives.
• GINA protects against health-insurance and employment discrimination but NOT life, disability, or long-term-care insurance.

Tumor analysis informing germline susceptibility

• Tumor pathology can be the first signal: TNBC (BRCA1, BARD1, RAD51C/D), medullary thyroid (RET), hypermutated/MSI-H tumors (Lynch).
• Somatic NGS (tumor profiling) may reveal variants that are also germline; guidelines exist for when a somatic finding should trigger germline referral (based on variant type, allele fraction, ClinVar classification, and age). Absence of a somatic mutation does NOT exclude a germline variant.

• Screen all CRC and endometrial tumors by MSI (PCR or NGS) or MMR-IHC (MLH1, MSH2, MSH6, PMS2). MSI and IHC are highly concordant; IHC also indicates which gene may be affected.
• If MLH1 loss: test for MLH1 promoter hypermethylation (CRC or endometrial) and/or BRAF V600E (CRC only; present in ~68% of MLH1-hypermethylated CRC). If either is present, Lynch is unlikely (sporadic).
• If MSH2/MSH6 loss, isolated MSH6 loss, isolated PMS2 loss, or MLH1 loss without methylation/BRAF: proceed to germline testing (combined MLH1/PMS2 loss follows the MLH1 methylation pathway).
• Germline testing is still warranted regardless of tumor screening if onset is <50 or family history is significant. In one 15,045-patient study, 16% of MSI-H tumors were due to Lynch across >50 tumor types.

Spectrum of germline test results (interpretation)

• Multigene panel testing is now standard (tumor-specific or pan-cancer). Advantages: efficient when heterogeneity exists. Drawbacks: more VUS, unexpected high-penetrance findings (e.g., TP53, CDH1) without pretest preparation, moderate-penetrance genes with unclear management, and recessive-carrier findings with reproductive implications.

Major hereditary syndromes

• Breast: BRCA1 ~55 to 72%, BRCA2 ~45 to 69% lifetime risk.
• Ovarian: BRCA1 ~39 to 44%, BRCA2 ~11 to 17%.
• Other: pancreatic (BRCA2 > BRCA1), male breast (BRCA2), prostate (BRCA2, aggressive).
• Management:
  • Breast: annual breast MRI from age 25; add annual mammography at age 30; consider risk-reducing mastectomy.
  • Ovarian: RRSO at 35 to 40 (BRCA1) or 40 to 45 (BRCA2). No effective screening.
  • Pancreas: consider annual EUS/MRCP if family history of pancreatic cancer.
  • Tx implications: PARP inhibitors (olaparib, talazoparib, niraparib, rucaparib) in ovarian, breast, prostate, pancreatic cancer.

• Genes: MLH1, MSH2, MSH6, PMS2, EPCAM (3' deletions silencing MSH2).
• Cancers: CRC (right-sided, mucinous, MSI-H, gene-dependent: up to ~50 to 60% for MLH1/MSH2, lower for MSH6/PMS2), endometrial (up to ~40 to 55%), ovarian, gastric, urothelial, small bowel, pancreatic, bile duct, brain (Turcot variant), sebaceous (Muir-Torre).
• Screening:
  • Colonoscopy q1 to 2 yr from age 20 to 25 for MLH1/MSH2 (EPCAM per MSH2); q1 to 3 yr from age 30 to 35 for MSH6/PMS2.
  • Endometrial biopsy q1 to 2 yr starting age 30 to 35; consider risk-reducing BSO/hysterectomy at 40 to 45.
  • Upper endoscopy q2 to 4 yr from age 30 to 40 (esp. MLH1/MSH2).
  • Universal MMR IHC on CRC and endometrial cancers.
  • Tx implications: MSI-H/dMMR tumors are highly IO-responsive (pembrolizumab, dostarlimab, tumor-agnostic).
  • Aspirin chemoprevention: CAPP2 (600 mg/d, ≥2 yr) reduced Lynch CRC ~50% (NCCN includes as consideration).
  • Constitutional MMR deficiency (CMMRD) = biallelic MMR loss; cafe-au-lait, T-cell lymphoma, brain tumors, childhood GI cancer.

• APC gene: hundreds to thousands of polyps, essentially inevitable lifetime CRC if untreated (mean diagnosis ~39 yr; ~87% by 45, ~93% by 50).
• Variants: attenuated FAP (later, fewer polyps), Gardner (osteomas, desmoids, dental abnormalities), Turcot (medulloblastoma).
• Screening: flexible sigmoidoscopy from age 10 to 12, then colonoscopy when adenomas appear.
• Surgery: prophylactic total colectomy (timing per polyp burden).
• Other surveillance: upper endoscopy (duodenal/ampullary), thyroid (papillary risk), desmoids.

