---
title: "Genome Damage and Cancer"
book: "High School Biology"
subject: biology
language: en
chapter: 17
exercises: 15
source: https://one-course.com/books/biology/2/en/chapter/17-genome-damage-and-cancer
---

# Chapter 17 — Genome Damage and Cancer

Under the microscope, a slice of healthy gut lining is a picture of order: [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) in neat layers, each with a modest [nucleus](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-organelle), dividing at the bottom of the layer and dying at the top, in step. A few millimetres away, in the same slice, a patch of [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) has broken ranks: crowded, oddly shaped, with huge dark nuclei, dividing anywhere and pushing into the tissue beneath. Every [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) of the patch descends from one [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) that, some years earlier, acquired a [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) letting it divide when it should not have — and then, over the years, a few more. This chapter is about how the controls of the [cell cycle](https://one-course.com/books/biology/2/en/chapter/12-the-cell-cycle-and-mitosis#def-g11-cell-cycle-mitosis-cycle) fail, what damages them, and what can be done before and after.

## 17.1 Dividing when one should not

**Definition 17.1 (Cancer).**

A *cancer* is a population of [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) that divide without the controls that limit the division of normal [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell), and that invade the surrounding tissues. It begins with one [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) whose [DNA](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-information) has accumulated [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) in the [genes](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) controlling the [cell cycle](https://one-course.com/books/biology/2/en/chapter/12-the-cell-cycle-and-mitosis#def-g11-cell-cycle-mitosis-cycle); the [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell)’s descendants form a *tumour*. A tumour that stays confined is *benign*; one whose [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) invade neighbouring tissue and travel through the blood or lymph to found new tumours elsewhere (*metastases*) is *malignant*.

**Proposition 17.2 (Cancer is a disease of the genome).**

The [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) of a [tumour](#def-g11-cancer-cancer) carry [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) that its owner’s other [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) do not: somatic [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation), arisen in one [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) and inherited by its descendants. The [tumour](#def-g11-cancer-cancer) is a *clone*, and it evolves — [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) that divide faster or survive better take over, and later [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) add the ability to invade and to spread.

**Evidence.** Sequencing the [DNA](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-information) of [tumour](#def-g11-cancer-cancer) [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) beside that of the patient’s normal [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) finds thousands of differences, all present in the [tumour](#def-g11-cancer-cancer), none in the healthy tissue; the same few [genes](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) are found mutated in [tumour](#def-g11-cancer-cancer) after [tumour](#def-g11-cancer-cancer). Every [tumour](#def-g11-cancer-cancer) [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) of a woman carries the same one of her two X [chromosomes](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-information) switched off — the signature of descent from a single [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell). And [mutagens](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutagen) are [carcinogens](#def-g11-cancer-carcinogen): the agents that raise the [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) rate ([Chapter 13](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#ch-g11-mutations)) raise the [cancer](#def-g11-cancer-cancer) rate, with a delay of decades. ∎

![A stained tissue section: on the left, orderly cells in neat layers; on the right, a disordered mass of crowded cells with large, irregular nuclei pushing into the tissue. The border between the two is the border of the tumour.](https://one-course.com/images/onecourse/chapters/biology-2/g11-cancer/img-a75030f58026.jpg)

*A stained tissue section: on the left, orderly [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) in neat layers; on the right, a disordered mass of crowded [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) with large, irregular nuclei pushing into the tissue. The border between the two is the border of the [tumour](#def-g11-cancer-cancer).*

## 17.2 Accelerators and brakes

**Proposition 17.3 (Two kinds of gene control the cycle).**

The decision of a [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) to divide is taken by [proteins](https://one-course.com/books/biology/2/en/chapter/14-from-gene-to-protein#def-g11-gene-expression-protein) that act like the accelerator and the brakes of a vehicle.

