Cancer Genetics¶
Chapter 76 | Part 4: Oncology and Hematology
KEY CLINICAL POINTS¶
- Cancer arises from clonal expansion of a single cell with sequential somatic mutations, requiring at least 3 driver gene alterations for most solid tumors.
- Oncogenes (e.g., KRAS, BRAF) drive tumor growth through gain-of-function mutations, while tumor suppressor genes (e.g., APC, TP53) are inactivated via biallelic mutations.
- Familial cancer syndromes (e.g., Lynch syndrome, FAP) are caused by germline mutations in DNA repair genes (e.g., MLH1, APC) and increase cancer risk through inherited predisposition.
- Genetic testing for cancer predisposition requires pretest counseling and is indicated for individuals with family history or ethnic risk factors (e.g., BRCA1/2 in Ashkenazi Jews).
- Tumor heterogeneity (intra-tumor, inter-tumor) complicates treatment, necessitating precision medicine approaches targeting specific genetic alterations.
1. DEFINITION & OVERVIEW¶
Cancer is a genetic disease characterized by clonal expansion of a single cell through sequential somatic mutations. The multistep model of carcinogenesis involves three cumulative mutations leading to malignant transformation. This process is akin to Darwinian microevolution, where mutated cells gain a growth advantage and expand clonally.
Table 76-1: Oncogenes Commonly Altered in Human Cancers¶
| FUNCTION | ALTERATION IN CANCER | NEOPLASM |
|---|---|---|
| Serine/threonine kinase | Point mutation | Skin |
| Serine/threonine kinase | Point mutation | Melanoma, thyroid, colorectal |
| Cell cycle progression | Amplification | Esophageal, head and neck |
| Signal transduction | Point mutation | Lung |
| Chromatin modification | Point mutation | Glioma |
| Inhibitor of p53 | Amplification | Breast |
| Transcription factor | Amplification | Ovarian, bladder |
| Phosphoinositol-3-kinase | Point mutation | Multiple cancers |
| GTPase | Point mutation | Pancreatic, colorectal, lung |
1.1 Clonal Origin¶
All cancers originate from a single cell with mutations in DNA. This clonal origin distinguishes neoplasia from hyperplasia. The process involves three key stages: initiation (genetic mutation), expansion (clonal growth), and invasion (metastasis).
1.2 Genetic Instability¶
Genetic instability (microsatellite instability [MSI] or chromosomal instability [CIN]) accelerates tumor progression by increasing mutation rates. Chromosomal instability is more common in solid tumors, while MSI is associated with DNA mismatch repair defects.
2. ETIOLOGY & PATHOPHYSIOLOGY¶
Cancer development involves oncogene activation and tumor suppressor gene inactivation. Oncogenes (e.g., KRAS, BRAF) drive proliferation through gain-of-function mutations, while tumor suppressors (e.g., APC, TP53) are inactivated via biallelic mutations. Chromosomal instability and DNA repair defects contribute to genomic instability.
Table 76-2: Oncogenes at Chromosomal Translocations¶
| GENE (CHROMOSOME) | TRANSLOCATION | MALIGNANCY |
|---|---|---|
| BCR-ABL (9;22)(q34;q11) | Chronic myeloid leukemia | |
| BCL2 (18q21.3)–IgH (14;18)(q32;q21) | Follicular lymphoma | |
| LCK-TCRB (1;7)(p34;q35) | T-cell acute lymphocytic leukemia | |
| PAX3-FOXO1 (2;13)(q35;q14) | Rhabdomyosarcoma | |
| TMPRSS2-ERG | Prostate cancer | Chr21q22 |
2.1 Oncogene Activation¶
Oncogenes are activated by point mutations (e.g., KRAS in pancreatic cancer), DNA amplification (e.g., ERBB2 in breast cancer), or chromosomal rearrangements (e.g., BCR-ABL in CML). These mutations confer a growth advantage to cells.
2.2 Tumor Suppressor Inactivation¶
Tumor suppressor genes (e.g., APC, TP53) are inactivated by biallelic mutations. Loss of function leads to uncontrolled proliferation and genomic instability. Chromosomal instability (CIN) and microsatellite instability (MSI) are key mechanisms.
3. CLINICAL FEATURES¶
Clinical features vary by tumor type but include genetic predisposition syndromes (e.g., Lynch syndrome, FAP) and tumor heterogeneity. Familial cancers often present with early-onset malignancies and multiple tumors.
