Cancer

What is cancer? Explain its relationship with cell cycle alteration.

Distinguish between a benign tumour and a malignant tumour, and explain what metastasis is.

Analyze the following two clinical cases seen in an oncology unit:

• Patient A: A 65-year-old smoker diagnosed with lung squamous cell carcinoma. Genomic analysis reveals inactivating mutations in the TP53 gene exclusively in cells from the tumor biopsy, but not in his blood lymphocytes or his sperm.

• Patient B: A 32-year-old woman diagnosed with bilateral breast cancer. Genetic testing detects a pathogenic mutation in the BRCA1 gene in all her somatic cells and in her oocytes, an alteration also present in her mother and maternal grandmother.

1. a) Based on these data, refute the apparent contradiction in the statement "cancer is always a genetic disease, but rarely hereditary," by assigning and justifying for each patient the type of mutation (somatic or germline) and its impact on offspring.
2. b) Applying Knudson's two-hit hypothesis for tumor suppressor genes, explain why Patient B developed the tumor at such an early age, and clarify why inheriting this germline mutation does not mean being born with an already developed tumor.

The diagram compares the role of two types of genes in controlling cell division, in their normal form and when mutated. Explain which type of gene (proto-oncogene or tumour suppressor gene) corresponds to A and B, which kind of mutation (activating or inactivating) alters it in each case, and how each contributes to the onset of cancer.

Tobacco is responsible for most lung cancers. Explain what a carcinogen (or carcinogenic agent) is and give two more examples of carcinogens other than tobacco, stating the type of cancer they promote.

Human papillomavirus (HPV) can cause cervical cancer. Explain how a virus can induce cancerous transformation of a cell and what effective preventive measure exists against HPV.

A chemotherapy drug acts by inhibiting the depolymerisation of the spindle apparatus during the M phase, which blocks the spindle assembly checkpoint and induces programmed cell death.

1. a) Justify at the molecular and tissue levels why this drug causes acute side effects such as neutropenia, anaemia, alopecia, and gastrointestinal mucosal lesions, whereas striated muscle tissue and nervous tissue experience almost no immediate toxicity.
2. b) A solid tumour has a growth fraction (percentage of cells actively dividing versus cells in G0 phase) of only 10%, while the remaining 90% is in quiescence. Predict and justify the efficacy of this chemotherapy agent against this tumour, and explain the risk posed by G0 cells re-entering the cell cycle after treatment ends.

In a preclinical trial, tumor cells are cultured to form three-dimensional multicellular spheroids in vitro. It is observed that the spheroid halts its net volumetric growth upon reaching a diameter of about 1.5 mm, at which point a central core of necrotic cells appears surrounded by a peripheral rim of proliferating cells.

1. a) Justify at a biophysical and metabolic level why central necrosis occurs once this critical size is exceeded in the absence of a vascular network.
2. b) Upon implanting this spheroid into an immunocompromised mouse, the tumor induces angiogenesis and resumes rapid growth. If a neutralizing anti-VEGF monoclonal antibody is administered to the animal, predict and justify what will happen to the size of the primary tumor and to the likelihood of hematogenous metastasis formation.

Name three lifestyle habits that reduce the risk of developing cancer and briefly explain why each has that protective effect.