- *Proto-oncogenes* encode [proteins](https://one-course.com/books/biology/2/en/chapter/14-from-gene-to-protein#def-g11-gene-expression-protein) that push the [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) into the cycle when a growth signal arrives — receptors for growth signals, and the relays that carry the signal to the [nucleus](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-organelle) . A [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) that leaves such a [protein](https://one-course.com/books/biology/2/en/chapter/14-from-gene-to-protein#def-g11-gene-expression-protein) permanently active turns the [gene](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) into an *oncogene* : the accelerator is jammed down. One mutant [allele](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) is enough.
- *Tumour suppressor genes* encode [proteins](https://one-course.com/books/biology/2/en/chapter/14-from-gene-to-protein#def-g11-gene-expression-protein) that halt the cycle — at the checkpoints before S and before [mitosis](https://one-course.com/books/biology/2/en/chapter/12-the-cell-cycle-and-mitosis#def-g11-cell-cycle-mitosis-cycle) — when the [DNA](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-information) is damaged, and that trigger repair or, if the damage is beyond repair, the [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) ’s self-destruction. A [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) that inactivates such a [protein](https://one-course.com/books/biology/2/en/chapter/14-from-gene-to-protein#def-g11-gene-expression-protein) removes a brake; since the [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) has two [alleles](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) , both must be lost.

The best-known suppressor, the [protein](https://one-course.com/books/biology/2/en/chapter/14-from-gene-to-protein#def-g11-gene-expression-protein) p53, is inactivated in half of all human [cancers](#def-g11-cancer-cancer).

**Proof.** *Admitted at this level.* ∎

![The controls of division. Proto-oncogene proteins relay growth signals and push the cell into the cycle (accelerator); tumour suppressor proteins stop it when the DNA is damaged (brake). An oncogene is an accelerator jammed on; a lost suppressor is a brake removed.](https://one-course.com/images/onecourse/chapters/biology-2/g11-cancer/fig-9e88221beda2.svg)

*The controls of division. Proto-oncogene [proteins](https://one-course.com/books/biology/2/en/chapter/14-from-gene-to-protein#def-g11-gene-expression-protein) relay growth signals and push the [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) into the cycle (accelerator); [tumour](#def-g11-cancer-cancer) suppressor [proteins](https://one-course.com/books/biology/2/en/chapter/14-from-gene-to-protein#def-g11-gene-expression-protein) stop it when the [DNA](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-information) is damaged (brake). An oncogene is an accelerator jammed on; a lost suppressor is a brake removed.*

**Example 17.4 (Two familiar genes).**

A receptor for a growth signal sits in the membrane of many [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell); one substitution in its [gene](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) makes it signal continuously, without any signal outside — an oncogene found in a third of colon and lung [cancers](#def-g11-cancer-cancer). The [gene](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) of p53, on the other hand, is inactivated by [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) in every possible way: substitutions that alter its shape, deletions, a premature stop. A [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) that has lost p53 does not stop to repair its [DNA](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-information) before copying it, so it accumulates further [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) faster: losing that brake accelerates the whole process.

## 17.3 Several steps, many years

**Proposition 17.5 (Cancer is a multi-step process).**

A single [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) does not make a [cancer](#def-g11-cancer-cancer). A [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) must accumulate several — typically an oncogene activated and two or more suppressors lost — and each successive [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation), by increasing the clone’s proliferation, increases the number of [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) in which the next can occur. The sequence takes years to decades, which is why the incidence of most [cancers](#def-g11-cancer-cancer) rises steeply with age, and why a [carcinogen](#def-g11-cancer-carcinogen)’s effect appears twenty or thirty years after exposure.

