GENETIC AND CANCER

DECEMBER 2013K. ETEMADI

CANCER GENETICS

All cancer is a genetic disease of somatic cells because of aberrant cell division or loss of normal programmed cell death, but a small proportion is strongly predisposed by inherited germ line mutations behaving as Mendelian traits. This does not contradict our traditional understanding that for many cancers environmental factors are of primary etiological importance, whilst heredity seems to play little or no part.

As a general principle it is now clear that cancers arise as the end result of an accumulation of both inherited and somatic mutations in proto-oncogenes and tumor suppressor genes.

Differentiation between Genetic and environmental factors in cancer

Epidemiologic studies Family studies Twin studies Disease association Viral factors

VirusesViruses—mostly in the form of DNA viruses—have been causally linked to cancer.

human papillomaviruses—primarily types 16 and 18, which are sexually transmitted—have been linked to cervical cancer;

more than 25 other types of papillomaviruses have been linked to cancer as well

hepatitis B and C—linked to cancer of the liver human immunodeficiency virus (HIV)—linked

to sarcoma and lymphoma retroviruses—linked to cancers in animals

other than humans

Cancer terminology

Benign tumours are generally slow growing and enclosed in a fibrous

capsule are relatively innocuous, although their location can

make them serious (such as a tumour located in the brain)

are not considered cancerous (that is, they are not malignant)

Malignant tumours proliferate rapidly, invading neighbouring tissues can metastasise, or spread, to other sites of the body are named using the conventions of tissue, cell type,

and origin

e.g. A tumour of the bone is an osteoma if benign and an osteosarcoma if malignant

Cancer terminology

Classification by tissue type: carcinoma

epithelial Tissue (Intestine,Bronchi,mammary ducts) 90% of all tumours

derived from ectoderm (mostly) or endoderm (some)

sarcomaMesenchymal tissue(Bone,muscle,or conective tissue)

2% of all tumoursderived from mesoderm

leukaemiacirculatory or lymphatic8% of all tumoursderived from mesoderm

Types of genes which may mutate to cause cancer:

Tumour suppressor genes Proto oncogenes Telomerase

Tumour suppressor genes

The gene’s normal function is to regulate cell division. Both alleles need to be mutated or removed in order to lose the gene activity.

The first mutation may be inherited or somatic. The second mutation will often be a gross event

leading to loss of heterozygosity in the surrounding area.

Retinoblastoma

Retinoblastoma (RB) is a malignant tumor of the developing retina that occurs in children, usually before the age of five years.

All forms of retinoblastoma represent a mutation in the gene RB1 located in in the region 13q14.1-q14.2.

The gene is about 180 kb in length with 27 exons that code for a transcript of only 4.7 kb.

individual mutations are heterogeneous: 20% are deletions larger than 1kb; 30% are small deletions or insertions; 45% are point mutations.

mutations have been found in 25 of the 27 coding exons and in promoter elements.

(mean of less than 2 tumor foci)

CANCER GENETICS - TUMOR SUPPRESSOR GENES

RETINOBLASTOMARetinoblastoma (Rb) is a relatively rare, highly malignant childhood cancer of the developing retinal cells of the eye that usually occurs before the age of 5 years. Rb can occur either sporadically (non-hereditary form, ussually involve only one eye), or be familial (hereditary form, more commonly bilateral), which is inherited in an AD manner, and also tend to present at an earlier age. ‘Two-hit’ hypothesis – in 1971, Knudson proposed, that affected individuals with a positive family history had inherited one non-functional gene that was present in all cells of the individual (germline mutation), with the second gene at the same locus becoming inactivated somatically in a developing retinal cell. The second mutation was likely given the large number of retinal cells, explaining the AD patterns. It was recognized by

cytogenetic analysis of blood samples that about 5% children revealed also interstitial deletion on chromosome 13 (13q14). Tumor material of these children with Rb showed the loss of an allele at the Rb locus – what is known as loss of heterozygosity (LOH). LOH can occur through several mechanisms (loss of a chromosome,a deletion, cross-over between the two homologous genes leading to homozygosity for the mutant allele.In contrast, in the non-heritable form, two inactivating somatic mutations would need to occur independently in the same retinoblast. The Rb tumor will only occur when both RB1 genes are mutated.

Knudsen’s “two hit” hypothesis

Two hit hypothesisAll cells in the hereditary form have one mutated copy of the gene RB1,i.e. the mutation is in the germline.

Two-hit hypothesisIn the non-hereditary form a mutation in RB1 gene arises as a post-zygotic (somatic) event sometime early in development.

