Cancer Genetics¶
Chapter 76 | Harrison's 22e · Part 4 – Oncology: Solid Tumors · Chapter 76
Key Clinical Points¶
- Cancer is a genetic disease resulting from somatic mutations that disrupt normal cellular proliferation control mechanisms.
- Two primary classes of driver genes: oncogenes (activated) and tumor-suppressor genes (inactivated).
- Multistep clonal expansion typically requires 3 cumulative mutations for common solid tumors, but only 2 for liquid tumors (leukemias/lymphomas).
- Germline mutations in cancer predisposition genes lead to familial cancer clustering and hereditary syndromes.
- Tumor heterogeneity (intratumoral, intermetastatic, intrametastatic, and interpatient) results from ongoing clonal evolution and genetic instability.
- Genetic testing algorithms identify pathogenic mutations in an index patient to guide screening of asymptomatic relatives.
- The 'Two-Hit Hypothesis' explains how tumor suppressor genes like RB1 require two hits (e.g., via Loss of Heterozygosity) for malignancy.
- Specific translocations, such as t(9;22), create fusion proteins (e.g., BCR-ABL) that drive leukemia.
- Genetic instability (MIN/CIN) accelerates the progression from benign to malignant states.
- Negative genetic tests must be interpreted with caution due to limited sensitivity of current molecular assays.
1. DEFINITION & OVERVIEW¶
Cancer is a genetic disease arising from somatic mutations that disrupt normal cellular proliferation control mechanisms.
Definition (Harrison's 22e): Cancer driver gene: A gene containing a mutation that increases the selective growth advantage of the cell containing it.
• Clonal Origin of Cancer: ◦ Most cancers originate from a single cell through clonal expansion. ◦ Multistep clonal development requires multiple cumulative mutations. ◦ Each mutation provides an incremental growth advantage. ◦ Tumor progression follows Darwinian microevolution principles. ◦ Transformation to malignancy typically takes decades in most cases.
• Mutation Requirements: ◦ Solid tumors: Typically require 3 cumulative mutations (Initiation, Expansion, Invasion). ◦ Liquid tumors (leukemias/lymphomas): May require only 2 driver gene alterations. ◦ Benign tumorigenesis requires fewer mutations than malignant transformation.
2. GENETIC BASIS OF CANCER¶
Cancer arises through somatic alterations in DNA that disrupt normal proliferation control mechanisms.
• Mutational Processes: ◦ Initiation: First mutation provides growth advantage (e.g., APC inactivation). ◦ Expansion: Second mutation enhances clonal expansion (e.g., KRAS/BRAF activation). ◦ Invasion: Third mutation enables metastatic potential (e.g., TP53 loss). ◦ Genetic instability (MIN/CIN) increases the likelihood of mutation at each step.
• Genetic Basis of Cancer: ◦ Somatic mutations: Arise from replication errors, carcinogen exposure, or faulty DNA repair. ◦ Germline mutations: Occur in cancer predisposition genes and cause familial clustering. ◦ Oncogenes: Activated by mutations or aberrant regulation (e.g., RAS, MYC). ◦ Tumor-suppressor genes: Inactivated by loss-of-function mutations (e.g., TP53, APC).
Key Driver Genes and Mechanisms¶
• Oncogenes Commonly Altered in Human Cancers: ◦ AKT1: Serine/threonine kinase (Point mutation). ◦ BRAF: Serine/threonine kinase (Point mutation). ◦ CCND1: Cell cycle progression (Amplification) → Esophageal, head and neck. ◦ CTNNB1: Signal transduction (Point mutation). ◦ EGFR: Signal transduction (Point mutation) → Lung. ◦ FLT3: Signal transduction (Point mutation). ◦ IDH1: Chromatin modification (Point mutation) → Glioma. ◦ MDM2/MDM4: Inhibitor of p53 (Amplification; MDM4 associated with Breast cancer). ◦ MYC/MYCL1: Transcription factor (Amplification) → Ovarian, bladder.
