7.4 about 30 minDeep Learning viewL7 p.13–15, 18–21

Who gets cancer, and which genes break

Cancer is common, rises with age and differs between populations. Underneath, every cancer is a set of mutations in four classes of genes: accelerators, brakes, apoptosis regulators and DNA repair.

Epidemiology: causes, age and populations

L7 p.13

Cancer is the second most common cause of death in developed countries. The lecture sorts its causes into three groups: external factors (tobacco, the leading one; alcohol, for example squamous carcinoma of the esophagus; chemicals; radiation; microbes, for example Epstein–Barr virus and nasopharyngeal carcinoma), internal factors (hormones, immune status, inherited mutations) and geographic and ethnic factors.

Patterns the lecture highlightsL7 p.13

  • Age

    Pattern
    Incidence rises after ~55 (colorectal, lung, prostate); some cancers peak earlier and then decline (melanoma)
    Why it makes sense
    Mutations accumulate with each division and each exposure

  • Ethnicity

    Pattern
    Prostate cancer more common in Black than white Americans; low in Japanese men
    Why it makes sense
    Genetic background, hormones and diet

  • Skin pigment

    Pattern
    Skin cancer more common in fair-skinned people
    Why it makes sense
    Melanin absorbs UV light

  • Geography

    Pattern
    Breast cancer low in Japanese and other Asian women, high in North America and Europe
    Why it makes sense
    Reproductive patterns, diet and environment; risk shifts in migrants

  • Children (1–14 y)

    Pattern
    Cancer is the leading disease-related cause of death; top three: leukemia (ALL), CNS tumors (cerebellar), neuroblastoma
    Why it makes sense
    Embryonal tumors arise from developing tissues

Screening: catching the clone early

L7 p.14

Screening rests on three facts from the lecture. Cancer begins as one mutated cell. A cancer that causes symptoms only late has gone through more divisions and accumulated more mutations. Cancers detected late have a worse prognosis. Screening therefore looks for dysplasia before it becomes carcinoma, or for carcinoma before it causes symptoms or spreads.

Common screening methodsL7 p.14

  • Pap smear (with HPV testing)

    Detects
    Cervical dysplasia (CIN)
    Aim
    Treat CIN before it invades

  • Mammography

    Detects
    In situ carcinoma (DCIS, often as microcalcifications) or small invasive cancers
    Aim
    Find cancer before it is palpable

  • PSA and digital rectal exam

    Detects
    Prostate carcinoma
    Aim
    Find it before it spreads

  • Fecal occult blood and colonoscopy

    Detects
    Colonic adenomas and early carcinomas
    Aim
    Remove adenomas before they become carcinoma

A screening test is not a diagnosis

Screening

  • Applied to people without symptoms
  • Cheap, safe, sensitive: Pap smear, mammogram, PSA, occult blood
  • A positive result means 'look closer'

Tissue diagnosis

  • Applied to a lesion that has been found
  • Biopsy, excision or cytology read by a pathologist
  • Names the tumor, its grade and whether it has invaded (7.6)
L7 p.14, 22

Four classes of cancer genes

L7 p.15, 18

Cancer starts with DNA damage in a stem cell that overcomes repair but does not kill the cell. The damage can be a point mutation, a balanced translocation, insertion of a viral genome, a deletion, amplification of a gene or its overexpression. What matters is which genes are hit. The lecture names four classes:

Teaching schematic

  • Proto-oncogene → oncogene

    Accelerator stuck down

    One mutated allele is enough (gain of function)

    RAS point mutation · ERBB2 amplification · BCR–ABL t(9;22) · MYC t(8;14)

  • Tumor suppressor

    Brakes cut

    Both alleles must be lost (two hits)

    RB · TP53 · APC · NF1 · NF2 · VHL · WT1

  • Apoptosis regulator

    Self-destruct disabled

    Overexpression keeps damaged cells alive

    BCL2 t(14;18) in follicular lymphoma

  • DNA repair gene

    Proofreader asleep

    Mutations in the other three classes accumulate faster

    Mismatch repair (Lynch) · nucleotide excision repair (XP) · BRCA1/2

Four classes of genes and what their mutation does: oncogenes (accelerator stuck on, one allele is enough), tumor suppressors (brakes lost, both alleles), apoptosis regulators (self-destruct disabled), DNA repair genes (mutations accumulate faster).L7 p.15

Proto-oncogenes are normal genes for growth factors, their receptors, signal transducers and nuclear transcription factors. A gain-of-function mutation turns one into an oncogene, and one mutated allele is enough because the abnormal protein acts regardless of the normal one. Tumor suppressor genes restrain growth; both alleles must be lost before the cell escapes (the two-hit hypothesis). Apoptosis regulators such as BCL2 keep damaged cells alive when overexpressed. DNA repair genes do not drive growth themselves; when they fail, mutations in the other three classes accumulate faster.

