Premed · Premed · Genetics
Lecture 21: Cancer Genetics
Genetics
Learning Objectives
By the end of this lecture, students will be able to:
- Explain why cancer is fundamentally a genetic disease of somatic cells
- Distinguish between oncogenes and tumor suppressor genes and describe their roles in tumorigenesis
- Explain Knudson's two-hit hypothesis and its application to retinoblastoma
- Describe the multi-step model of carcinogenesis using colorectal cancer as an example
- Identify the major DNA repair deficiency syndromes that predispose to cancer
- Discuss the clinical applications of cancer genomics, including targeted therapies and genetic testing for hereditary cancer syndromes
Lecture Content
I. Cancer as a Genetic Disease
Cancer results from the accumulation of genetic alterations in somatic cells that disrupt normal cell growth, division, and death. Hanahan and Weinberg defined the Hallmarks of Cancer (2000, updated 2011) as the key capabilities that cancer cells acquire: sustaining proliferative signaling, evading growth suppressors, resisting cell death (apoptosis), enabling replicative immortality (through telomerase activation), inducing angiogenesis, activating invasion and metastasis, reprogramming energy metabolism, evading immune destruction, genome instability and mutation, and tumor-promoting inflammation.
Most cancers (approximately 90-95%) are sporadic, arising from somatic mutations acquired during life, while hereditary (familial) cancers account for approximately 5-10% and involve germline mutations in cancer predisposition genes. Cancer development follows a model of clonal evolution: a single cell acquires a mutation that confers a selective growth advantage, leading to clonal expansion; further mutations accumulate in the expanding clone, creating tumor heterogeneity. It is important to distinguish driver mutations, which confer a selective growth advantage and are causally involved in cancer, from passenger mutations, which are present in cancer cells but do not contribute to tumor development.
<image>Panel A: The Hallmarks of Cancer diagram (based on Hanahan and Weinberg) — a circular or grid layout showing all ten hallmarks with icons representing each capability: sustained proliferative signaling, evading growth suppressors, resisting cell death, replicative immortality, angiogenesis, invasion and metastasis, metabolic reprogramming, immune evasion, genome instability, and tumor-promoting inflammation. Panel B: Clonal evolution model — a branching tree diagram showing a normal cell acquiring an initial driver mutation, expanding clonally, then subclones acquiring additional mutations, leading to tumor heterogeneity with multiple genetically distinct subpopulations. Panel C: Pie chart showing the proportion of cancers that are sporadic (~90-95%) vs. hereditary (~5-10%), with examples of each category listed.</image>
II. Oncogenes
Proto-oncogenes are normal cellular genes that promote cell growth, proliferation, and survival. They encode growth factors, growth factor receptors, signal transduction molecules, transcription factors, and cell cycle regulators. Oncogenes are mutated or overexpressed forms of proto-oncogenes that drive uncontrolled cell growth. They act in a dominant gain-of-function manner, meaning mutation in just one allele is sufficient to promote cancer.
Proto-oncogenes can be activated through several mechanisms. Point mutations can produce constitutively active proteins, as seen in the RAS family (KRAS G12V in pancreatic and colon cancer). Gene amplification increases copy number and leads to overexpression, as with HER2/ERBB2 in breast cancer and MYC in many cancers. Chromosomal translocations can create fusion genes or place genes under strong promoters: the Philadelphia chromosome t(9;22) produces the BCR-ABL fusion in chronic myelogenous leukemia (CML), and the t(8;14) translocation in Burkitt lymphoma places MYC under the immunoglobulin heavy chain enhancer. Viral insertion near a proto-oncogene can also drive activation.
Key oncogenes in human cancer include RAS (KRAS, NRAS, HRAS), which encodes a GTPase in the MAPK/PI3K signaling pathway and is mutated in approximately 30% of all cancers; MYC, a transcription factor amplified or overexpressed in many cancer types; HER2, a receptor tyrosine kinase amplified in approximately 20% of breast cancers; BCR-ABL, a fusion tyrosine kinase in CML; BRAF (V600E mutation in melanoma); and PIK3CA, the catalytic subunit of PI3K mutated in breast, endometrial, and other cancers.