© 2005 Elsevier

Section of an eye shoving a retinoblastoma in situ.

p53

suppresses progression through the cell cycle in response to DNA damage

initiates apoptosis if the damage to the cell is severe

acts as a tumour suppressor is a transcription factor and once

activated, it represses transcription of one set of genes (several of which are involved in stimulating cell growth) while stimulating expression of other genes involved in cell cycle control

Tumor suppressor Genes in Autosomal dominant cancer syndrome

Li-Fraumeni Syndrome Retinoblastoma Neurofibromatosis,type1 Familial breast cancer due to mutation in BRCA1

and BRCA2

Gene locations that Causes Heriditary Cancers

Early onset familial breast cancer 17q Familial adenomatous polyposis 5q Retinoblastoma – Rb gene 13q Familial melanoma 9p Li- Fraumeni syndrome 17p Wilms tumor 11p

Li- Fraumeni Syndrome

As mutation in Tp53 appear to be a common event in the genetic of many cancers,an inherited or germline mutation of Tp53 woud be expected to have serious consequences.Members of families with this rare syndrome that inherited as an AD trait,are highly susceptible to developing a variety of malignancy at a early age.Point mutations in highly conserved region of the Tp53 gene identified in the germ line of family members

CANCER GENETICS - ONCOGENES

ONCOGENESOncogenes are the altered forms of normal genes – proto-oncogenes –that have key roles in cell growth and differentiation pathways. In normal mammalian cells there are sequences of DNA that are homologous to viral oncogenes, and it is these that are named proto-oncogenes or cellular oncogenes. Although the terms proto-oncogene and cellular oncogene are often used interchangeably, strictly speaking proto-oncogene is reserved for the normal gene and cellular oncogene, or c-onc, refers to a Mutated proto-oncogene, which has oncogenic properties like the viral oncogenes, or v-onc. Some 30 oncogenes have been identified. IDENTIFICATION OF ONCOGENESChromosome aberrations are common in malignant cells (variation in chromosome number and structure). Certain chromosomes seem to be more commonly involved. It has been found that chromosomal translocation can lead to novel chimeric genes with altered biochemical function or level of proto-oncogene activity.

Activation of oncoges by chromosome translocation

Chronic Myelogenous Leukemia Burkitt Lymphoma Acute lymphoblastic leukemia Acute lymphocytic leukemia Acute Promyelocytictic leukemia

CANCER GENETICS

Chronic myeloid leukemia(CML)In 1960, investigators in Philadelphia were the first to describe an abnormal chromosome(Ph1) in white blood cells from patients with Cml. The abnormal chromosome was found in blood or bone marrow cells but not in other tissues from these patients. The Ph1 is a tiny chromosome – now known to be a chromosome 22, from which material from the long arm has been reciprocally translocated to and from the long arm of chromosome 9 i.e. t(9;22)(q34;q11). This chromosomal rearrangement is seen in 90% ofpersons with Cml. This translocation has been found to transfer cellular ABL(Abelson) oncogene from chromosome 9 into a region of chromosome 22 known as the break-point cluster, or BCR, region, resulting in a chimeric transcript derived from both the c-ABL (70%) and the BCR genes. This results in a chimeric gene expressing a fusion protein (with transforming activity) consisting of the BCR protein at the amino end and ABL protein at the carboxy end.

The "Philadelphia chromosome"

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© 2005 Elsevier

Karyotype from a patient with Cml, showing the chromosome 22(arrowed) or Philadelphia chromosome that has material translocated to the long arm of one of the number 9 chromosome (arrowed).

Cytogenetic change in cancer(colorectal)

Cancer karyotype Stable karyotype

EPIGENETIC and CANCER

GENETIC OF COMMON CANCER

It is estimated that about 5% of colorectal and breast cancers arise as a result of an inherited cancer susceptibility gene. A similar proportion of many other cancers are due to inherited predisposing genetic factors. But there are some notable exceptions, where only very low incidences of dominantly inherited carcinomas are recorded These include the lung and cervix, leukemias, lymphomas. Here external agents or stimuli are presumably the main factors.

Multi-step Theory

Stage of initiation Latent stage Stage of promotion Stage of malignant transformation

Transformation is a multistep process

Amodel for the step production of colon cancer

Colorectal Cancer

11% of cancer-related deaths

Tumor progression may take 10-35 years

Adenomatous polyp develops into carcinoma

Number of Mutation Associated with Some Cancers

Cancer Chr. Site No. of Mutation Required

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Retinoblastoma 13q 2

Wilms Tumor 11p 2 Colon Cancer 5p, 12p, 17p, 18q 4- 5

Small- Cell Lung 3p, 11p, 13q, 17p 10- 15 Cancer

GENETICS OF COMMON CANCERS BREST CANCER

BREAST CANCER is the most common cancer in women between 40 and 55 years of age. Fifteen to 20% of women who develop breast cancer have a family history of the disorde

Approximately 40-50% of families with early-onset autosomal dominant breast cancer have a mutation in the BRCA1 gene (chrom.17q). A mutation in the BRCA1 gene also increases risk of developing bowel cancer, ovarian cancer and prostate cancer.

