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Author: Diana Bianchi, M.D.
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Cancer Genetics


Jorde, Carey, Bamshad & White: Medical Genetics, 3rd edition

  • Chapter 11 - pages 228-247

Prader, B. Genetic Testing for Cancer Risk. Science 278:1050-1054, 1997

Web Site: (Facing Our Risk of Cancer Empowered)


  1. To understand the different classes of genes responsible for inherited cancer.
  2. To be able to identify different aspects of the regulation of the cell cycle that can lead to tumor formation.
  3. Understand the definition and significance of "loss of heterozygosity".
  4. Learn how medical geneticists use DNA testing to identify individuals at risk for developing cancer.

Cancer is a collection of disorders that share the common feature of uncontrolled cell growth. This abnormal growth leads to a mass of cells termed a neoplasm. All cells in the body are programmed to develop, grow, differentiate, and die in response to a complex system of biochemical signals. Cancer results when any cell is freed from these constraints and its abnormal progeny are allowed to proliferate.

Biology of Cancer

Genetics vs. the Environment

Genetic events are the primary basis of carcinogenesis. The frequency of these events can be altered by exposure to mutagens, which is the link to environmental carcinogens. Because these genetic events occur in somatic cells (and not germline), they are not transmitted to future generations. Although they are genetic events, they are not inherited. Cancer events can occur in germline cells. This results in the transmission of cancer-causing genes from one generation to the next, producing families that have a high frequency of specific cancers.

Somatic Cancer

A cancer cell may emerge from within a population of growing cells, through the accumulation of several independent mutations in genes that are involved in the various processes regulating cell growth. The requirement for more than one mutation in a cell to produce a cancer cell has been called the Knudson hypothesis, or "multi-hit concept of carcinogenesis". This hypothesis states that a cell can initiate a tumor only when it contains two mutant alleles. A person who inherits a mutant allele must experience a second somatic mutation to initiate tumorigenesis.

Genes Involved in Tumorigenesis

Oncogenes - Gain of Function

Protooncogenes encode products that control cell growth and differentiation. When mutated, they may become oncogenes and result in cancer. Most oncogenes act as dominant gain of function mutations that cause the rate of cell growth to increase. Protooncogenes are involved in the four basic mechanisms of cell growth and regulation: growth factors, growth factor receptors, signal transduction molecules and nuclear transcription factors. Mutations in any one of these types of genes may cause the cell to proceed from regulated to unregulated growth. Such cells are called "transformed". A number of oncogenes have been discovered through the study of retroviruses that can transform cells and cause tumor development.

Tumor Suppressor Genes - Loss of Function

Tumor suppressor genes normally restrain cell growth; when missing or inactivated by a mutation, they allow cells to grow and divide uncontrollably. Tumors caused by tumor suppressor genes are caused by a loss of function of the gene product. Many of the mutations causing this loss of function are small deletions within the responsible gene. A number of tumor suppressor genes have been isolated using deletion mapping and a modified form of deletion mapping called "loss of heterozygosity". Loss of heterozygosity mapping utilizes highly polymorphic microsatellite repeat markers to demonstrate the small areas of DNA that are deleted within the tumor gene.

DNA Repair Genes - Loss of Function

DNA repair genes can cause cancer by failing to correct mistakes that occur during DNA replication. Mutations accumulate in the affected tissue until cell growth is no longer regulated.

Specific Examples


Retinoblastoma is an excellent example of a loss of function of a tumor suppressor gene. The retinoblastoma gene codes for a protein that appears to be an inhibitory component of the E2F transcription complex. Loss of both copies of the RB gene leads to deregulation of the cell cycle and uncontrolled cell division. In hereditary retinoblastoma, one mutant copy of the gene is transmitted through the germline, and a "second hit" mutation to the remaining normal copy of the gene results in tumor formation, often bilaterally. Retinoblastoma may also be sporadic. In the sporadic cases, random mutations occur in both copies of the retinoblastoma gene causing tumor formation. Patients affected by sporadic retinoblastoma will not have germline mutations, and will not be able to transmit the disease to subsequent offspring.


Mutations in p53 can occur in somatic cells, or in germ line cells causing loss of function. Germ line mutations result in the autosomal dominant Li-Fraumeni syndrome. p53 has been associated with a number of different types of cancers including bladder, brain, breast, cervix, colon, esophagus, larynx, liver, lung, ovary, pancreas, prostate, skin, stomach, and thyroid. Specific mutations in the p53 gene result from specific carcinogens. p53 encodes a phosphorylated nuclear protein that can bind DNA. It acts as a transcription factor and can interact with a number of other genes. One of its functions particularly related to tumorigenesis is its ability to activate a gene called WAF1. The protein product of this gene halts the cell cycle in G1, before DNA replication occurs, giving the cell time to repair damaged DNA. If p53 is mutated, than WAF1 is not activated, and the cell may replicate damaged DNA that will cause other mutations in genes involved in the regulation of cell growth. p53 can also play a role in apoptosis or programmed cell death. Mutations in p53 allows cells to continuously grow.

