Lecture 5. Uncovering the cancer genome
Cancer is a common complex disease, caused by a mix of the environment and genetics.
Hereditary cancers are rare types of cancers that account for 5 to 10% of all cancer cases.
Examples include the autosomal dominant Lynch syndrome which is associates with an
increased risk of colorectal cancer and the autosomal recessive Fanconi Anaemia which
increases the risk of leukaemia. Sporadic cancer patients have no significant family history of
the same cancer, such as first degree relatives of cancer patients have a 2 to 4 fold increase
of getting the same cancer. Mutations increases genomic instability such as if the other copy
of the same gene acquires a mutation then cancer develops, the increased cellular genomic
instability also increases the risk of developing cancer.
An example of inherited condition, conferring high risks of cancer, is the autosomal recessive
Ataxia Telangiectasia. Mutations in the gene ATM, a DNA repair gene, cause AT. ATM
mutations that cause AT in biallelic carriers are breast cancer susceptibility alleles in
monoallelic carriers. Additionally, to ATM, carriers of CHEK2 and PALB2 mutations were
significantly high in breast cancer patients. Carriers of PALB2 mutations have a 40% risk of
developing breast cancer, whereas the risk in the general population is 15%. These mutations
in DNA repair genes are however not common, therefore it does not help account for all
genetic risk in people negative for these mutations. Certain alleles are associated with cancer
development, together, these alleles increase cancer susceptibility. These low penetrance
alleles are common and only confer high risk when added up. Rare, high penetrance risk
alleles, such as pathogenic variants of TP53 and BRCA1, are cancer susceptibility genes and
highly increase cancer risk .
Genetic linkage studies and exome sequencing were successful methods to identify
susceptibility genes in family cancers but are not useful in screening the general population.
In the past, looking at the DNA sequence in affected individuals, directly, only allowed to study
one gene at a time. Since then, systemic genome wide association studies (GWAS) in 2006-
2007 allowed to study common diseases. GWAS collected DNA from 1000s of disease cases
and controls. This study allowed to genotype DNA on SNP arrays of 1 million SNPs. The SNPs
