Cancer genetics

Cancer genetics

“all cancer is genetic, but some cancers are more genetic than others”

“cancer runs in families”

Cancer genetics

acquired somatic genetic diseases95% of all casessomatic mutation mostly caused by environmental factors

hereditary cancer5% of all cases

susceptibility/major genesgermline mutation

Differentiation between genetic and environmental factors in cancer

1. epidemiological study:breast cancer

association with reproduction and menstruation having children vs. nulliparous first menstrual age: early vs. late indicative in genetic vs. environment

incidence highest in European origin populations

8 times lower in Chinese, Japanese indicating genetic component

migration migration from low to high incidence areas:

increased incidence indicating environmental factors

Differentiation between genetic and environmental factors in cancer

2. family studybreast cancer incidence

risk 1.5-3 folds than general population, if having one 1st degree relative patientgastric cancer

risk 2-3 folds than general population if one 1st degree relative patient liability curve

3. twin studyconcordance rates for breast cancer

monozygotic twins: 17%dizygotic twins: 13%indicating importance of environment

Differentiation between genetic and environmental factors in cancer

4. association studyblood group A people have an 20% increased

risk for gastric cancer over the general population

5. animal models

6. viral factorsDNA viruses: table 14.1, p198retroviruses:

RNA – DNA (reverse transcriptase) – integration into host genome

Oncogenes

concept proto - oncogen

normal cellular geneshave key roles in cell growth and differentiationhave the potential to be tumorogenic

oncogeneconverted from proto – oncogenehas tumorogenic (carcinogenic) effects

cellular oncogene (C-oncogene)cellular origin has tumorogenic (carcinogenic) function

viral oncogene (V-oncogene)viral origin has tumorogenic (carcinogenic) property

Oncogenes identification of oncogenes

1. at chromosomal translocation breakpoints Philadelphia chromosome:

Fig in Li Pu’s book Burketts lymphoma chromosome:

Fig in Li Pu’s book

2. amplification of oncogenes 10,000, or 1,000 folds of increased gene copies ERBB2 gene copy number increased 20% in breast cancer cases MYC gene copy number increased 30% neuroblastoma cases

Philadelphia chromosome

Burketts lymphoma gene

OncogenesTypes of oncogens

growth factor: v-SIS gene: codes for part of platelet-derived growth factorHST: homologous of fibroblast growth factor

growth factor receptors:ERB-B: epidermal growth factor receptor

intracellular signal transduction factors:proteins with GTPase activities RAS genescytoplasmic serine threonine kinases RAF gene

DNA-binding nuclear proteins:transcription factors FOS, JUN

cell cycle genes:loss of cell cycle inhibitory genes cyclin-dependent kinases

cyclin D1loss of genes lead to apoptosis

Tumor suppressor genes RB1 and retinoblastoma

retinoblastoma phenotype: Fig

hereditary non-hereditary two-hint theory:

Fig loss of heterozygosity (LOH)

Fig 14.7, p204table 14.2, p205

TP53 and Li-Fraumeini syndrome

TP53: the most mutated tumor suppressor genes

in cancer checkpoint control of G1-> S

Li-Fraumeini syndrome: phenotype: familial cancer

multiple organ cancers TP53 somatic and germ-line mutations

familial cancer due to tumor suppressor gene mutation table 14.3, p208

Tumor suppressor genes

Epigenetics and cancer

epigenetics

1. concept heritable changes to gene expression that are not due to difference in gene code

(DNA sequence), transmitted either through mitosis or meiosis

2. rolesimprinting

• the phenomenon of a gene or a region of a chromosome showing differential expression depending on the parent of origin.Fig 7.22

X-inactivationregulation of gene expression

Prader-Willi and Angelman syndrome genes

Epigenetics and cancer

3. mechanisms of epigenetics

re-imprinting in gamatogenesis methylation of DNA sequences

reduced expressionmaintain genome stability

chromatin remodeling (histone modification)condensed or loosened super-coil structures

changes in transcriptional activity of sex genes during development

4. epigenetics in cancers

hypomethylation of oncogeneshypermethylation of tumor suppressor genes

Telomere length and cancer

telomere: chromosomal ends

tandem repeats: TTAGGG for 10-15 Kb

length maintained by telomerase

shortened telomere in cancer

aging

Fig 14.9

Telomere length and cancer

Genetics of common cancers

colorectal cancer

1. multistage hypothesis of carcinogenesis

Fig 14.10

multistage hypothesis of carcinogenesis

Multistage (multistep) theory

Genetics of common cancers

colorectal cancer

2. familial adenomatous polypsis (FAP)

phenotype: Figs x 2

genetics: autosomal dominant

APC gene

treatment: prophylactic colectomy

hereditary familial adenomatous polyposis

Colorectal cancer

3. hereditary non-polypsis colorectal cancer (HNPCC)phenotype: less polyps

site specific: proximalright

genetics: autosomal dominant gene: DNA mismatch repair genes

table 14.4 microsatellite instability (MSI)

(replication error) somatic or germline

Breast cancer

1. incidence in west:

1 in 12 women aged 40-55

1 in 3 will be metastatic

2. genetics (somatic form):

cumulative changes

amplification: ERB-B1ERB-B2

LOH: 7q, 16q, 13q, 17p, etc

Fig 14.7

Breast cancer

3. familial breast cancer

(1) autosomal dominant

(2) BRCA1: chr 17

mutations in 40-50% early onset families

lifetime risk for family members:

60-85%

if having the mutation

increased risk for : ovarian cancer in female prostate cancer in male

Breast cancer

(3) BRCA2, chr 13 30-40% early onset autosomal dominant families

female mutations carrierslifetime risk for family member as BRCA1

heterozygotes: increased risk of ovarian cancer

male mutations carriers 6% lifetime risk for breast cancer, which is

100 - fold increased risk in comparison with the general population

Genetic counseling in familial cancer

inherited cancer-predisposing syndrome

individual has more than one site cancers or at

different sites in various individuals of a family

than would be expected

box 4.1

risk estimation

table 14.6, 14.7

Risk estimation

Genetic counseling in familial cancer

screening for familial cancer phenotype screening

genotype screening

treatment prophylactic medications: Asprin in FAP

tamoxifen for breast cancer

(anti - estrogen) life style change prophylactic surgery: table 14.9