Lecture 15: Cancer Predisposition

Cancer

A genetic disease triggered by mutations in tumor suppressors and oncogenes.

Characteristics of cancer cells

grow in absence of signals telling them to grow

ignore signals that tell cells to stop dividing or to enter apoptosis

invade into nearby areas and spread (metastasis)

encourage formation of new blood vessels to feed themselves

grow progressively more abnormal at genetic level, evolve

find ways to evade immune system

origin of cancer causing mutations (3)

damage to DNA by mutagens

inherited from parents

mistake during S phase

Somatic mutations

arise in cell after zygote is formed

only present in subset of cells

high somatic mutation rate increases risk of cancer

Germline mutations

variant is present in fertilized egg

mutation will be present in every cell of body

Germline mutation location

A somatic mutation must occur in the ovaries or testes of a parent to produce a child with a germline mutation.

Tumour micro-environment

Non-tumour cells and the extracellular matrix that surrounds tumour

Neurofibromatosis 1 (NF1)

caused by LOF in NF1 protein

dominant inheritance pattern

heterozygous phenotype is variable

somatic mutatoin in WT copy is required for neurofibroma formation

Cell types transformed by NF1 mutations

Melanocytes and Schwann cells

Tumor supressor

Normally acts as cellular brakes to slow or pause cell growth.

Oncogene

Encodes a protein that normally promotes cell growth

Features of hereditary cancer

positive family history

occurrence of multiple tumors in one individual (mutation in all cells)

early onset of tumors

Why is hereditary cancer syndrome caused by mutations in tumor suppressors?

Tumor suppressors have LOF mutations - can be inherited as heterozygous mutations
Oncogneic mutations are typically dominant - disrupt essential processes related to proliferation and survival → not passed on

MAPK nuclear signaling

Stimulates growth and division in cells

RAS → RAF → MEK → ERK

Final step: ERK, when phosphorylated, goes into the nucleus to bind DNA.

How to increase MAPK signalling

Increase ligand expression
Loss of function mutation in NF1
Gain of function mutation in RAS
Gain of function mutation in RAF

Ectoderm

differentiates into skin, neural crest derived cells, nervous tissue

Endoderm

forms epithelial tissues that line organ system like the gastrointestinal tract and urinary systemMes

Mesoderm

differentiates into dermis, muscle, connective tissue, bone, kidney, gonad and some blood cells

Axial mesoderm

makes notochord

Paraxial mesoderm

makes somites

Intermediate mesoderm

Makes gonads and kidneys

Lateral mesoderm

Makes ventral dermis, limb buds, cardiovascular organs, blood cells