• Autosomal recessive (biallelic MUTYH).
• Phenotype: similar to attenuated FAP.

• TP53 germline.
• Cancers: sarcomas (osteo, soft tissue), breast, brain, adrenocortical carcinoma, leukemia, choroid plexus carcinoma; multiple primaries across life.
• Screening: Toronto protocol (annual whole-body MRI and brain MRI from childhood; annual breast MRI from age 20).
• Avoid radiation when possible (increases secondary malignancies).

• Cancers: breast, thyroid (follicular), endometrial, RCC; hamartomas (GI, skin), macrocephaly.
• Screening: breast, thyroid US, endometrial sampling, colonoscopy.

• STK11 (LKB1): mucocutaneous pigmentation plus GI hamartomatous polyps.
• Cancers: breast (~45%), GI (CRC, gastric, pancreatic, small bowel), gynecologic (sex cord tumors with annular tubules, SCTAT), testicular large-cell calcifying Sertoli cell tumors.

• Phenotype: diffuse gastric cancer plus lobular breast cancer.
• Management: prophylactic total gastrectomy in early adulthood (NCCN 18 to 40; IGCLC classically 20 to 30); annual expert endoscopic surveillance with biopsies if surgery is deferred (IGCLC 2020); annual breast MRI from age 30, consider risk-reducing mastectomy. An unexpected CDH1 finding without matching history poses a management dilemma about gastrectomy.

• VHL gene (3p25).
• Manifestations: clear cell RCC (bilateral, multifocal), pheochromocytoma, hemangioblastomas (cerebellar, retinal, spinal), pancreatic NETs and serous cystadenomas, endolymphatic sac tumors, epididymal cystadenomas.
• Screening: intensive multimodality from age 1 to 10.
• Tx: belzutifan (HIF-2alpha inhibitor) for VHL-associated RCC, pNET, hemangioblastoma.

• MEN1 (menin): pituitary + parathyroid + pancreatic NETs (the 3 P's); also thymic NET, lipomas, facial angiofibromas.
• MEN2A (RET, codon 634): medullary thyroid + pheochromocytoma + parathyroid.
• MEN2B (RET, M918T): MTC (very early) + pheo + marfanoid habitus + mucosal neuromas.
• Prophylactic thyroidectomy in childhood for MEN2 (timing per specific RET mutation).

• NF1: cafe-au-lait, neurofibromas, optic pathway glioma, MPNST, pheo, GIST, JMML.
• NF2: bilateral vestibular schwannomas, meningiomas, ependymomas.

• Retinoblastoma (RB1): retinoblastoma plus osteosarcoma (esp. post-RT) plus soft tissue sarcoma.
• Hereditary paraganglioma (SDHx): head/neck and abdominal paraganglioma, pheo, GIST, RCC.
• Hereditary leiomyomatosis and RCC (FH): FH-deficient RCC (variable morphology; papillary RCC no longer split into type 1/2), cutaneous/uterine leiomyomas.
• Birt-Hogg-Dube (FLCN): fibrofolliculomas plus chromophobe/oncocytic RCC plus lung cysts/pneumothorax.
• Ataxia-telangiectasia (ATM): lymphoma, leukemia, breast (heterozygotes).
• Fanconi anemia: pancytopenia plus AML plus HNSCC.
• Bloom syndrome: leukemia, lymphoma, GI cancer; growth retardation.
• Xeroderma pigmentosum (NER): UV-induced skin cancer at young age.

Counseling principles (summary)

• Pre-test: informed consent, implications for relatives, insurance (GINA protects health/employment but NOT life/disability).
• Post-test: cascade testing for relatives.
• VUS: do NOT base management on a VUS.

Key tumor-agnostic / hereditary-driven approvals

• Pembrolizumab: MSI-H/dMMR solid tumors; TMB ≥10.
• Olaparib: germline BRCA-mutated breast (adjuvant OlympiA), ovarian, prostate, pancreatic.
• Talazoparib: germline BRCA-mutated breast; prostate (HRR+, incl. ATM in TALAPRO-2).
• Niraparib, rucaparib: ovarian.
• Belzutifan: VHL-related RCC, pNET, hemangioblastoma.
• Selpercatinib: RET-altered (RET-mutant MTC, RET-fusion NSCLC, tumor-agnostic RET fusion); pralsetinib: RET-fusion NSCLC (US MTC indication withdrawn 2023).
• Larotrectinib, entrectinib, repotrectinib: NTRK-fusion tumors.

