Molecular BIology of Cancer Topics             

Cancer Genetics

Cancer is a genetic disease. While most cancer-causing mutations occur somatically, in some individuals the mutations are inherited. However, inherited cancer is rare, accounting for ounly about 10% of cases.

There are several inherited cancer syndromes that occur in "cancer prone" families. These syndromes are characterized by the appearance of rare types of cancers in several membres, or generations, of a family, or the occurrence of more common cancers at an early age. Examples of such syndromes include Li-Fraumeni Syndrome (90% lifetime risk of breast, sarcoma, brain or other cancers), Retinoblastoma (90% lifetime risk, also osteosarcoma), Familial Adenomatous Polyposis (90% lifetime risk of colon cancer), and breast cancer (due to mutation in BRCA1 gene).

Li-Fraumeni Syndrome (LFS) is due to a mutant p53 tumor supressor gene. People with LFS have inherited one mutant allele of the p53 gene, usually a mutation at codon 133 which changes methionine (ATG) to threonine (ACG) . Fifty-percent of the people with such an inherited mutation will develop cancer by age 30, versus the 1% of the general population that develops cancer before age 30. Ninty-percent of the poeple with LFS will develop cancer before age 70.

Inherited cancer syndromes have been extremely valuable for identifying tumor suppressor genes. DNA in normal cells can supress the cancer phenotype. Transfer of certain single chromosomes into tumor cells results in a normal phenotype. This was shown by cell fusion studies, when fusion of a normal cell with a tumor cell produced a normal phenotype. In some cases, fusion of two cells from different tumor cell lines also produces a normal phenotype.

Retinoblastoma

Retinoblastoma is a childhood tumor, ussually occurs before age 2, may involve both eyes, and can be removed by surgery. People affected with inherited retinoblastoma are born with one mutant allele of the Rb tumor supressor gene. 95% of individuals with an inherited mutant Rb allele will develop retinoblastoma, versus 0,0025% of the general population. Inheritance is involved in 40% of retinoblastoma cases. Sporadic retinoblastoma due to somatic mutations of the Rb gene have a late age of onset and usually involve only one eye.

Retinoblastoma tumor cells often show a loss of part of chromosome 13 (13q14). The same mutation cosegrates with inheritance of the disease. Thus retinoblastoma results when both loci of a "tumor suppressor gene" are lost or mutated. In retinoblastoma-prone families, one Rb locus is lost or mutated in the germline, thus the first "hit " is inheited. The second "hit" or mutation/loss of the Rb allelle occurs somatically. In sporadic retinoblastoma both Rb loci are lost or mutated somatically. This "two hit" model for development of a tumor is known as the Knudson Hypothesis (1971).

The 2-hit model applies to both inherited and sporadic retinoblastoma. In the inherited cancer, the mutation can be inherited from either parent. There is a loss of heterozygosity (LOH) in the tumor rather than having two different alleles (heterozygosity), i.e. there is only one allele and it is mutant. The wild-type allele is lost.

Genetic Instability

Genetic instability in human cancers may be due to either subtle sequence alterations or chromosomal instability. The subtle sequence alterations include point mutations and small deletions or insertions. Microsatellite instability (MIN) are small insertions of repetitive DNA sequences, e.g. CACACA ----> CACACACACA .

Chromosomal instability (CIN) may be due to either chromosomal loss, translocation (part of one chromosome is translocated into another), or gene amplification. Cancer-causing mutations due to CIN are less common than those due to MIN. On the other hand, CIN is responsible for most allelic loss in cancer cells.

Restriction fragment length polymorphism (RFLP) analysis can be used to determine if an allele has been lost. DNA is treated with two different restriction enzymes, A and B, which cut at different sequences. The resulting fragments are subjected to Southern blot analysis, i.e. they are separated by electrophoresis, transfered to nitrocellulose, and detected by hybridization with a radioactive probe specific to the gene of concern (?). <incomplete>. <insert picture>

Progression of Genetic Changes

Human colon specimens have been analyzed for genetic changes at every stage of progression from normal to malignant carcinoma tissue (Fearon & Vogelstein1990, A genetic model for colorectal tumorigenesis. Cell 61: 757 ).

The earliest change detected, as normal epithelium becomes hyperproliferative, is loss of chromosome 5q (codes for APC?). DNA hypomethylation can be detected as cells start forming early adenomas. K-ras is activated as cells move ibto a intermediate adenoma stage. By the late adenoma stage, chromosome 18q (codes for DCC?) has been lost. Loss of chromosome 17p (codes for p53) marks the beguining of the carcinoma stage. Other additional genetic alterations may be found in carcinoma cells.