**Evidence.** In the colon, the stages can be seen: a small benign polyp carrying one suppressor [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation); a larger polyp with an oncogene added; an invasive [tumour](#def-g11-cancer-cancer) with p53 lost as well — a sequence of some four to six [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) over ten to twenty years, each stage found in the [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) of the next. [Cancer](#def-g11-cancer-cancer) incidence rises roughly as the fifth power of age, the curve expected if about five or six independent rare events must all occur in one [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell). People who inherit one mutant [allele](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) of a suppressor [gene](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) develop the corresponding [cancer](#def-g11-cancer-cancer) earlier and more often, having one step already taken in every [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell). ∎

![Clonal evolution. Each mutation that speeds division enlarges the clone in which the next mutation can occur; after several such steps, over years, one lineage has lost every control. The tumour is a nest of clones, the most recent inside the older.](https://one-course.com/images/onecourse/chapters/biology-2/g11-cancer/fig-e1fa353e87bd.svg)

*Clonal evolution. Each [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) that speeds division enlarges the clone in which the next [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) can occur; after several such steps, over years, one lineage has lost every control. The [tumour](#def-g11-cancer-cancer) is a nest of clones, the most recent inside the older.*

![Yearly incidence of all cancers against age (rounded from national registries). The rise is far steeper than proportional: from 35 to 70 the age doubles and the incidence rises twentyfold, the signature of several rare events that must all happen in one cell.](https://one-course.com/images/onecourse/chapters/biology-2/g11-cancer/fig-349f372fc919.svg)

*Yearly incidence of all [cancers](#def-g11-cancer-cancer) against age (rounded from national registries). The rise is far steeper than proportional: from 35 to 70 the age doubles and the incidence rises twentyfold, the signature of several rare events that must all happen in one [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell).*

## 17.4 What damages the genome

**Definition 17.6 (Carcinogen).**

A *carcinogen* is an agent that raises the risk of [cancer](#def-g11-cancer-cancer). Most are [mutagens](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutagen): the ultraviolet of sunlight (skin [cancers](#def-g11-cancer-cancer)), the tars of tobacco smoke (lung, mouth, bladder), ionising radiation, asbestos fibres, alcohol, some moulds. Some act otherwise: certain viruses carry [genes](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) that jam the [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell)’s brakes — human papillomaviruses cause nearly all [cancers](#def-g11-cancer-cancer) of the cervix, hepatitis viruses many [cancers](#def-g11-cancer-cancer) of the liver — and chronic inflammation or hormones that keep a tissue dividing raise the number of divisions in which [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) can occur.

![Risk of lung cancer relative to a non-smoker, against the number of cigarettes smoked per day over decades (rounded from long-term studies). The risk rises with the dose, as expected from a mutagen delivered to the lungs.](https://one-course.com/images/onecourse/chapters/biology-2/g11-cancer/fig-682840a3ce5b.svg)

*Risk of lung [cancer](#def-g11-cancer-cancer) relative to a non-smoker, against the number of cigarettes smoked per day over decades (rounded from long-term studies). The risk rises with the dose, as expected from a [mutagen](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutagen) delivered to the lungs.*

**Example 17.7 (Tobacco).**

Smoke carries some seventy [carcinogens](#def-g11-cancer-carcinogen); benzopyrene, once activated by the [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell)’ own [enzymes](https://one-course.com/books/biology/2/en/chapter/15-enzymes-and-the-phenotype#def-g11-enzymes-and-phenotype-enzyme), attaches to guanines and causes substitutions at those positions. The p53 [gene](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) of a smoker’s lung [tumour](#def-g11-cancer-cancer) typically carries exactly such a substitution, at one of a few positions where benzopyrene binds most readily — the [mutagen](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutagen) leaves its signature in the sequence. Lung [cancer](#def-g11-cancer-cancer) was a rarity before cigarettes; smoking causes nine cases in ten, and stopping halves the risk within ten years, because the [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) that carried the early steps are gradually replaced.