High-yield genetics pearls

• BRCA1 associates with TNBC; BRCA2 with male breast and prostate.
• Lynch: MSI-H, right-sided CRC; endometrial cancer often the sentinel. In MLH1-deficient CRC, BRAF V600E or MLH1 promoter hypermethylation strongly favors sporadic disease but does not fully exclude Lynch; in endometrial cancer use MLH1 promoter methylation (not BRAF). Young onset or strong history still warrants germline evaluation.
• FAP: total colectomy. Li-Fraumeni: TP53, avoid radiation.
• CDH1: diffuse gastric plus lobular breast, prophylactic gastrectomy.
• VHL: bilateral RCC plus hemangioblastoma plus pheo. MEN2: RET, prophylactic thyroidectomy in childhood.
• NF1: MPNST plus GIST plus JMML.
• GINA protects health/employment, NOT life/disability insurance.
• Do not act on a VUS; do not offer relatives predictive testing for a VUS. Cascade testing is offered for known familial pathogenic variants.

2024-2026 Genetic Testing Updates

• Universal genetic testing expanding: ASCO/NCCN now recommend germline testing for ALL pancreatic, ovarian, and metastatic prostate cancer, and colorectal <50 (consider for all CRC); breast: all newly diagnosed ≤65 per ASCO-SSO and PARP inhibitor candidates with metastatic disease; all regardless of family history.
• HBOC (BRCA1/2): PARP inhibitors active in BRCA-mutated breast, ovarian, prostate, pancreatic; prophylactic mastectomy plus BSO recommendations refined.
• Lynch: universal MMR/MSI testing on all CRC and endometrial; pembrolizumab for any dMMR/MSI-H tumor (2017, then 1L 2020 KEYNOTE-177 CRC; KEYNOTE-158 all dMMR; KEYNOTE-868 (pembrolizumab) and RUBY (dostarlimab) frontline endometrial).
• TP53 (Li-Fraumeni): avoid radiation; Toronto protocol (annual whole-body MRI starting in childhood, annual brain MRI, annual breast MRI from age 20).
• MCED tests: Galleri (Grail), clinical validity emerging (PATHFINDER 2023); not yet universally recommended.
• Germline DDX41, RUNX1, GATA2 in heme: increasingly recognized; affect donor selection and family screening (avoid affected related donors).

2025-2026 genetic testing landscape updates

• ASCO germline testing guidelines (2024 to 2025): offer germline testing to ALL patients with epithelial ovarian, exocrine pancreatic, and metastatic prostate cancer (germline plus somatic, Yu JCO 2025); breast (ASCO-SSO, Bedrosian JCO 2024): all newly diagnosed ≤65 and selected >65 (family history, ancestry, TNBC, PARP-i candidates); CRC: recommended for all <50, consider for all CRC.
• Universal genetic testing in prostate cancer: NCCN 2024, germline testing for ALL metastatic, high-risk localized, node-positive, or family-history-positive prostate cancer; guides PARP-i (olaparib PROpel/PROfound, talazoparib TALAPRO-2) and IO eligibility.
• Polygenic risk scores (PRS): commercial offerings (Ambry AmbryScore, MyRisk with RiskScore); CanRisk (free BOADICEA web tool) can incorporate a PRS into risk estimates; NCCN 2024 acknowledges but does NOT recommend for clinical decision-making pending validation; utility highest in European-ancestry populations (equity concerns).
• ATM, CHEK2, BARD1, RAD51C/D, PALB2: increasingly actionable, ATM for prostate PARP-i (TALAPRO-2), CHEK2 breast risk, PALB2 breast risk-reducing mastectomy consideration.
• Germline testing in AML/MDS: NCCN 2024 recommends germline evaluation for all young AML/MDS, familial clustering, or aberrant marrow features; DDX41, RUNX1, GATA2, ANKRD26, ETV6, TP53; critical for donor selection and family cascade.
• Digital cascade-testing platforms: Ambry FamilyLink, Invitae Family Testing; some states (NY) have specific cascade-outreach requirements.
• Lynch syndrome aspirin chemoprevention: CAPP2 long-term (Burn Lancet 2020: 10-yr follow-up with registry-based 20-yr data), aspirin 600 mg/d for ≥2 yr reduces CRC incidence ~50% in Lynch carriers; NCCN 2024 includes aspirin as a consideration.