Genetic Testing & Hereditary Cancer Risk
Clinical indications for germline and somatic genomic sequencing, hereditary cancer risk assessment, pharmacogenomics, and genetic counseling.
Overview
Genetic testing analyzes human DNA, RNA, and chromosomes to identify pathogenic mutations, copy number alterations, and structural rearrangements. In oncology, testing is split into two primary categories: Germline Testing (inherited mutations present in every cell that increase lifetime cancer susceptibility) and Somatic Tumor Testing (acquired alterations unique to malignant tissue guiding targeted therapy).
Germline vs. Somatic Genetic Testing
| Parameter |
Germline Testing (Inherited) |
Somatic Testing (Tumor Tissue) |
| Specimen Source |
Peripheral whole blood, saliva, or buccal swab |
Formalin-fixed paraffin-embedded (FFPE) biopsy tissue or plasma ctDNA |
| Biological Scope |
Heritable alterations present in all constitutional cells |
Acquired somatic mutations restricted to neoplastic clones |
| Primary Clinical Goal |
Cancer risk quantification, cascade family testing, proactive surveillance |
Predicting drug sensitivity, therapeutic matching, residual disease tracking |
| Example Genes |
BRCA1, BRCA2, MLH1, MSH2, TP53, APC, PALB2 |
EGFR, KRAS, BRAF, HER2, ALK, PIK3CA, ROS1 |
Major Hereditary Cancer Syndromes
- Hereditary Breast and Ovarian Cancer (HBOC): Caused by pathogenic germline mutations in BRCA1 or BRCA2; carries up to a 70% lifetime risk of breast cancer and 40% risk of epithelial ovarian cancer.
- Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer): Caused by germline mismatch repair defects (MLH1, MSH2, MSH6, PMS2, EPCAM); elevates risk for colorectal, endometrial, gastric, and ovarian cancers.
- Li-Fraumeni Syndrome: Autosomal dominant TP53 germline mutations predisposing to early-onset sarcomas, breast carcinomas, brain tumors, and adrenocortical carcinomas.
- Familial Adenomatous Polyposis (FAP): APC gene mutations leading to hundreds of colorectal adenomatous polyps with near 100% malignant progression if untreated.
Clinical Indications for Genetic Evaluation
Genetic counseling and multi-gene panel testing are strongly recommended for individuals with:
- Cancer diagnosed at an unusually early age (e.g., breast or colorectal cancer diagnosed before age 50).
- Multiple primary malignancies diagnosed in the same individual.
- Rare tumor types such as male breast cancer, medullary thyroid carcinoma, or pheochromocytoma.
- Three or more close relatives across generations diagnosed with related cancers.
Pharmacogenomic Testing
Pharmacogenomics analyzes how inherited genetic variations alter drug metabolism and toxicity profiles:
- DPYD Testing: Identifies dihydropyrimidine dehydrogenase deficiency to prevent life-threatening toxicity before administering 5-Fluorouracil (5-FU) or Capecitabine.
- UGT1A1 Testing: Screens for polymorphic alleles (e.g., UGT1A1*28) causing severe neutropenia and diarrhea with Irinotecan.
- TPMT & NUDT15 Testing: Prevents lethal myelosuppression prior to thiopurine chemotherapy (Mercaptopurine, Azathioprine).
Pre-test and post-test genetic counseling by a certified genetic counselor ensures patients understand test implications, variant classifications (pathogenic vs. VUS), and family cascade testing strategies.