Five ways DNA damage changes a geneL7 p.15, 18

  • Point mutation

    What happens
    One base change alters the protein
    Lecture example
    RAS locked in its active GTP-bound form; RET, KIT

  • Balanced translocation

    What happens
    A gene is moved next to a strong enhancer, or two genes fuse
    Lecture example
    t(9;22) BCR–ABL, t(8;14) MYC, t(14;18) BCL2, t(11;14) cyclin D1

  • Amplification

    What happens
    Many copies of one gene
    Lecture example
    ERBB2 (HER2) in breast; MYCN in neuroblastoma; L-MYC in small cell carcinoma; CDK4 in melanoma

  • Deletion

    What happens
    A gene or chromosome segment is lost
    Lecture example
    Loss of the second RB1 or TP53 allele (the 'second hit')

  • Overexpression

    What happens
    Too much of a normal protein
    Lecture example
    PDGFB autocrine loop in astrocytoma; BCL2

Genes organized by what their proteins doL7 p.15, 18–20

  • Growth factor

    Gene
    PDGFB
    Change in cancer
    Overexpression (autocrine loop)
    Tumor
    Astrocytoma

  • Growth factor receptor

    Gene
    ERBB2 (HER2/neu)
    Change in cancer
    Amplification
    Tumor
    Subset of breast carcinomas

  • Growth factor receptor

    Gene
    RET
    Change in cancer
    Point mutation (germline in MEN 2)
    Tumor
    MEN 2A, 2B; medullary thyroid carcinoma

  • Growth factor receptor

    Gene
    KIT
    Change in cancer
    Point mutation
    Tumor
    Gastrointestinal stromal tumor

  • Signal transducer

    Gene
    RAS family
    Change in cancer
    Point mutation
    Tumor
    Carcinomas (pancreas, colon), melanoma, lymphoma

  • Signal transducer (tyrosine kinase)

    Gene
    ABL
    Change in cancer
    t(9;22) BCR–ABL fusion
    Tumor
    CML, some ALL

  • Nuclear transcription factor

    Gene
    c-MYC
    Change in cancer
    t(8;14) beside IgH
    Tumor
    Burkitt lymphoma

  • Nuclear transcription factor

    Gene
    MYCN / L-MYC
    Change in cancer
    Amplification
    Tumor
    Neuroblastoma / small cell lung carcinoma

  • Cell-cycle driver

    Gene
    Cyclin D1 (CCND1)
    Change in cancer
    t(11;14) beside IgH
    Tumor
    Mantle cell lymphoma

  • Cell-cycle driver

    Gene
    CDK4
    Change in cancer
    Amplification
    Tumor
    Melanoma

  • Cell-cycle brake (G1 → S)

    Gene
    RB (holds E2F)
    Change in cancer
    Loss of both alleles
    Tumor
    Retinoblastoma, osteosarcoma; breast, lung, colon

  • Cell-cycle brake and DNA-damage sensor

    Gene
    TP53 (induces p21)
    Change in cancer
    Loss of both alleles
    Tumor
    Li–Fraumeni; most human cancers

  • Cell-cycle brake (growth inhibitory signal)

    Gene
    TGF-β pathway
    Change in cancer
    Loss of signaling
    Tumor
    Pancreatic and colorectal carcinoma

  • Brake on a growth pathway

    Gene
    APC (degrades β-catenin)
    Change in cancer
    Loss → β-catenin reaches the nucleus
    Tumor
    FAP; colon and stomach cancer

  • Brake on a growth pathway

    Gene
    NF1 (neurofibromin, a RAS GTPase activator)
    Change in cancer
    Loss → RAS stays on
    Tumor
    Neurofibromatosis 1

