Genetics and Cancer

What causes cancer?

Cancer

• A genetic disease at the somatic cell level

• A disease of mosaicism largely caused by post-zygotic mutation

• Heterogenous

Driver mutations

• Mutations that drive carcinogenesis

• Two classes - oncogenes and tumour suppressors

Passenger mutations

• Incidental mutations that happen because the tumour is unstable

Epigenetics

• The study of changes in gene expression without a change in DNA sequence
• DNA methylation
• Interaction with histone proteins

DNA methylation

• Usually occurs on cytosine bases just before guanine bases

• Prevents transcription (leads to modification of histones)

• Deficient DNA repair genes or tumour suppressor genes due to hypermethylation → cancer

Oncogenes

• Produce their own extracellular growth factors

• Overexpress growth factor receptors

• Have constitutionally active proteins that do not require phosphorylation

Activation

• Activated from proto-oncogenes due to dominant gain of function mutations

• Activated by:

• BRAF: codes for a Raf Kinase protein involved in MAP-K signal pathway

• Point mutation removes the need for phosphorylation - signal is always on

• Vemurafenib - BRAF inhibitor HOWEVER easily overcome due to multiple activation pathways for Raf kinase

• e.g. HER2 in breast cancer: amplification results in too many HER2 receptors → increased signal for proliferation
• Trastuzumab binds to HER2 receptors, blocking proliferation signal

• Philadelphia chromosome: translocation which produces a hyperactive fusion protein (BCR-ABL)

• Imatinib fixes BCR-ABL protein closed - non-functional

Tumour suppressors

• Genes whose loss (deletions, point mutations) results in carcinogenesis

Retinoblastoma

• pRB - functions at G1 checkpoint

• Mutation in RB gene → loss of function of pRB → retinoblastoma

Two-hit hypothesis

• Mutation of both alleles necessary to inactivate tumour suppressor genes

• The reason cancers are often associated with old age - mutation rates are slow so over a longer time, increased chance of two 'hits'

DNA repair

Oncogenic signature

• Characteristic of a cancer is determined by its driver mutations

• Cancer cells gain a high level of mutability - promotes evolution of cancers

Mismatch repair complex

• Lynch syndrome: hereditary form of cancer due to mutation in mismatch repair gene

Cancer risk

• Usually multifactorial - rarely purely genetic

Features which indicate inherited cancer susceptibility

• Several first/second degree relatives with cancer

• Several close relatives with related cancers

• Unusually early onset

• Bilateral tumours in paired organs

• Tumours in two organ systems in one individual