III. Tumor Suppressor Genes
Tumor suppressor genes (TSGs) encode products that inhibit cell proliferation, promote apoptosis, or maintain genomic integrity. They act as "brakes" on the cell cycle and require loss of function of both alleles for tumor development, making them recessive at the cellular level.
Knudson's two-hit hypothesis (1971), formulated from studies of retinoblastoma (a childhood eye tumor), elegantly explains this requirement. In hereditary retinoblastoma, the first hit is an inherited germline mutation in one RB1 allele, present in every cell. The second hit is a somatic mutation in the remaining allele of a retinal cell, leading to bilateral tumors with early onset. In sporadic retinoblastoma, both hits are independent somatic mutations occurring in the same retinal cell, resulting in unilateral tumors with later onset. This two-hit model applies broadly to tumor suppressors. Loss of heterozygosity (LOH) is the mechanism by which the remaining wild-type allele is lost, occurring through deletion, mitotic recombination, chromosome loss, or epigenetic silencing via promoter methylation.
Key tumor suppressor genes include RB1 (the retinoblastoma protein, a master regulator of the G1/S checkpoint that inhibits E2F transcription factors), TP53 (the "guardian of the genome," a transcription factor that activates cell cycle arrest, DNA repair, and apoptosis genes, mutated in approximately 50% of all cancers and associated with Li-Fraumeni syndrome when mutated in the germline), APC (a component of the Wnt signaling pathway, with germline mutations causing familial adenomatous polyposis), BRCA1 and BRCA2 (essential for homologous recombination repair, with germline mutations causing hereditary breast and ovarian cancer syndrome), VHL (regulating HIF degradation in von Hippel-Lindau disease), and PTEN (a negative regulator of the PI3K/AKT pathway, mutated in Cowden syndrome).
<image>Panel A: Knudson's two-hit hypothesis illustrated for retinoblastoma — left side shows hereditary RB (germline first hit in all cells, somatic second hit in one retinal cell, bilateral tumors, early onset); right side shows sporadic RB (two independent somatic hits in the same retinal cell, unilateral tumor, later onset); both pathways converge on complete loss of RB1 function. Panel B: Mechanisms of loss of heterozygosity (LOH) — starting from a cell heterozygous at a tumor suppressor locus (+/-), showing five paths to loss of the wild-type allele: chromosome deletion, mitotic nondisjunction with chromosome loss, mitotic recombination, point mutation, and promoter methylation. Panel C: Comparison table of oncogenes vs. tumor suppressor genes — listing mode of action (gain-of-function vs. loss-of-function), number of hits required (1 vs. 2), mutation type (activating vs. inactivating), inheritance pattern in familial syndromes, and key examples of each.</image>
IV. Multi-Step Carcinogenesis: The Vogelstein Model
The multi-step model holds that cancer develops through the sequential accumulation of mutations in multiple genes. The Vogelstein model for colorectal cancer is the best-characterized example of this process. Normal epithelium first loses both copies of APC, producing dysplastic and hyperproliferative epithelium. An activating KRAS mutation then drives progression to an early adenoma (small polyp). Loss of SMAD4/DCC on chromosome 18q produces an intermediate adenoma. Loss of TP53 on chromosome 17p leads to a late adenoma or carcinoma in situ. Additional mutations then drive progression to invasive carcinoma and metastasis. Each step confers a selective growth advantage to the affected cell clone.
Typically 4-7 driver mutations are needed for a solid tumor, with fewer required for hematologic malignancies. Genomic instability accelerates mutation accumulation through three mechanisms: chromosomal instability (CIN), which produces aneuploidy, large-scale deletions, and translocations; microsatellite instability (MSI), resulting from defective mismatch repair; and the CpG island methylator phenotype (CIMP), involving widespread aberrant promoter methylation that silences tumor suppressor genes. The multi-step model also explains why cancer incidence increases with age, as time is needed to accumulate the requisite mutations.