• Translocation-Driven Oncogenes: ◦ BCR-ABL: (9;22)(q34;q11) → Chronic myeloid leukemia (CML). ◦ BCL2 (18q21.3)–IgH (14q32): (14;18)(q32;q21) → Follicular lymphoma. ◦ LCK-TCRB: (1;7)(p34;q35) or (2;13)(q35;q14) → T-cell acute lymphocytic leukemia. ◦ PAX8-PPARG: (2;3)(q13;p25) or (3;16)(q27;p11) → Thyroid. ◦ TAL1-TCTA: (1;3)(p34;p21) → Acute T-cell leukemia.
• Hereditary Cancer Syndromes: ◦ Ataxia telangiectasia (ATM, 11q22-q23): Breast. ◦ Birt-Hogg-Dubé syndrome (FLCN, 17p11.2): Kidney (hybrid oncocytic, chromophobe). ◦ Cowden syndrome (PTEN, 10q23): Breast, thyroid. ◦ Familial melanoma (CDKN2A, 9p21): Melanoma, pancreatic. ◦ Hereditary breast/ovarian cancer (BRCA1, BRCA2, 17q21; 13q12.3; 16q22). ◦ Hereditary nonpolyposis colon cancer (HNPCC) (MSH2, MLH1, MSH6, PMS2): Colon, endometrial, ovarian, stomach, small bowel, ureter. ◦ Juvenile polyposis syndrome (SMAD4, BMPR1A): Gastrointestinal, pancreatic. ◦ Multiple endocrine neoplasia type 1 (MEN1): Parathyroid, endocrine, pancreas, pituitary. ◦ Neurofibromatosis type 1 (NF1): Neurofibroma, neurofibrosarcoma, brain. ◦ Gorlin’s syndrome (PTCH1): Basal cell carcinoma, medulloblastoma. ◦ Tuberous sclerosis (TSC1, TSC2): Angiofibroma, renal angiomyolipoma.
• Signaling Pathways Altered in Cancer: ◦ Cell cycle regulation/apoptosis: RB1, BCL2. ◦ RAS pathway: KRAS, BRAF. ◦ PI3K pathway: PTEN, PIK3CA. ◦ JAK/STAT: JAK2, FLT3. ◦ MAPK: MAP3K, ERK. ◦ TGF-β: BMPR1A, SMAD4. ◦ Other pathways: Notch, Hedgehog, WNT/APC. ◦ Genome maintenance: ATM, BRCA1.
3. HISTORICAL PERSPECTIVE¶
• Otto Warburg's combustion theory (abnormal oxygen metabolism) was disproven. ◦ Viral theories were partially validated (e.g., HPV in cervical cancer). ◦ Retroviral studies identified first human oncogenes (V-SRC). ◦ Molecular identification of somatic mutations established the genetic basis.
Evolution of Understanding¶
• 19th century: Tumors recognized as cellular masses. ◦ Early 20th century: Warburg's oxygen metabolism theory. ◦ Mid-20th century: Chemical mutagenesis and radiation studies. ◦ Late 20th century: Molecular identification of driver genes.
4. GENETIC TESTING ALGORITHM¶
The following steps outline the clinical decision-making process for genetic testing in a family with cancer predisposition (see Figure 2):
- Patient Selection: Identify patients from three categories: ◦ Family with a known cancer syndrome. ◦ Family with a history of cancer. ◦ Any recent cancer.
- Pre-test Workup: ◦ Provide pretest counseling. ◦ Review family history. ◦ Obtain informed consent.
- Index Patient Testing: Perform molecular analysis on the cancer patient to identify specific disease-causing mutations.
- Decision Branch (Mutation Found): → Identify mutation → Proceed to screening of asymptomatic family members.
- Decision Branch (No Mutation Found): → No mutation identified → No basis for increased risk in family members based on that specific gene.
- Follow-up & Action: → If relative tests positive: Implement increased screening or surgical intervention. → If relative tests negative: No greater risk than general population.