**Proposition 17.8 (Inherited predisposition).**

[Cancer](#def-g11-cancer-cancer) itself is not inherited — it is a disease of somatic [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) — but a mutant [allele](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) of a suppressor [gene](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) can be. A person who inherits one non-working [allele](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) of such a [gene](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) has taken one step in every [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) of the body; a single somatic [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) of the other [allele](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) completes the loss in any [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell), instead of the two required in other people. The result is a high risk of the corresponding [cancers](#def-g11-cancer-cancer), earlier in life: some 70% of women carrying a mutant [allele](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) of one particular [breast-cancer](#def-g11-cancer-cancer) [gene](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) develop the disease, against 12% in general.

**Proof.** *Admitted at this level.* ∎

## 17.5 Prevention, detection, treatment

**Method 17.9 (Reducing the risk).**

Since most of the [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) behind [cancers](#def-g11-cancer-cancer) come from identifiable exposures, and since the process takes years, [cancer](#def-g11-cancer-cancer) is largely preventable and detectable.

1. *Avoid the [mutagens](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutagen)* : no tobacco (a third of all [cancer](#def-g11-cancer-cancer) deaths), little alcohol, sun protection, no unnecessary radiation.
2. *Vaccinate* against the cancer-causing viruses: the papillomavirus vaccine prevents nearly all cervical [cancers](#def-g11-cancer-cancer) when given before exposure.
3. *Screen* : find the [tumour](#def-g11-cancer-cancer) at the polyp stage — smear tests of the cervix, colonoscopy, mammography — when removing it is simple and curative.
4. *Know the family* : an inherited predisposition calls for earlier and closer surveillance.

**Example 17.10 (Treatments and what they target).**

Surgery removes a [tumour](#def-g11-cancer-cancer) that has not spread. Radiotherapy breaks the [DNA](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-information) of [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) in the beam beyond repair, killing dividing [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) preferentially. Chemotherapy uses drugs that block replication or the spindle ([Chapter 12](https://one-course.com/books/biology/2/en/chapter/12-the-cell-cycle-and-mitosis#ch-g11-cell-cycle-mitosis)): [tumour](#def-g11-cancer-cancer) [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell), dividing constantly, die faster than normal [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) — but the fast-dividing normal tissues (bone marrow, gut lining, hair roots) suffer too, which is where the side effects come from. Newer treatments target the specific mutant [protein](https://one-course.com/books/biology/2/en/chapter/14-from-gene-to-protein#def-g11-gene-expression-protein) of a [tumour](#def-g11-cancer-cancer), or unleash the immune system on it.

**Remark 17.11 (Why we all carry the beginnings).**

Every adult carries clones of [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) with cancer-related [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) — in the skin, the gut, the blood — that never become [cancers](#def-g11-cancer-cancer): the remaining brakes hold, the immune system removes the worst, and the person dies of something else first. [Cancer](#def-g11-cancer-cancer) is the occasional outcome of a process that runs in everyone; the aim of prevention is to keep the number of steps taken, in any one [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell), below the number needed.

## 17.6 Exercises

**Exercise 17.1 ★.**

Define [cancer](#def-g11-cancer-cancer), [tumour](#def-g11-cancer-cancer) and metastasis.

**Solution of Exercise 17.1.**

[Cancer](#def-g11-cancer-cancer): [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) dividing without the normal controls and invading neighbouring tissue. [Tumour](#def-g11-cancer-cancer): the mass formed by such a clone. Metastasis: a new [tumour](#def-g11-cancer-cancer) founded elsewhere by [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) that travelled through blood or lymph.

**Exercise 17.2 ★.**

What is a proto-oncogene, and what does it become when mutated? Why does one mutant [allele](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) suffice?

**Solution of Exercise 17.2.**

A [gene](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) whose [protein](https://one-course.com/books/biology/2/en/chapter/14-from-gene-to-protein#def-g11-gene-expression-protein) relays growth signals and pushes the [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) into the cycle; mutated so that the [protein](https://one-course.com/books/biology/2/en/chapter/14-from-gene-to-protein#def-g11-gene-expression-protein) is permanently active it becomes an oncogene. One jammed accelerator drives the [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) whatever the other [allele](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) does.