  • Cytoskeletal stability

    Gene
    NF2 (merlin)
    Change in cancer
    Loss
    Tumor
    Schwannoma, meningioma (NF2)

  • Oxygen-sensing brake

    Gene
    VHL (degrades HIF)
    Change in cancer
    Loss → HIF and VEGF ↑
    Tumor
    Renal cell carcinoma, hemangioblastoma

  • Nuclear transcription (kidney development)

    Gene
    WT1
    Change in cancer
    Loss
    Tumor
    Wilms tumor

  • Apoptosis regulator

    Gene
    BCL2
    Change in cancer
    Overexpression, t(14;18)
    Tumor
    Follicular lymphoma

  • DNA repair (double-strand breaks)

    Gene
    BRCA1 / BRCA2
    Change in cancer
    Loss
    Tumor
    Breast, ovary (BRCA2: male breast)

  • DNA repair (base mismatches)

    Gene
    Mismatch repair genes
    Change in cancer
    Loss → microsatellite instability
    Tumor
    Lynch syndrome

  • DNA repair (UV pyrimidine dimers)

    Gene
    Nucleotide excision repair genes
    Change in cancer
    Loss
    Tumor
    Xeroderma pigmentosum

Read the table from left to right and the logic of cancer genes appears. Everything in the top half pushes a cell forward (growth signal → receptor → transducer → nucleus → cell cycle), and a gain of function at any step is enough. The middle rows are brakes placed along the same path; they must be lost on both alleles. The bottom rows do not touch growth directly: BCL2 keeps damaged cells alive and the repair genes decide how fast all the other mutations accumulate.

Translocations into the immunoglobulin heavy-chain locus on chromosome 14 are a recurring theme in B-cell tumors: the strongly active Ig enhancer drives whatever gene is moved next to it. In follicular lymphoma, t(14;18) places BCL2 (chromosome 18) beside IgH; B cells overexpress BCL2, cannot undergo apoptosis and accumulate.

No single mutation makes a cancer. The lecture's colon diagram shows the steps: a carcinogen (activated by the liver) initiates a crypt cell by mutating its DNA; promotion makes the initiated cell proliferate; conversion produces a benign adenomatous polyp; further mutations bring progression to an invasive carcinoma, whose subclones become invasive, metastatic and nonantigenic. Each step adds a mutation from the table above (for colon: APC, then RAS, then TP53).

Lecture slide

Lecture diagram: an ingested carcinogen is activated by the liver and initiates a colonic crypt cell; promotion, conversion to an adenomatous polyp, progression to invasive carcinoma, clonal expansion and liver metastases follow.
Initiation → promotion → conversion → progression in the colon. The tumor that finally metastasizes to the liver is a set of subclones descended from one initiated crypt cell. Section 7.5 shows how initiators and promoters differ.L7 p.9

The brakes: RB and p53

L7 p.19–20

Both classic tumor suppressors guard the same door: the transition from G1 to S phase, the point after which a cell is committed to copying its DNA.

Teaching schematic

RB: the G1 gate

  1. Growth factor → cyclin D + CDK4
  2. Cyclin D–CDK4 phosphorylates RB
  3. E2F released from RB
  4. S-phase genes transcribed → G1 → S

RB lost (or cyclin D / CDK4 overactive) → E2F permanently free → the gate never closes.

p53: the damage sensor

  1. DNA damage → p53 stabilized
  2. p21 inhibits CDKs → RB stays active → G1 arrest
  3. DNA repair enzymes ↑
  4. Repair fails → BAX/BAK over BCL2 → cytochrome c → apoptosis

p53 lost → no arrest, no extra repair, no apoptosis: the cell divides carrying its damage.

RB holds E2F until cyclin D–CDK4 phosphorylates it; p53 answers DNA damage by making p21 (which keeps RB active) and, if repair fails, by tipping BAX/BAK against BCL2 so the mitochondrion releases cytochrome c.L7 p.19

RB is the gatekeeper. In its hypophosphorylated form it binds the transcription factor E2F, which is needed to transcribe S-phase genes. Growth factor signals induce cyclin D, which activates CDK4; cyclin D–CDK4 phosphorylates RB, E2F is released and the cell enters S phase. Losing RB (or overactivating cyclin D or CDK4, both in the lecture's oncogene table) leaves E2F permanently free.

p53 is the guardian that responds to DNA damage. It slows the cell cycle by inducing p21, a CDK inhibitor that keeps RB hypophosphorylated; it upregulates DNA repair; and if the damage cannot be repaired it induces apoptosis, activating BAX and BAK and counteracting BCL2 so the mitochondrion releases cytochrome c. A cell without p53 keeps dividing with damaged DNA, and every division adds mutations. TP53 is the most frequently mutated gene in human cancer.