V. Hereditary Cancer Syndromes and DNA Repair Defects
Hereditary breast and ovarian cancer (HBOC) involves germline mutations in BRCA1 (chromosome 17q) and BRCA2 (chromosome 13q), inherited in an autosomal dominant pattern with incomplete penetrance. BRCA1 mutation carriers face approximately 70% lifetime risk of breast cancer and 40% risk of ovarian cancer, while BRCA2 carriers face approximately 70% breast cancer risk and 15% ovarian cancer risk, along with elevated risks of male breast cancer, pancreatic cancer, and prostate cancer. Because BRCA1 and BRCA2 are essential for homologous recombination repair, their loss creates a vulnerability exploited by PARP inhibitors (olaparib, talazoparib) through synthetic lethality: BRCA-deficient cells cannot repair DSBs by HR, and PARP inhibition blocks the alternative BER pathway, causing cell death.
Lynch syndrome involves germline mutations in mismatch repair genes (MLH1, MSH2, MSH6, PMS2), inherited in an autosomal dominant pattern. It increases the risk of colorectal, endometrial, ovarian, gastric, and other cancers, with tumors characteristically showing microsatellite instability (MSI-high). Familial adenomatous polyposis (FAP) results from germline APC mutations and produces hundreds to thousands of colonic polyps by adolescence with near 100% risk of colorectal cancer without prophylactic colectomy. Li-Fraumeni syndrome involves germline TP53 mutations and predisposes to early-onset breast cancer, sarcomas, brain tumors, adrenocortical carcinoma, and leukemia. Xeroderma pigmentosum involves defective nucleotide excision repair, causing extreme UV sensitivity and skin cancer. Ataxia-telangiectasia involves ATM gene mutations that impair DSB signaling and predispose to lymphomas and leukemia.
<image>Panel A: The Vogelstein multi-step model of colorectal carcinogenesis — a horizontal progression diagram showing normal epithelium → small adenoma → large adenoma → carcinoma → metastasis, with the specific genetic alterations (APC loss, KRAS activation, SMAD4 loss, TP53 loss) indicated at each transition step with arrows. Panel B: Synthetic lethality concept for PARP inhibitors in BRCA-mutant cancers — diagram showing that normal cells with intact BRCA can repair DSBs via HR even when PARP is inhibited; BRCA-mutant cancer cells cannot use HR and when PARP is also inhibited, both repair pathways are blocked, leading to cell death. Panel C: Summary table of major hereditary cancer syndromes listing the syndrome name, gene(s) involved, inheritance pattern, associated cancers, and recommended surveillance strategies.</image>
VI. Cancer Genomics and Precision Oncology
Tumor genomic profiling involves sequencing tumor DNA to identify actionable driver mutations. This can be performed using targeted gene panels (50-500 cancer genes), whole exome sequencing, or whole genome sequencing, and identifies mutations, copy number changes, fusions, microsatellite instability status, and tumor mutational burden (TMB).
Targeted therapies matched to specific molecular alterations have transformed cancer treatment. Imatinib (Gleevec), a BCR-ABL inhibitor for CML, established the paradigm of targeted therapy. Trastuzumab (Herceptin) targets HER2-amplified breast cancer. Vemurafenib inhibits BRAF V600E in melanoma. Erlotinib and osimertinib target EGFR mutations in lung cancer. Olaparib targets BRCA-mutant breast and ovarian cancer through PARP inhibition.
Immunotherapy intersects with cancer genetics because tumors with high TMB or MSI-high status respond better to immune checkpoint inhibitors such as anti-PD-1/PD-L1. Pembrolizumab received tissue-agnostic approval for any MSI-high/dMMR solid tumor. Liquid biopsy, which detects circulating tumor DNA (ctDNA) in blood, enables non-invasive monitoring of mutations, treatment response, and relapse detection. Resistance mechanisms, including secondary mutations, bypass pathway activation, and tumor heterogeneity, remain a significant challenge and drive the rationale for combination therapies.