**Exercise 17.3 ★.**

What does a [tumour](#def-g11-cancer-cancer) suppressor [protein](https://one-course.com/books/biology/2/en/chapter/14-from-gene-to-protein#def-g11-gene-expression-protein) such as p53 do? Why must both [alleles](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) be lost?

**Solution of Exercise 17.3.**

It halts the cycle when [DNA](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-information) is damaged and triggers repair or self-destruction. One working [allele](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) still makes enough [protein](https://one-course.com/books/biology/2/en/chapter/14-from-gene-to-protein#def-g11-gene-expression-protein) to brake; only the loss of both removes the brake.

**Exercise 17.4 ★.**

Name four [carcinogens](#def-g11-cancer-carcinogen) and, for two of them, the [cancer](#def-g11-cancer-cancer) they cause.

**Solution of Exercise 17.4.**

Ultraviolet light (skin [cancers](#def-g11-cancer-cancer)), tobacco tar (lung [cancer](#def-g11-cancer-cancer)), ionising radiation, asbestos, alcohol, papillomavirus (cervical [cancer](#def-g11-cancer-cancer)).

**Exercise 17.5 ★.**

Why is a [cancer](#def-g11-cancer-cancer) described as a clone?

**Solution of Exercise 17.5.**

All its [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) descend from one [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) in which the first [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) occurred; they share that [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) and the ones that followed, and markers such as the same inactive X [chromosome](https://one-course.com/books/biology/2/en/chapter/12-the-cell-cycle-and-mitosis#def-g11-cell-cycle-mitosis-chromosome).

**Exercise 17.6 ★★.**

From the age figure, read the incidence at 40 and at 80, and compute the factor. Compare with the factor 2 in age.

**Solution of Exercise 17.6.**

About 200 at 40 and 2700 at 80: a factor of 13 for a factor of 2 in age — several events multiplying, not one proportional cause.

**Exercise 17.7 ★★.**

From the tobacco figure, give the relative risk at 10 and at 20 cigarettes a day. If a non-smoker’s lifetime risk is 1%, what is a 20-a-day smoker’s?

**Solution of Exercise 17.7.**

About 10 and 17. A 20-a-day smoker: $17 \times 1\% = 17\%$, one in six.

**Exercise 17.8 ★★.**

Explain why a [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) that has lost p53 accumulates further [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) faster than a normal [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell).

**Solution of Exercise 17.8.**

Without p53 the [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) no longer pauses to repair damaged [DNA](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-information) before replication, nor destroys itself when the damage is severe: lesions are copied into [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) at every division, and [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) with scrambled genomes survive.

**Exercise 17.9 ★★.**

A woman inherits one mutant [allele](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) of a [breast-cancer](#def-g11-cancer-cancer) suppressor [gene](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene). Explain, in terms of "steps", why her risk is high and her [cancers](#def-g11-cancer-cancer) early; and why her sisters have a one-in-two chance of the same.

**Solution of Exercise 17.9.**

Every [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) of her body already lacks one [allele](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene); a single somatic [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) of the other completes the loss, instead of two independent ones. With one step taken from birth, the remaining steps are reached sooner and in more [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell). Her sisters inherit the [allele](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) from the same parent with probability $1/2$.

**Exercise 17.10 ★★.**

Why do chemotherapy drugs cause hair loss, nausea and a fall in white blood [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell)?

**Solution of Exercise 17.10.**

The drugs kill dividing [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) indiscriminately: hair-root [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell), the gut lining and the bone marrow divide fast and are hit along with the [tumour](#def-g11-cancer-cancer) — hence hair loss, nausea, and a shortage of white [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell).

**Exercise 17.11 ★★.**

A smoker who stops at 40 has, at 60, half the [lung-cancer](#def-g11-cancer-cancer) risk of one who continued. Explain with the multi-step model why the risk falls but does not return to a non-smoker’s.