3.1 Familial Cancer Syndromes¶
Hereditary cancer syndromes (e.g., Lynch syndrome, FAP) are caused by germline mutations in DNA repair genes (e.g., MLH1, APC). These syndromes increase cancer risk and often present with early-onset tumors and multiple lesions.
3.2 Tumor Heterogeneity¶
Tumor heterogeneity (intra-tumor, inter-tumor) complicates treatment. Intra-tumor heterogeneity arises from clonal evolution during tumor growth, while inter-tumor heterogeneity reflects genetic differences between patients.
4. INVESTIGATIONS & DIAGNOSIS¶
Diagnostic investigations include genetic testing for predisposition syndromes, molecular profiling of tumors, and assessment of chromosomal instability (CIN/MSI). Next-generation sequencing (NGS) enables comprehensive mutation analysis.
Table 76-3: Cancer Predisposition Syndromes and Associated Genes¶
| SYNDROME | GENE | CHROMOSOME | INHERITANCE | TUMORS |
|---|---|---|---|---|
| Hereditary nonpolyposis colon cancer (HNPCC) | MSH2 | 2p16 | AD | Colon, endometrial, ovarian, stomach, small bowel, ureter carcinoma |
| Hereditary nonpolyposis colon cancer (HNPCC) | MLH1 | 3p21.3 | AD | Colon, endometrial, ovarian, stomach, small bowel, ureter carcinoma |
| Hereditary nonpolyposis colon cancer (HNPCC) | MSH6 | 2p16 | AD | Colon, endometrial, ovarian, stomach, small bowel, ureter carcinoma |
| Hereditary nonpolyposis colon cancer (HNPCC) | PMS2 | 7p22 | AD | Colon, endometrial, ovarian, stomach, small bowel, ureter carcinoma |
| Familial adenomatous polyposis | APC | 5q21 | AD | Colorectal (early onset) |
4.1 Genetic Testing¶
Genetic testing is indicated for individuals with family history of cancer or ethnic risk factors (e.g., BRCA1/2 in Ashkenazi Jews). Testing requires pretest counseling and is used to assess cancer risk and guide targeted therapies.
4.2 Molecular Profiling¶
Molecular profiling identifies driver mutations (e.g., BRAF, RET) and MSI status. This informs treatment decisions (e.g., immune checkpoint inhibitors for MSI-high tumors).
5. MANAGEMENT & TREATMENT¶
Management includes targeted therapies (e.g., BRAF inhibitors for KRAS-mutated tumors), immunotherapy (e.g., checkpoint inhibitors for MSI-high tumors), and surgical intervention for familial syndromes (e.g., colectomy for FAP).
5.1 Targeted Therapies¶
Targeted therapies inhibit specific driver mutations (e.g., BRAF inhibitors for BRAF-mutated melanoma, RET inhibitors for RET-mutated thyroid cancer). These therapies are most effective in tumors with actionable genetic alterations.
5.2 Immunotherapy¶
Immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1) are effective in MSI-high tumors and tumors with neoantigens. These therapies harness the immune system to target cancer cells.
6. PROGNOSIS & COMPLICATIONS¶
Prognosis depends on genetic alterations (e.g., MSI-high tumors have better outcomes with immunotherapy), tumor heterogeneity, and response to treatment. Complications include drug resistance and metastasis.
6.1 Drug Resistance¶
Acquired resistance to targeted therapies is common due to clonal evolution and heterogeneity. Combination therapies and early intervention may mitigate resistance.
6.2 Metastasis¶
Metastasis results from clonal expansion and genetic heterogeneity. Tumor cells acquire mutations that enable survival in distant organs, complicating treatment.
7. SPECIAL CONSIDERATIONS¶
Special considerations include genetic counseling for familial syndromes, ethical issues in genetic testing (e.g., GINA), and the role of viruses in cancer (e.g., HPV in cervical cancer).
7.1 Genetic Counseling¶
Genetic counseling is essential for individuals with family history of cancer. It helps interpret test results, assess risk, and guide preventive measures.
7.2 Viral Oncogenesis¶
Viruses (e.g., HPV, EBV) contribute to cancer by inactivating tumor suppressors (e.g., p53, pRB). HPV-related cancers (e.g., cervical, anal) are managed with targeted therapies and immunotherapy.
8. KEY POINTS & CLINICAL PEARLS¶
Cancer is a genetic disease driven by clonal expansion and sequential mutations. Oncogenes and tumor suppressors play critical roles in tumorigenesis. Familial syndromes require genetic testing and counseling. Targeted therapies and immunotherapy are effective in tumors with specific genetic alterations. Tumor heterogeneity complicates treatment and necessitates precision medicine approaches.