Neurofibromatosis Type 1 (NF1)

Patients with type 1 neurofibromatosis may develop tumors of the peripheral nerves (neurofibromas and plexiform tumors). The NF1 gene product is likely to play a role in signal transduction. Reduced levels of NF1 could lower the signal from the ras protein to stop cell growth such that the cell is permitted to escape from differentiation and continue to grow.

Familial Polyposis Gene

Familial polyposis is characterized by the appearance, early in life, of multiple adenomatous polyps of the colon. These polyps are the immediate precursors to colon cancer. The gene responsible for this syndrome (APC for Adenomatous Polyposis Coli) is a tumor suppressor gene.


Genes responsible for hereditary nonpolyposis colorectal cancer are responsible for repairing DNA mismatches. Mutations in MSH1, MLH2, MSH6 and others results in deficient repair and DNA by loss of function.

The Medical Geneticist's Perspective

Inherited mutations that predispose to cancer are transmitted as autosomal dominant traits (heterozygous individuals can develop the disease). However, at the cellular level, cancer is a recessive condition (2 mutant alleles are needed to form a tumor). All cancers are due to mutations in DNA. Most often these mutations are acquired by environmental insult (e.g. smoking) or by chance.

Clinical Example: Inherited Breast and Ovarian Cancer Syndromes

All women have an 11% risk of developing breast cancer at some point over their lifetime. However, of the approximately 182,000 cases of breast cancers that occur each year, only about 10% are thought to involve a genetic predisposition

Inherited Breast Cancer Susceptibility Genes

Gene Percentage of Total
BRCA1 30%
BRCA2 20%
PTEN (Cowden syndrome) < 1%
STK11 (Peutz Jeghers) < 1%
MSH2, MLH1, PMS2, MSH6 (HNPCC) < 1%
Other or unknown 50%

Inherited Ovarian Cancer Susceptibility Genes

Gene Percentage of Total
BRCA1 70%
BRCA2 20%
MSH2, MLH1, PMS1, PMS2, MSH6 2%
PTCH, STK11 < 1%
Other or unknown 8%

From the above tables it is apparent that of the inherited cases, BRCA1 and BRCA2 are two of the major genes involved in inherited breast and ovarian cancer. Both of these are very large and have been cloned. BRCA1 is on chromosome 17 and BRCA2 is on chromosome 13. They are both tumor suppressor genes.

When to Suspect a BRCA1 or BRCA2 Mutation

  • Multiple cases of early onset (< 45 years) breast cancer in a family.
  • Bilateral or two primary breast cancers in a woman.
  • Male breast cancer (BRCA2)
  • Ashkenazi (Eastern European) Jewish heritage.
  • Ovarian cancer at any age.

Prevalence of BRCA1 mutation in Ashkenazi (Eastern European) Jewish individuals: 1 in 40 individuals.

Prevalence of BRCA1 mutation in general population: 1 in 300 to 1 in 800 individuals.

Advantages of DNA Testing for BRCA1/2 Mutations

(Only adults > 18 years of age are tested due to lack of medical utility at any early age and lack of informed consent)

Disadvantages of DNA Testing for BRCA1/2 Mutations

In the Symptomatic Individual

  1. Guilt and concern over passing gene to family members (especially young daughters)
  2. Worry over risk of developing additional cancers
  3. Insurance discrimination generally NOT an issue (insurer already knows he/she has cancer)

In the Asymptomatic Individual

  1. "Like opening Pandora's box"
  2. Psychological distress over knowing he/she carries a gene that will predispose him/her to cancer
  3. Insurance discrimination – should not be an issue following HIPAA
  4. Massachusetts Genetic Privacy Act prevents discrimination on the basis of genetic status (became effective November 2000).

Prevention Strategies for Known BRCA1/2 Mutation Carriers (Burke et al, JAMA 1997; 277: 997)

Breast Cancer

  1. Annual mammogram beginning age 25-35 years
  2. Clinical breast exam every 6 to 12 months, beginning age 25 to 35 years
  3. Self breast exam monthly
  4. Consider bilateral mastectomy
  5. Consider other options for postmenopausal hormone replacement therapy
  6. Consider prophylactic oophorectomy (reduce estrogen exposure).

Ovarian Cancer

  1. Transvaginal ultrasound examination with color flow doppler and serum CA-125 levels every 6 to 12 months, beginning at age 25-35 years
  2. Consider prophylactic bilateral oophorectomy
  3. Consider chemoprevention with oral contraceptives (? increased risk of breast cancer)

Other Cancers

  1. For colon cancer, flexible sigmoidoscopy at diagnosis of mutation and then every 3 to 5 years beginning at age 50 years
  2. For prostate cancer, prostate biopsy at diagnosis of mutation and then every three years. Digital rectal exams and serum PSA testing every year beginning at age 50 years.

Limitations of DNA Testing

  1. Genetic tests assay for DNA sequence variation; one cannot always be sure that a DNA variant is clinically significant
  2. A "negative" BRCA1/2 test does not completely rule out the possibility of an inherited predisposition to cancer. There are other genes involved in the development of breast cancer that are not studied in this assay.
  3. Identification of a mutation indicates that an individual has an increased cancer susceptibility. It cannot determine if or when cancer will develop.