**Solution of Exercise 17.11.**

Stopping ends the supply of new [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation), and the lining’s [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) are gradually replaced, removing many clones that carried early steps. But some clones with several steps persist, and the [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) already present are not erased; the risk stays above a non-smoker’s.

**Exercise 17.12 ★★★.**

Suppose a [cancer](#def-g11-cancer-cancer) requires 3 specific [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation), each occurring with probability $10^{-7}$ per [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) division. A tissue’s stem [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) divide $10^{12}$ times over a life. Estimate the expected number of [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) that acquire the first [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation); explain why the naive product $10^{-21}$ for all three is far too low, using clonal expansion.

**Solution of Exercise 17.12.**

$10^{12} \times 10^{-7} = 10^5$ [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) acquire the first [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation). Each founds a clone that may divide thousands of times, so the second [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) is sought not in one [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) but in the whole clone’s divisions, and likewise the third: the steps multiply the target, and the true probability is many orders of magnitude above $10^{-21}$.

**Exercise 17.13 ★★★.**

A papillomavirus carries a [gene](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) whose [protein](https://one-course.com/books/biology/2/en/chapter/14-from-gene-to-protein#def-g11-gene-expression-protein) binds and inactivates p53. Explain how the virus causes [cancer](#def-g11-cancer-cancer) without mutating any human [gene](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene), why the vaccine prevents it, and why vaccinating before exposure matters.

**Solution of Exercise 17.13.**

The viral [protein](https://one-course.com/books/biology/2/en/chapter/14-from-gene-to-protein#def-g11-gene-expression-protein) removes the brake without touching the [gene](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene): the infected [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) behaves as if p53 were lost and accumulates [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) that complete the process. The vaccine makes the immune system destroy the virus before it infects the cervix; once [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) are infected and transformed, the vaccine no longer helps — hence vaccination in early adolescence.

**Exercise 17.14 ★★★.**

Screening for colon [cancer](#def-g11-cancer-cancer) by colonoscopy every ten years from age 50 removes polyps found. Using the multi-step model, explain why this prevents [cancer](#def-g11-cancer-cancer) rather than only detecting it, and why ten years is a reasonable interval.

**Solution of Exercise 17.14.**

A polyp is a clone that has taken one or two steps; removing it removes the [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) in which the remaining steps could occur, so the [cancer](#def-g11-cancer-cancer) never forms. Since the polyp-to-cancer sequence takes ten to twenty years, a ten-year interval catches most polyps before they complete it.

**Exercise 17.15 ★★★.**

"[Cancer](#def-g11-cancer-cancer) is a disease of old age, so there is nothing to be done." Discuss in a paragraph with the age curve, the delay of [carcinogens](#def-g11-cancer-carcinogen), the fraction of [cancers](#def-g11-cancer-cancer) attributable to known exposures, and screening.

**Solution of Exercise 17.15.**

Incidence rises with age because the steps take decades, but the steps are taken during life, largely under exposures — tobacco alone accounts for a third of [cancer](#def-g11-cancer-cancer) deaths, and infections, alcohol, sun and diet for much of the rest. Removing an exposure at any age reduces the [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) still to come; screening removes clones before the last step. Old age is when the account is presented, not when it is written.

## 17.7 Problem: The Signature in the Gene

**Problem 17.1.**

Weekend problem — a lung tumour sequenced: the mutations counted, the smoker’s signature read, the years reckoned, and the risk a cigarette carries

A lung [tumour](#def-g11-cancer-cancer) and healthy tissue from the same patient, a smoker of 20 cigarettes a day for 35 years, are sequenced. The [tumour](#def-g11-cancer-cancer) carries $5000$ somatic substitutions not found in the healthy tissue; 75% of them replace a G by a T, the change benzopyrene causes. Among them: one in the p53 [gene](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene), creating a premature stop, on one [allele](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene); the other [allele](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) of p53 is deleted; and one in a growth-signal receptor [gene](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene), making the [protein](https://one-course.com/books/biology/2/en/chapter/14-from-gene-to-protein#def-g11-gene-expression-protein) permanently active.