DNA damage has three possible outcomes

  1. DNA damage (radiation, carcinogen, replication error)
  2. p53 stabilized → arrest in G1 (p21)
  3. Repair succeeds → the cell resumes dividing
  4. Repair fails → apoptosis (BAX/BAK, cytochrome c)
  5. p53 lost → none of these: the cell divides with the damage and the mutation is passed on
L7 p.19

The two-hit hypothesis: retinoblastoma and Li–Fraumeni

L7 p.19

Knudson studied retinoblastoma, a malignant tumor of the infant retina, and noticed two patterns: some children had tumors in both eyes, early, and often had affected relatives; others had a single tumor in one eye, later, with no family history. He proposed that the tumor needs two hits, one to each copy of the same gene (RB1, chromosome 13q14).

Teaching schematic

Familial (germline first hit)

Every cell at birth

One RB1 allele is already mutated, in all cells of the body.

Any retinal cell

A single somatic hit completes it. Tumors are bilateral, often multifocal, and early.

Later risk of **osteosarcoma**. Dominant in the pedigree, recessive in the cell.

Sporadic (both hits somatic)

Every cell at birth

Both RB1 alleles are normal.

One retinal cell

Two independent hits must strike the same cell: rare, so one tumor, one eye, later.

No inherited risk of second tumors.

Familial cases inherit the first hit in every cell, so one somatic hit in any retinal cell is enough: tumors are bilateral, multiple and early. Sporadic cases need two somatic hits in the same cell: one tumor, one eye, later.L7 p.19

Familial retinoblastoma

  • Germline first hit in every cell; second hit somatic
  • Bilateral, often multifocal; earlier onset
  • Later osteosarcoma risk (and other sarcomas)
  • Autosomal dominant in the pedigree

Sporadic retinoblastoma

  • Both hits somatic, in the same retinal cell
  • Unilateral, single tumor; later onset
  • No inherited risk of second cancers
  • No family history
L7 p.19

Lecture image

Whole-mount section of an eye: a large, purple, cellular tumor fills much of the posterior globe behind the lens.
Retinoblastoma: a whole-mount section of an enucleated eye; a large, cellular, purple tumor fills much of the globe behind the lens. Leukocoria (a white pupillary reflex) is the usual presenting sign.L7 p.19

The same logic applies to TP53. A germline TP53 mutation causes Li–Fraumeni syndrome: one hit is inherited, the second is somatic, and carriers develop multiple carcinomas and sarcomas (breast carcinoma, brain tumors, leukemia, soft-tissue and bone sarcomas, adrenocortical carcinoma), often young and often more than one.

Core activity · The Missing Arrow

The Missing Arrow

Complete the causal chain. Place the missing step by dragging a card onto a gap, or tap a card and then tap the gap. Some gaps need an event; others need the mechanism that links one event to the next.

A child is born to a parent with familial retinoblastoma. Complete the chain from the inherited mutation to a tumor.

  2. the remaining normal allele still makes enough RB protein
  3. Retinal cells behave normally; the child is healthy at birth
  5. That cell has no functional RB protein
  7. Uncontrolled proliferation: retinoblastoma, often in both eyes and early
  8. the same inherited first hit is present in osteoblast precursors

Cards

Tap or drag a card. Placing a used card moves it.

Inherited cancer syndromes

L7 p.15, 20–21

Most inherited cancer syndromes are germline mutations of tumor suppressor or DNA repair genes. The family inherits one defective allele; each tumor arises when a cell loses the second. Recognize them by the pattern: young patients, multiple or bilateral tumors, the same cancer in relatives, and characteristic non-tumor signs.

