Week 6 - Cancer Genetics and Evolution

1. What percentage of cancer deaths are linked to metastasis?

Around 90%.

2. Why is systemic therapy often required in advanced cancer?

Because surgery alone is not curative once the disease has spread.

3. What is the main problem with cancer therapy resistance?

Resistant clones evolve, rendering treatments ineffective.

4. What are the three Darwinian principles applied to cancer evolution?

Diversity, heritability, and selection of advantageous traits.

5. Why is cancer described as an evolutionary system?

Because cancer cells undergo variation, selection, and inheritance.

6. What creates diversity within tumours?

Genetic and phenotypic variation among cancer cells.

7. How do therapies act as a selection pressure?

They kill sensitive cells, allowing resistant clones to survive and expand.

8. What are the implications of clonal competition?

Some cancer clones outcompete others under therapy.

9. What is the concept behind “therapy holidays”?

Temporarily stopping treatment to allow sensitive cells to suppress resistant ones.

10. What is “the sucker’s gambit”?

A treatment strategy to exploit evolutionary trade-offs in resistant cells.

11. What is ecological therapy?

Targeting the tumour microenvironment rather than the tumour directly.

12. Give an example of ecological therapy.

Anti-angiogenic drugs.

13. What are immunotherapies?

Treatments that stimulate the immune system to attack cancer cells.

14. What are virotherapies?

Use of genetically modified viruses to selectively infect and kill cancer cells.

15. What did Peter Nowell propose about cancer therapy in 1976?

Each cancer is unique and therapy must account for evolutionary processes.

16. What drug drives KRAS mutant clone emergence in colorectal cancer?

Cetuximab (anti-EGFR).

17. What is the main drawback of using maximum tolerated dose (MTD) therapy?

It selects for resistant clones.

18. Why is pre-existing resistance almost inevitable in large tumours?

Due to high cell numbers and mutation rates.

19. What is the key idea of adaptive therapy?

Modulate drug dosage to control tumour growth and delay resistance.

20. Who developed the adaptive therapy concept?

Gatenby et al., 2009.

21. What is field cancerization?

Preconditioning of an epithelial field toward cancer growth.

22. Who first described field cancerization?

Slaughter et al., 1953.

23. What is the main clinical challenge of field cancerization?

Morphologically normal tissue can harbor mutations.

24. What initiates a cancerous field?

Mutations in long-lived stem cells.

25. What organs commonly show field cancerization?

Colon, lung, and head and neck epithelium.

26. What is the mutational theory of carcinogenesis?

Cancer arises from sequential mutations in stem cells.

27. How long does it take for a benign adenoma to become malignant?

Around 17 years.

28. What is Lgr5 and why is it important?

A marker of intestinal stem cells and Wnt pathway target gene.

29. What technique allows stem cell lineage tracing in mice?

Genetic labeling with reporter constructs (e.g., Lgr5-EGFP).

30. What enzyme activity is detected by COX/SDH histochemistry?

Mitochondrial cytochrome c oxidase activity.

31. Why can’t lineage tracing be performed in humans?

It requires genetic manipulation not possible in humans.

32. Why is mtDNA used as a clonal marker?

It mutates frequently and persists for life.

33. What does clonal expansion indicate?

A single mutated stem cell has produced many progeny.

34. How do crypts in the colon expand?

By fission into adjacent crypts.

35. What does G6PD staining reveal?

X-inactivation patterns showing clonal patches.

36. How often do normal crypts divide?

Roughly once every 30–40 years.

37. What disease shows accelerated clonal expansion?

Crohn’s disease.

38. What mechanism might drive expansion in Crohn’s disease?

Chronic inflammation promoting mutation and clone spread.

39. What gene is often mutated in field cancerization of the lung?

TP53.

40. What are the clinical implications of field cancerization in the lung?

High recurrence risk and inoperable spread.

41. What is clonal evolution in cancer?

Stepwise accumulation and selection of mutations.

42. Who proposed the clonal evolution model of cancer?

Peter Nowell, 1976.

43. What is the significance of multi-region sequencing?

It reveals spatial and temporal tumour evolution.

44. What are the three tenets of clonal evolution?

Monoclonal origin, heritable genotypes, and selection of traits.

45. What does clonal diversity indicate about tumour evolution?

It reflects ongoing evolutionary processes.

46. What does phylogenetic analysis reveal in tumours?

Relatedness and ancestry of cancer clones.

47. How do adenomas differ from carcinomas in clonality?

Adenomas are more clonally diverse; carcinomas are usually clonal.

48. What genetic event distinguishes adenoma from carcinoma?

Aneuploidy and chromosomal instability.

49. What is punctuated evolution in cancer?

Sudden genome doubling or catastrophic mutations driving progression.

50. What is meant by a “neutral growth pattern” in CRC?

Tumour growth dominated by random drift rather than selection.

51. How are gland-level spatial studies in CRC conducted?

Tumour glands are separated and individually sequenced.

52. What does a single clonal sweep indicate?

One dominant clone outcompeted all others.

53. What are the two main sources of genetic variation?

Mutation and recombination.

54. What are germline mutations?

Mutations inherited from parents, present in all cells.

55. What are somatic mutations?

Acquired mutations present only in specific tissues.

56. What is a de novo mutation?

A new mutation not inherited from either parent.

57. What is an SNP?

Single nucleotide polymorphism — the most common form of variation.

58. What is a transition mutation?

Purine-to-purine or pyrimidine-to-pyrimidine substitution.

59. What is a transversion mutation?

Purine-to-pyrimidine (or vice versa) substitution.

60. What is a frameshift mutation?

Insertion or deletion that disrupts the reading frame.

61. What disease is caused by trinucleotide expansion?

Huntington’s disease.

62. What type of mutation occurs in the HTT gene in Huntington’s disease?

CAG repeat expansion.

63. What proportion of cancers have TP53 mutations?

Around 50%.

64. What distinguishes driver from passenger mutations?

Drivers confer growth advantage; passengers do not.

65. What is a mutational signature?

A pattern of mutations that reflects the underlying mutagenic process.

66. What is SBS4 associated with?

Smoking-induced mutations.

67. How genetically similar are humans and chimps?

Around 96–99%.

68. How many SNPs differ between two humans?

About 3.2 million.

69. What does Hardy-Weinberg equilibrium describe?

Stable genotype frequencies in the absence of evolutionary forces.

70. What does Hardy-Weinberg disequilibrium indicate?

Selection or other evolutionary forces acting on a population.

71. What is linkage disequilibrium?

Non-random association of alleles at nearby loci.

72. What causes linkage disequilibrium?

Physical proximity of genes on the same chromosome.

73. What are copy number variations (CNVs)?

Gains or losses of large DNA segments.

74. What causes Down syndrome?

Trisomy 21 (extra copy of chromosome 21).

75. How do CNVs contribute to cancer?

Cause aneuploidy and gene dosage imbalance.

76. What is tumour heterogeneity?

Genetic or phenotypic diversity within or between tumours.

77. What are the two types of tumour heterogeneity?

Inter-tumour and intra-tumour heterogeneity.

78. Why does inter-tumour heterogeneity occur?

Different evolutionary paths produce similar phenotypes.

79. Why is intra-tumour heterogeneity clinically important?

It affects diagnosis, biomarker reliability, and treatment response.

80. What is the ultimate implication of tumour evolution for therapy?

Cancer should be managed as an evolving ecosystem rather than eradicated.