**Part I — Reading the sequence.**

1. Why are the $5000$ substitutions called somatic? Where would they be found if they were germline?
2. In a non-smoker’s [tumour](#def-g11-cancer-cancer) , substitutions are of all kinds in roughly equal proportions. What does the 75% of G-to-T changes tell you?
3. Classify the p53 [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) (with the vocabulary of [Chapter 14](https://one-course.com/books/biology/2/en/chapter/14-from-gene-to-protein#ch-g11-gene-expression) ) and its effect on the [protein](https://one-course.com/books/biology/2/en/chapter/14-from-gene-to-protein#def-g11-gene-expression-protein) .
4. Explain why both [alleles](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) of p53 had to be lost, but one mutant [allele](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) of the receptor [gene](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) was enough.
5. Which of the two [genes](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) is an accelerator and which a brake?

**Part II — The years.**

6. The patient smoked about $20 \times 365 \times 35$ cigarettes. Compute the number.
7. If each cigarette produces, on average, one lasting substitution in each of the lung’s lining [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) , how many substitutions would a [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) carry after 35 years? Compare with the $5000$ found.
8. The [tumour](#def-g11-cancer-cancer) ’s [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) are not all in the same [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) ’ order: the p53 and receptor [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) are in every [tumour](#def-g11-cancer-cancer) [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) , the other thousands only in subsets. What does this say about when the two key [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) occurred?
9. The [tumour](#def-g11-cancer-cancer) is $3\,\mathrm{cm}$ across, about $10^{10}$ [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) , and [tumour](#def-g11-cancer-cancer) [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) double every 100 days. How many doublings from one [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) , and how many years, at least?
10. Combine questions 8 and 9: roughly when in the 35 years did the last of the key [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) occur?

**Part III — The risk of a cigarette.**

11. From the tobacco figure, the patient’s relative risk was about 17. If 1% of non-smokers develop lung [cancer](#def-g11-cancer-cancer) , what fraction of smokers like him do?
12. Among 100 such smokers, how many [cancers](#def-g11-cancer-cancer) are attributable to smoking?
13. Had he stopped at 40 (after 20 years), his risk would have been about a third of the continuing smoker’s. Explain, with the multi-step model and the renewal of the lung lining, why the risk falls after stopping.
14. Why does a smoker’s [cancer](#def-g11-cancer-cancer) , when it comes, usually come after thirty years and not after five?
15. A student argues that since a cigarette causes "only one [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) per [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) ", it is harmless. Answer with the arithmetic of question 7 and the number of [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) .

**Part IV — Prevention and the population.** In a country of 60 million, 25% of adults smoke; lung [cancer](#def-g11-cancer-cancer) kills $30\,000$ people a year, 90% of them smokers.

16. Compute the yearly [lung-cancer](#def-g11-cancer-cancer) deaths among smokers and among non-smokers, and the death rate per 100 000 in each group (take 45 million adults).
17. By what factor is the rate higher among smokers? Compare with the figure’s relative risk and comment.
18. If smoking disappeared today, what would the yearly number of [lung-cancer](#def-g11-cancer-cancer) deaths become in the long run? Why not immediately?
19. Screening by low-dose scans finds [tumours](#def-g11-cancer-cancer) earlier and lowers deaths among heavy smokers by about 20%. Compare, in deaths avoided per year, screening every smoker with stopping smoking.
20. State the result: what the G-to-T signature proved about the origin of the [tumour](#def-g11-cancer-cancer) ’s [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) , the three genetic events that made the [cancer](#def-g11-cancer-cancer) , and the one decision that would have prevented it.