Syndromes from the lectureL7 p.15, 20

  • Familial adenomatous polyposis

    Gene and normal function
    APC: degrades β-catenin, a nuclear transcription activator
    Tumors and clues
    Hundreds of colonic adenomas → colorectal carcinoma almost certain without colectomy

  • Lynch syndrome (HNPCC)

    Gene and normal function
    Mismatch repair genes: correct base-pairing errors
    Tumors and clues
    Colorectal (often right-sided, younger), endometrial, ovarian and gastric carcinoma; microsatellite instability

  • Hereditary breast–ovarian cancer

    Gene and normal function
    BRCA1/BRCA2: repair of DNA double-strand breaks
    Tumors and clues
    Breast and ovarian carcinoma; BRCA2 also male breast, prostate, pancreas

  • Li–Fraumeni

    Gene and normal function
    TP53
    Tumors and clues
    Sarcomas, breast, brain, leukemia, adrenocortical carcinoma

  • Familial retinoblastoma

    Gene and normal function
    RB1
    Tumors and clues
    Bilateral retinoblastoma, osteosarcoma

  • Neurofibromatosis 1

    Gene and normal function
    NF1 (neurofibromin): inhibits RAS signaling
    Tumors and clues
    Neurofibromas, café-au-lait macules, axillary freckling; pheochromocytoma; malignant nerve sheath tumors

  • Neurofibromatosis 2

    Gene and normal function
    NF2 (merlin): cytoskeletal stability
    Tumors and clues
    Bilateral vestibular (acoustic) schwannomas, meningiomas

  • von Hippel–Lindau

    Gene and normal function
    VHL: targets HIF for degradation
    Tumors and clues
    Bilateral renal cell carcinoma, cerebellar hemangioblastoma, retinal angioma, pheochromocytoma

  • WT1 syndromes

    Gene and normal function
    WT1: nuclear transcription
    Tumors and clues
    Wilms tumor

  • Xeroderma pigmentosum

    Gene and normal function
    Nucleotide excision repair: removes UV pyrimidine dimers
    Tumors and clues
    Skin cancers (BCC, SCC, melanoma) in childhood on sun-exposed skin

Lecture image

Four panels of skin: light-brown café-au-lait macules (A, D), axillary freckling (B), and many soft, flesh-colored cutaneous neurofibromas on the back (C).
Neurofibromatosis type 1: café-au-lait macules (A, D), axillary freckling (B) and many soft cutaneous neurofibromas (C). Without neurofibromin, RAS stays active in Schwann cells and melanocytes.L7 p.21

Lecture image

Axial contrast MRI of the posterior fossa: two bright, enhancing masses at both cerebellopontine angles.
Neurofibromatosis type 2: MRI with enhancing masses at both cerebellopontine angles, bilateral vestibular schwannomas.L7 p.21

Knowledge check · 7.4

Answer, read why, and try again whenever you like. Answers are kept in both study modes.

0 of 6 correct
  1. Q1Two-hit hypothesisL7 p.19

    An 8-month-old girl has a white pupillary reflex in both eyes. Examination shows several retinal tumors in each eye.

    Whole-mount section of an eye: a large, purple, cellular tumor fills much of the posterior globe behind the lens.

    Which statement best explains her disease and her future risk?

  2. Q2BCL2 t(14;18)L7 p.15

    A 58-year-old man has generalized painless lymphadenopathy. A node shows a follicular pattern of neoplastic B cells; cytogenetics shows t(14;18).

    How does this translocation promote the tumor?

  3. Q3Lynch syndromeL7 p.15, 20

    A 38-year-old woman has a carcinoma of the right colon. Her mother had endometrial carcinoma at 45 and her uncle colon cancer at 40. The tumor shows microsatellite instability.

    Which gene class is most likely defective?

  4. Q4NF1 and RASL7 p.20–21

    A 19-year-old man has the skin findings shown: light-brown macules on the trunk, freckling in the axilla and many soft cutaneous nodules.

    Four panels of skin: light-brown café-au-lait macules (A, D), axillary freckling (B), and many soft, flesh-colored cutaneous neurofibromas on the back (C).

    Loss of which protein's function underlies these lesions, and what does that protein normally do?

  5. Q5Li–Fraumeni syndromeL7 p.19–20

    A 29-year-old woman has breast carcinoma. She had a rhabdomyosarcoma at 6; her brother died of a brain tumor at 22; her mother had an adrenocortical carcinoma.

    A germline mutation in which gene is most likely?

  6. Q6Screening: adenoma removalL7 p.9, 14

    Why does removing colonic adenomas at colonoscopy reduce deaths from colorectal cancer?

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