Clinical Implications¶
• Positive test: Indicates a specific mutation; requires increased screening or prophylactic surgery for at-risk relatives. ◦ Negative test: No mutation identified in the index patient means no basis for risk in others. If a relative tests negative after an index positive, they are at no greater risk than the general population. ◦ Sensitivity Warning: No molecular assay is 100% sensitive; negative results must be interpreted with caution as they do not rule out all risks if the correct gene was not targeted.
5. TUMOR HETEROGENEITY¶
Tumor heterogeneity is the inevitable result of cell proliferation and clonal evolution.
• Types of Heterogeneity: ◦ Intratumoral: Distinct subclones within a single tumor (e.g., primary tumor). ◦ Intermetastatic: Genetic differences between different metastatic lesions in the same patient. ◦ Intrametastatic: Genetic differences among cells within a single metastatic lesion. ◦ Interpatient: Unique mutations in different patients; tumors are not monolithic.
• Clinical Significance: ◦ Heterogeneity is critical for precision medicine. ◦ Different clones may respond differently to treatment, explaining why a drug might work at one site but not another.
6. GENETIC MECHANISMS OF MALIGNANCY¶
Specific mechanisms drive the transition from normal cells to malignancy:
• The Two-Hit Hypothesis: ◦ Required for tumor suppressor genes (e.g., RB1) in hereditary syndromes. ◦ Requires Loss of Heterozygosity (LOH). ◦ LOH can occur via: → Mitotic crossing over. → Independent mutation or small deletion.
• APC Mutation Dynamics: ◦ APC encodes a 2843-amino-acid protein with domains: O, ARM, 15 aa, 20 aa, B, and E/D. ◦ All known pathogenic mutations result in truncation of the protein. ◦ Mutation Hotspots: Positions 1061 and 1309 account for one-third of cases in Familial Adenomatous Polyposis (FAP).
• Colorectal Cancer Progression: → Normal epithelium → Early adenoma (Initiation) → Late adenoma (Expansion) → Carcinoma (Invasion) → Metastasis. ◦ Germline APC mutations place patients at Step 1 (Early adenoma). ◦ Genetic instability (MIN/CIN) accelerates progression through these steps.
7. KEY PEARLS & HIGH-YIELD POINTS¶
• Mutation Thresholds: ◦ 3 mutations → common solid tumors. ◦ 2 mutations → liquid tumors (leukemias/lymphomas).
• Clinical Utility of Testing: → Identifying a mutation in an index patient is the prerequisite for screening asymptomatic relatives.
• Tumor Heterogeneity: → Essential concept for precision medicine; tumors are not monolithic. → Different sites (e.g., primary vs. metastasis) may have different genetic profiles and respond differently to treatment.
