Cancer genetics

General historical steps in investigating cancer genetics

1. First published scientific work on pedigree analysis of cancer families (Broca P.P., 1869). Introduction of term Altered heredity.

2. Proving hereditary nature of the cancer. Mendelian variants of cancer (30-40 years of XX century). 3. Theory of multistage process of the cancer (Knudson A.L., Strong L.C., 1972). Twohit hypothesis of carcinogenesis.

Pedigree of the Bonaparte family

Napoleon, his father, grandfather, brother and four sisters all died of stomach cancer.

General historical steps in investigating cancer genetics

4. Perfection of cytogenetic methods: developing the differential staining of chromosomes to study the genetic background of cancer (70-80 years). -studying genetic origin of chronic myeloid leukemia: t (9/22), del 9q34; - Studying genetic origin of inherited retinoblastoma: 13q.

CHROMOSOMAL ABNORMALITIES ASSOCIATED WITH HUMAN CANCERS

Chronic myeloid leukemia

Philadelphia chromosome in the leukocyte nucleus (at the left) and at the metaphase plate (at the right) / FISH-method

General historical steps in investigating cancer genetics

5. Application of molecular biology tools to the investigation of genetic mechanisms of cancer (80-90 years).
- Dissecting monogenic and polygenic variants of malignant tumors; - Discovering of oncogenes and tumorsuppressors; -Investigating molecular mechanisms of DNA repair defects; - Studying DNA methylation level; - Discovering of xenobiotic metabolizing genes; - Mapping human genome.

Why is cancer different from other common diseases?

There are very few cancers with non-Mendelian inheritance, but which have large sib relative risks (unless stratified by age)

Common cancers (such as those of the colon, breast, or bronchus) are usually late onset and the parents of patients (even those who present "early") are often dead.
Many cancers are fatal, making samples difficult to obtain retrospectively and even contemporaneously.

Why is cancer different from other common diseases?

Not only does cancer require particular combinations of genes and environment (like other diseases), but it also has a truly random component in that several somatic mutations must occur for a carcinoma or sarcoma to develop. The challenge of discovering genes mutated somatically in cancer, but with no germline effects, has been a worthy distraction for the geneticist from the task of studying cancer as a complex genetic disease.

 Twohit hypothesis of carcinogenesis

Germ line mutation (1st event)

Increasing the sensitivity of somatic cell to environmental cancerogenes

Acquisition of somatic mutation (2nd event)

A model for the multi-step development of colon cancer

Four ways of activating proto-oncogenes

1. Activation by amplification.
2. Activation by point mutation.

3. Activation by a translocation that creates a novel chimeric gene.

4. Activation by translocation into a transcriptionally active chromatin region.

General classes of the genes involved to carcinogenesis

Genes regulating cell cycle Genes of common control

Cancer

General classes of the genes involved to carcinogenesis

Genes regulating cell cycle
Germ line mutations affect on the genes regulating cell cycle (first mutational event). For development of cancer the second mutation in normal allele should arise (point mutation, loss or inactivation of normal allele.

General classes of the genes involved to carcinogenesis

Genes of common control
Genes support the genome instability by affecting DNA reparative processes (multi-stage process). One dose of mutation (single allele mutation) does not lead to a cell transformation. Inactivation of second allele of the same gene leads to an instability of genes of the cell thereby predisposing to the carcinogenesis. Subsequent mutations including within genes regulating cell cycle accumulate and by that invoke malignancy.

Ways for the genetic induction of carcinogenesis

1. Way of suppressors.
More 20 genes-suppressors have been described in literature. These genes do control the mitogenic capacity of cells via their protein products which support both normal growth and differentiation of cells.

Ways for the genetic induction of carcinogenesis

2. Way of proto-oncogenes.
About 100 proto-oncogenes have been described. These genes are normal genes controlling the proliferation rate and intercellular signal transduction. Their mutations lead to transformation of protooncogenes into oncogenes which disregulates the processes of cell division and differentiation.

Ways for the genetic induction of carcinogenesis

3. Way of abnormal DNA reparation.
Genes involved in reparation of DNA defects may be responsible for genome instability and carcinogenesis. The products of these genes recognize and repair DNA damages before division of the cell.

Ways for the genetic induction of carcinogenesis

4. Involvement of chemical detoxifying system in carcinogenesis.
Xenobiotic metabolizing enzymes play a crucial role in the metabolism of carcinogens. Mutant alleles in xenobiotic metabolizing enzymes increase a sensitivity of tissues to environmental cancerogenes.

Main phases of detoxification

Phase I Phase II Phase III

Metabolic activation of xenobiotics and accumulation of carcinogenic intermediates

Detoxification of active carcinogenic intermediates into non-cancerogenic substances

Excretion of inactivated substances from organism

Oxidative stress, carcinogenesis

Etiological classification of tumors

1. Inherited variants of tumors in which single gene mutation is responsible for disease (Mendelian cancers) 2. Multifactorial variants of tumors resulted due to combined effects of genetic and environmental factors.

Etiological classification of tumors

3. Tumors arising due to spontaneous mutations in somatic cells under usual physiological conditions without additional effects of environment.

4. Tumors arising due to actions of environmental mutagenes and cancerogenes (chemical, physical, biological)

Mendelian cancers

Nephroblastoma

Nephroblastoma
Prevalence: 1 : 8000-10000 Onset: 10-12 years Etiology: inactivation of supressor gene WT1 Genetic variants: 40% patients germ line mutations with autosomal dominant type of inheritance; 60% patients somatic cell mutations (de novo) which are not inherited.

Nephroblastoma
Criterions of inherited nephroblastoma

1. Bilateral affections of kidneys 2. Polyfocal affections in kidneys

3. At least one affected by nephroblastoma relative in the family.

Nephroblastoma

Giant nephroblastoma in five years' boy

Nephroblastoma

Nephroblastoma (at the Large nephroblastoma (at right) survey abdominal the left) on a computer roentgenogram tomogram

Retinoblastoma

Large retinoblastoma in a vitreous anucleated eye

Retinoblastoma
Prevalence: 1 : 10000-15000
Onset: usually during first year of life.

Etiology: germ line mutation (deletion 12q13) in RB1 gene (1st event), somatic cell mutation (inactivation of second allele of RB1 gene in retina.
Inheritance: autosomal-dominant with 90% penetrance.

Retinoblastoma

Retinoblastoma

Neuroblastoma

Large neuroblastoma (to the left of spine, thoracal part) on a computer tomogram

Neuroblastoma
Prevalence: 1 : 8000-10000 (10% malignant tumors among children) Etiology: Inactivation of supressor gene at 113. Genetic variants: 30% patients germ line mutations with autosomal dominant type of inheritance; 70% patients somatic cell mutations (de novo) which are not inherited.

Melanoma

Prevalence: 3% of malignant tumors among children

Etiology: unknown, some cases arise due to mutation of supressor gene CDKN2A (p16)

Melanoma

Melanoma on the skin

Melanoma

Melanoma on the face

Melanoma

Melanoma on the foot

Melanoma

Melanoma on the foot

Melanoma

Melanoma at the mouth and tongue

Melanoma

Melanosis (multiple melanomas) of the left leg