Both Ras mutation and chromosome 17p loss accumulate in colon cancer cells as they progress from adenoma to carcinoma. While Ras mutations are more prevalent in the adenoma, 17p loss is the most common genetic change in colon carcinoma cells.

The genetic model for colon carcinogenesis shows that multiple changes are needed from the development of malignant cancer. At least 5-6 independent events must occur:

Continue to "Retinoblastoma" or take a quiz: [Q1].

Need more practice? Answer the review questions below.

1- How common are inherited cancer syndromes compared to total cancer incidence?
Inherited cancer is rare, accounting for ouly about 10% of cases.

2- List 3 main characteriscs of inherited cancer syndromes.
appearance of rare types of cancer
several members or generations of the same family are affected
occurrence of common cancers but at a much earlier age than usual

3- List 4 main inherited cancer syndromes.
Li-Fraumeni syndrome
retinoblastoma
familial adenomatous polyposis (FAP)
breast cancer due to BRCA1 gene mutation

4- What is the cause of Li-Fraumeni syndrome?
An inherited mutant allele of the p53 tumor suppressor gene, ussually at codon 133 changing methionine (ATG) to threonine (ACG).

5- What is the incidence of cancer in patients with Li-Fraumeni syndrome?
Fifty-percent will develop cancer by age 30, versus the 1% of the general population that develops cancer before age 30. Ninty-percent will develop cancer before age 70.

6- How did inherited cancer syndromes helped understand tumor supressor genes?
In cells fusion studies that combined the DNA of the cancer cell with that of a noncacerous cell, the normal DNA seem to supress the cancer phenotype. Transfer of certain single chromosomes (containing the tumor supressor genes) from a normal cell to a cancer cell also results in a normal phenoptype. In some cases, fusion of two cells from different tumors also produces a normal phenotype.

7- What is retinoblastoma?
A cancer tumor of the retina. Can be removed by surgery.

8- What is the cause of inherited retinoblastoma?
Inherited mutant allele of the Rb tumor suppressor gene, often loss of part of chromosome 13 (13q14). Disease occurs when both loci are lost or mutated

9- What is the incidence of inherited retinoblastoma?
40% of retinoblastoma cases.

10- What are the main differences between inherited and sporadic retinoblastoma?
Inherited ussually occurs before age 2 and may involve both eyes. Sporadic is due to somatic Rb mutations, have a later age of onset and usually involves only one eye.

11- Explain the Knudsson Hypothesis as it applies to retinoblastoma.
In retinoblastoma-prone families, one Rb locus is lost or mutated in the germline, thus the first "hit" is inherited. The second "hit" is a mutation or loss of the Rb gene that occurs somatically. In sporadic retinoblastoma, both loci are mutated somatically. There is often loss of heterozygosity (LOH) rather than having two different alleles, i.e. there is only one allele and it is mutant.

12- List 2 overall causes of genetic instability in cancers.
subtle sequence alterations
chromosomal instability

13- List 3 subtle sequence alterations that cause genetic instability.
point mutations
small deletions
small insertions

14- What is microsatellite instability (MIN)?
Small insertions of repetitive DNA sequences, e.g. CACACA ----> CACACACACA

15- List 3 causes of chromosomal instability (CIN).
chromosomal loss
translocation of one chromosome into another
gene amplification

16- Which cancer causing mutations are most common, those due to MIN or those due to CIN?
mutations due to MIN

17- Which is responsible for most allelic loss in cancers, MIN or CIN?
CIN

18- Explain restriction fragment length polymorphism analysis.
<incomplete>

19- What is the earliest genetic change detected as normal colon epithlium becomes hyperproliferative?
Loss of chromosome 5q which codes for APC.

20- What genetic change can be first detected as colon epithelial cells start forming adenomas?
DNA hypomethylation.

21- What genetic change can be first detected as colon adenomas enter an intermediate stage?
K-ras activating mutation

22- What genetic change is first detected in colon epithelium by the late adenoma stage?
Loss of chromosome 18q which codes for DCC.

23- What genetic change marks the beguining of carcinoma in colon epithelium?
Loss of chromosome 17p, which codes for p53.

24- Which 2 genetic changes accumulate in colon cancer cells as they progress from adenoma to carcinoma, and which is more prevalent in each stage?
K-ras mutation is more prevalent in adenoma, and p53 loss in carcinoma.

25- List 4 facts learned from the study of the genetic model of colon cancer and other inherited cancer symdromes.
That multiple genetic changes are needed for the development of malignant cancer.
Most genetic changes leading to cancer are in tumor suppressor genes.
Genetic alterations can be either inherited or somatic, but in either case the same genes are changed.
The accumulation of genetic alterations is more important than the order in which they aoocrr.

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