Reference Tables¶
TABLE 76-1 Oncogenes Commonly Altered in Human Cancers¶
Harrison's 22e, p.520
| FUNCTION | ALTERATION IN CANCER | NEOPLASM |
|---|---|---|
| Serine/threonine kinase | Point mutation | Skin |
| Serine/threonine kinase | Point mutation | |
| Cell cycle progression | Amplification | Esophageal, head and neck |
| Signal transduction | Point mutation | |
| Signal transduction | Point mutation | Lung |
| Signal transduction | Point mutation | |
| Chromatin modification | Point mutation | Glioma |
| Inhibitor of p53 | Amplification | |
| Inhibitor of p53 | Amplification | Breast |
| Transcription factor | Amplification | |
| Transcription factor | Amplification | Ovarian, bladder |
| Transcription factor | Amplification | |
| Phosphoinositol-3-kinase | Point mutation | Multiple cancers |
| GTPase | Point mutation | |
| GTPase | Point mutation | Melanoma |
TABLE 76-2 Representative Oncogenes at Chromosomal Translocations¶
Harrison's 22e, p.521
| GENE (CHROMOSOME) | TRANSLOCATION | MALIGNANCY |
|---|---|---|
| BCR-ABL | (9;22)(q34;q11) | Chronic myeloid leukemia |
| (11;14)(q13;q32) | ||
| BCL2 (18q21.3)–IgH (14q32) |
(14;18)(q32;q21) | Follicular lymphoma |
| (11;22)(q24;q12) | ||
| LCK-TCRB | (1;7)(p34;q35) | T-cell acute lymphocytic leukemia |
| (2;13)(q35;q14) | ||
| PAX8-PPARG | (2;3)(q13;p25) | Thyroid |
| (3;16)(q27;p11) | ||
| TAL1-TCTA | (1;3)(p34;p21) | Acute T-cell leukemia |
| Rearrangement on Chr21q22 |
TABLE 76-3 Cancer Predisposition Syndromes and Associated Genes SYNDROME Ataxia telangiectasia Autoimmune…¶
Harrison's 22e, p.524
| SYNDROME GENE | CHROMOSOME INHERITANCE | TUMORS |
|---|---|---|
| Ataxia telangiectasia ATM | 11q22-q23 AR | Breast |
| 10q24 1q23 AD | ||
| Birt-Hogg-Dubé syndrome FLCN | 17p11.2 AD | Kidney (hybrid oncocytic, chromophobe) |
| 15q26.1 AR | ||
| Cowden syndrome PTEN | 10q23 AD | Breast, thyroid |
| 5q21 AD 1p34.1 AR |
||
| Familial melanoma CDKN2A | 9p21 AD | Melanoma, pancreatic |
| 11p13 AD | ||
| Hereditary breast/ovarian cancer BRCA1 BRCA2 |
17q21 AD 13q12.3 |
Breast, ovarian, prostate |
| 16q22 AD | ||
| Hereditary multiple exostoses EXT1 EXT2 |
8q24 AD 11p11-12 |
Exostoses, chondrosarcoma |
| 13q14.2 AD | ||
| Hereditary nonpolyposis colon cancer (HNPCC) MSH2 MLH1 MSH6 PMS2 |
2p16 AD 3p21.3 2p16 7p22 |
Colon, endometrial, ovarian, stomach, small bowel, ureter carcinoma |
| 7q31 AD | ||
| Juvenile polyposis syndrome SMAD4 BMPR1A |
18q21 AD | Gastrointestinal, pancreatic |
| 17p13.1 AD | ||
| Multiple endocrine neoplasia type 1 MEN1 | 11q13 AD | Parathyroid, endocrine, pancreas, and pituitary |
| 10q11.2 AD | ||
| Neurofibromatosis type 1 NF1 | 17q11.2 AD | Neurofibroma, neurofibrosarcoma, brain |
| 22q12.2 AD | ||
| Nevoid basal cell carcinoma syndrome (Gorlin’s syndrome) PTCH1 | 9q22.3 AD | Basal cell carcinoma, medulloblastoma, jaw cysts |
| 19p13.3 AD | ||
| Tuberous sclerosis TSC1 TSC2 |
9q34 AD 16p13.3 |
Angiofibroma, renal angiomyolipoma |
| 3p25-26 AD |
TABLE 76-4 Signaling Pathways Altered in Cancer PROCESS Cell survival¶
Harrison's 22e, p.526
| PROCESS | PATHWAY | REPRESENTATIVE DRIVER GENES |
|---|---|---|
| Cell survival | Cell cycle regulation/ apoptosis |
RB1, BCL2 |
| RAS | KRAS, BRAF | |
| PIK3CA | PTEN, PIK3CA | |
| JAK/STAT | JAK2, FLT3 | |
| MAPK | MAP3K, ERK | |
| TGF-β | BMPR1A, SMAD4 | |
| Notch | ||
| Hedgehog | ||
| WNT/APC | ||
| Chromatin modification | ||
| Transcriptional regulation | ||
| Genome maintenance | DNA damage signaling and repair |
ATM, BRCA1 |