cancer genetics

week 10 stibs

normal oncogenes: promote cell division and proliferation

mutated: gain of function mutations

• qualitative or quantitative

• increase in growth factors and receptors

• increase in signal transduction

• only one allele needs to be mutated

normal tumour suppressor genes:

• suppress growth signal

• induce apoptosis

• response to DNA damage

• cell-cycle regulated

mutated TSGs : loss of function

• inactivation by mutagenesis leads to increased proliferation

• deregulated growth signal

• recessive

organisation of tissues is critical to minimising somatic mutation

• longer lived cells: protected from damage via their positioning in tissue

• short lived cells: vulnerable to damage but fairly rapidly discarded

genetics of tumourigenesis: colon tumour progression

1. LOH (loss of heterozygosity)

2. chromosomal regions with LOH contain within them tumour suppressor genes whose loss proves a growth advantage to evolving pre-neoplastic colonic epithelial cells

3. oncogenes are overexpressed by genetic amplification or loss of repression to accelerate growth of cells

family adenomatous polyposis

• mutation of APC gene usually resulting in a truncated protein

• genetic diagnosis in family will definitely influence management

• colectomy in late teens advised for those who carry mutation

key points

• cell cycle tightly controlled by cyclins/CDKS

• cell cycle deregulated in cancer

• genetics

  • breaks in tumour suppressor genes

  • oncogenes (accelerators)

• cancer is multistep process

  • inherited syndromes

  • somatic cancer

  • LOH

causes of mutations

• carcinogens

  • xenobiotics

  • pollutants

  • cells attempting to detoxify mutagenic compounds

• chronic inflammatory processes

  • free radicals (damage DNA)
    derived from process of oxidative phosphorylation

how mutations occur

• accumulated mutations can be as a result of mis incorporated bases generated by errors in DNA replication

• single base pair substitutions account for majority of errors

• DNA polymerases have a low error rate

• array of proteins which correct errors

• defects in mismatch repair proteins can lead to increased susceptibility to certain cancers

classes of genome repair and damage

1. damage to nucleotides

2. damage to DNA strands

3. damage to chromosomal structure

4. changes in chromosome number

damage to nucleotides

1. network of proteins involved in base excision repair or nucleotide excision repair or nucleotide excision repair to remove majority of damaged bases

damage to DNA strands

• can be repaired in G1 phase by non-homologous end joining

• can be repaired in S or g2 phases by homology-dependent repair

• individuals with mutant BRCA1 or BRCA2 alleles (key genes have increased susceptibility to breast and ovarian cancer)

damage to chromosomal structure

• translocations created by fusion of unrelated chromosomal arms to one another

• can be triggered by eroded telomeres or unrepaired double strand DNA breaks

changes in chromosome number

• common in cancer cell genomes

• changes in no. may facilitate the accumulation of genes that proliferation and survival of neoplastic cells is augmented

• many of changes are derived from defects in mitotic apparatus

cancer from medical genetics perspective

• inherited mutations that predispose to cancer are transmitted as autosomal dominant traits

• cancer is recessive at cellular level

• most mutations are acquired by environmental insult or by chance

factors indicative of hereditary cancers

• combination of cancer types in family

• occurs at young age

• multiple tumours or bilateral tumours in paired organs

• autosomal dominant pattern or inheritance

• contributing factors absent

breast cancer

• 1 in 8 risk

• most common cancer

• 10% cases are familial

• BRCA1 and BRCA2 mutations account for 50% of cases

BRCA1

• BRCA1= breast cancer susceptibility gene

• very large gene located on 17q12-21

• tumour suppressor gene involved in double stranded DNA breaks

• associated with RNA polymerase II and interacts with histone deacetylase complexes

BRCA2

• part of double strand break repair complex

• stimulated strand invasion with RAD51 leading to homologous recombination

criteria for BRCA1/2 DNA testing

• diagnosis at 45

• multiple primary tumours or bilateral disease

• first degree relative diagnosed at 45

genetic testing changes management in women with breast cancer

• increased surveillance contralateral breast

• consider prophylactic mastectomy

• increased surveillance for ovarian cancer

• oophorectomy

how genetic testing changes management for healthy women with fam history of disease

• psychological relief

• lifestyle decisions

• increase surveillance for breast and ovarian cancers

prevention strategies for known BRCA1/2 mutation carriers

• annual mammogram

• clinical breast exam

• chemoprevention

• prophylactic oophorectomy

• hormone replacement therapy

limitations of DNA testing

• genetic tests assay DNA sequence variation

• cannot be sure that variant is clinically significant

• negative BRCA1/2 test doesn’t rule out unidentified familial mutation