Mutations in the BRCA2 gene account for 30-40% of families with early-onset AD breast cancer, but were not thought to be associated with increased risk of other cancers.

In some of the original families with familial breast cancer had males who developed breast cancer. Males with mutations in the BRCA2 gene have been shown to have a 6% lifetime risk of developing breast cancer.

breast cancer

her age, family history, age at which she began menstruating, whether she has given birth and her age at the time of the first birth, and whether or not a breast biopsy was performed in the past.

Within the general population, there is an 11% chance that any woman will develop breast cancer over her lifetime. For any one individual, this risk may be increased or decreased by a variety of factors:

OVARIAN CANCER

Approximately 1 in 70 women develops ovarian cancer,the incidence increasing with age.studies shown a high frequency of LOH at 11q25 in tumor tissues.Mutation in BRCA1,BRCA2 HNPCC,will be responsible for a proportion of these families

PROSTATE CANCER

Is the most common cancer affecting men being the most common cancer after breast,with men having a life time risk of 10% of developing prostate cancer and a 3% chance of dying from it.LOH showed at several chromosome location.A small proportion of familial prostate cancer is associated with BRCA1 or BRCA2.Men who carry mutations in BRCA1 or BRCA2 have an increasde risk .Screening by measuring prostate specific antigen (PSA) levels have been sugested.

GENETIC COUNSELING IN FAMILIAL CANCERS

Features suggestive of an inherited cancer susceptibility syndrome in a family:

Several close(first or second degree)relatives with a common cancer Several close relative with related cancers,e.g.breast cancer and ovary

cancer Two family members with the same rare cancers An unusual early age of onset Bilateral tumors in paired organs Synchronous or successive tumors Tumors in two different organ system in one individual

Inherited cancer predispoing syndromes

Families have been described in which cancer occure at more than one site in an individual or at different sites in various members of the family whoud be expected.

The majority of the rare inherited familial cancer currently recognized are dominant inherited.

There are also a number of syndromes usually inherited as autosomal recessive disorders with an increased risk of developing cancer associated with an increased number of abnormalities in the chromosomes that known as the chromosomal brakage syndrome(bloom,fancony,and Xeroderma pigmentosa with SCE)

SCREENING FOR FAMILIAL CANCER

Prevention or early detection of cancer is the ultimate goal of screening individuals at risk of familial cancers.

Familial cancer-predisposing syndromes ,are inherited as autosomal dominant trait that are fully penetrant,with cosequent risk for heterozygotes of developing cancer approximately100%,this level of risk means that more invasive means of screening with more frequent and earlier initiation of screening protocole are justified

Principles of Screening

• Properties of a good screening test - The test shoud detect a malignant or pre malignant codition at a

stage prior to its producing symptoms,with high sensevity and specifity

- Accurate and reproducible - Must be an important public health problem - Early detection and intervention must improve outcome - High morbidity and / or mortality associated with disease

condition if not treated - Have an accepted treatment for those identified - Non invasive - Has a good statistical profile - Adequate provision for presenting counseling and follow-up

shoud be available

WHAT age and how often

Most cancer screening programs don’t start until 25 years of age or later.

The highest risk age band for most inherited susceptibilities as

35-50 years Recommended that screening of at risk individuals 5 years

before the age of anset in the earliest affected member of the family

In colorectal cancer is thought that 5-yearly screening intervals is suffice.If however a polyp is found ,then the interval between screening down to 3 years.

Braest cancer isnot detectable in premalignant satage and early diagnosis is critical if there is to be a good prognosis.

Annual mammography for females at high risk is therefor recommended from the age of 35

What site shoud be screened?

Inherited susceptibility for the common cancers Colorectal cancer:Colonoscopy is the perfected screening

method.Minimal criteria suggest a familial form of colon cancer:1.At least 3 affected relatives(first degree),one a first degree relative of the other two;FAP excluded 2.At least two successive generation affected 3. Cancer diagnosed before age 50 in at least one relative

BREAST CANCER:Mammography is usually only offered to women at incraesed risk of the breast cancer after the age of 35 years,As a cosequence ,women at risk of developing breast cancer shoud be taught breast self examination and undergo regular clinical examination

OVARIAN CANCER:In the early stages is frquently asympatic and often incurable by the time a woman presents with symptoms.Early diagnosis is vital.Ultrasound imaging provides the most sensetive means of screening.Measuring the levels of CA125,an antigenic determinant of a glycoprotein that is present in increased levels in the blood of women with ovarian cancer and endometriosis thus not specific for ovarian cancer

Cancer and environment:

Some environmental agents associated with cancer are:

Viruses Tobacco smoke Food Radiation Chemicals Pollution

ELEMENTS