**Solution of Problem 17.1.**

**1.** They are present in the [tumour](#def-g11-cancer-cancer) and absent from the patient’s other [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell), so they arose in a body [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell). Germline [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) would be in every [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell), healthy tissue included.

**2.** That most of the [tumour](#def-g11-cancer-cancer)’s [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) were caused by benzopyrene — the [mutagen](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutagen) of tobacco smoke left its signature.

**3.** A nonsense [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation): a premature stop [codon](https://one-course.com/books/biology/2/en/chapter/14-from-gene-to-protein#def-g11-gene-expression-code) truncates p53, which cannot work.

**4.** p53 is a brake: one working [allele](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) still brakes, so both had to go (one mutated, one deleted). The receptor is an accelerator: one permanently active [protein](https://one-course.com/books/biology/2/en/chapter/14-from-gene-to-protein#def-g11-gene-expression-protein) drives the [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) whatever the other [allele](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) does.

**5.** The receptor [gene](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) is the accelerator (proto-oncogene turned oncogene); p53 is the brake ([tumour](#def-g11-cancer-cancer) suppressor).

**6.** $20 \times 365 \times 35 \approx 255\,000$ cigarettes.

**7.** About $255\,000$ substitutions per [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) — fifty times the 5000 found. Most lesions are repaired, and [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) with too many [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) die; 5000 is the surviving fraction.

**8.** They occurred early, in the founding [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) or its first descendants, so every [tumour](#def-g11-cancer-cancer) [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) inherited them; the others arose later in sub-clones.

**9.** $10^{10} \approx 2^{33}$: 33 doublings, at 100 days each about 9 years.

**10.** If the [tumour](#def-g11-cancer-cancer) took 9 years or more to grow from its founding [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell), the last key [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) occurred around 25 years into the 35 years of smoking, or earlier.

**11.** $17 \times 1\% = 17\%$.

**12.** 17 [cancers](#def-g11-cancer-cancer), of which 1 would have occurred anyway: 16 in 100 attributable to smoking.

**13.** No new [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) are added; the lining renews itself and many clones carrying early steps are shed and replaced over the years; the remaining clones have fewer steps than they would have acquired by continuing.

**14.** Several rare [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) must accumulate in one lineage, and the lineage must then grow to a detectable size: each stage takes years, and their sum is decades.

**15.** One [mutation](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) per [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) per cigarette, in some $10^9$ lining [cells](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell), over $255\,000$ cigarettes, is $10^{14}$ [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) scattered over the lung; a few will hit p53 or a proto-oncogene in a [cell](https://one-course.com/books/biology/2/en/chapter/2-cells-the-common-unit-of-life#def-g10-cells-common-unit-cell) that already carries another step. It is the number of trials that makes the improbable certain.

**16.** Smokers: $27\,000$ deaths among $11.25 \times 10^{6}$, about 240 per 100 000; non-smokers: 3000 among $33.75 \times 10^{6}$, about 9 per 100 000.

**17.** About 27 times — of the same order as the figure’s 17 to 25 for heavy smokers; the population figure mixes light and heavy smokers and ex-smokers.

**18.** About 3000 a year, the non-smokers’ share. Not immediately: the [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) already present in current and former smokers will produce [cancers](#def-g11-cancer-cancer) for another twenty or thirty years.

**19.** Screening every smoker saves about 20% of $27\,000$, some 5000 deaths a year; stopping smoking would eventually prevent about $24\,000$ — five times more.

**20.** The G-to-T signature proved the [tumour](#def-g11-cancer-cancer)’s [mutations](https://one-course.com/books/biology/2/en/chapter/13-mutations-and-genetic-variation#def-g11-mutations-mutation) came from tobacco smoke; the [cancer](#def-g11-cancer-cancer) was made by an oncogene activated and both [alleles](https://one-course.com/books/biology/2/en/chapter/3-dna-a-universal-genetic-molecule#def-g10-universal-dna-gene) of p53 lost; not smoking would have prevented it.