the genetic causes of cancer

1. Genes and cancer
BY
ALI FARIS

2. CANCER IS A CONTROL SYSTEM PROBLEM
 Cancer arises when multiple control systems within a single cell are
corrupted.
 These control systems are of two basic types:
1. systems that promote cell growth (proliferation),
2. and safeguard systems that protect against “irresponsible” cell growth.
 When controlled properly , cell proliferation is a good thing.

3.  After all, an adult human is made up of trillions of cells, so a lot of proliferation must take place
between the time we are a single, fertilized egg and the time we are full‐grown.
 However, once a human reaches adulthood, most cell proliferation ceases. For example, when
the cells in your kidney have proliferated to make that organ exactly the right size, kidney cells
stop proliferating.
 On the other hand, skin cells and cells that line our body cavities (e.g., our intestines) must
proliferate almost continuously to replenish cells that are lost as these surfaces are eroded by
normal wear and tear.
 All this cell proliferation, from cradle to grave, must be carefully controlled to insure that the right
amount of proliferation occurs at the right places in the body – and at the right times.

4.  Usually, the growth‐promoting systems within our cells work just fine.
 However, occasionally one of these systems may malfunction, and a cell
may begin to proliferate inappropriately.
 When this happens, that cell has taken the first step toward becoming a
cancer cell.
 Because these growth‐promoting systems are made up of proteins,
malfunctions occur when gene expression is altered, usually as a result
of a mutation.

5.  A gene that, when mutated, can cause a cell to proliferate
inappropriately is called a proto‐oncogene.
 And the mutated version of such a gene is called an
oncogene.
 The important point here is that uncontrolled cell growth
can result when a normal cellular gene is mutated.

6.  To protect against malfunctions in the control systems that promote cell proliferation, Mother
Nature has equipped cells with internal safeguard systems.
 These safeguards are of two general types: systems that help prevent mutations and
systems that deal with these mutations once they occur.
 For example, cells have a number of different repair systems that can fix damaged DNA,
helping safeguard against mutations. These DNA repair systems are especially important,
because mutations occur continuously in the DNA of all our cells. In fact, it is estimated
that, on average, each of our cells suffers about 25 000 mutational events every day.
 Fortunately, repair systems work non‐stop, and if the DNA damage is relatively small, it can be
repaired immediately as part of the “maintenance” repair program.

7.  Sometimes, however, the maintenance repair systems may miss a mutation,
especially when there are many mutations and the repair systems are
overwhelmed.
 When this happens, a second type of safeguard system comes into play –
one that monitors unrepaired mutations.
 If the mutations are not extensive, this safeguard system stops the cell from
proliferating to give the repair systems more time to do their thing. However, if
the genetic damage is severe, the safeguard system will trigger the cell to
commit suicide, eliminating the possibility that it will become a cancer cell.

8.  One of the important components of this safeguard system is a protein called
p53. Proteins like p53, which help safeguard against uncontrolled cell
growth, are called tumor suppressors, and the genes that encode them are
called anti‐oncogenes or tumor suppressor genes.

9.  Mutations in p53 have been detected in the majority of human tumors, and
scientists have created mice with mutant p53 genes. In contrast to normal
mice, which rarely get cancer, mice that lack functional p53 proteins usually
die of cancer before they are seven months old.
 So, if you are ever asked to give up one gene, don’t pick p53!

10.  The take‐home lesson is that every normal cell has both proto‐oncogenes and tumor
suppressor genes.
 Where things get dangerous is when proto‐oncogenes are mutated, so that the cell proliferates
inappropriately, and tumor suppressor genes are mutated so that the cell can’t defend itself
against proto‐oncogenes “gone wrong.” Indeed, cancer results when multiple control
systems, both growth‐promoting and safeguard, are corrupted within a single cell.
 It is estimated that between four and seven such mutations are required to produce most
common cancers. This is the reason why cancer is a disease which generally strikes late in life:
It usually takes a long time to accumulate the multiple mutations required to inappropriately
activate growth‐promoting systems and to disable safeguard systems.

11.  Mutations that affect growth‐promoting systems and safeguard systems can
occur in any order.
 However, one type of mutation that is especially insidious is a genetic alteration
which disrupts a safeguard system involved in repairing mutated DNA. When this
happens, the mutation rate in a cell can soar, making it much more likely that the
cell will accrue the multiple mutations required to turn it into a cancer cell.
 This type of “mutation‐accelerating” defect is found in many (perhaps all) cancer
cells.
 Indeed, one of the hallmarks of a cancer cell is a genetically unstable
condition in which cellular genes are constantly mutating.

12. Features of cancer cells:
1. Independent of Growing .
2. Ignores STOP signal.
3. No cell suicide (apoptosis).If this occurs,
treatments which damage dividing cells may
not work.
4. No limit to cell division

13. 5-Angiogenesis
 Angiogenesis - formation of blood
vessels
 All cancers require a functional
vascular network to ensure continued
growth and will be unable to grow
beyond 1 mm3 without stimulating the
development of a vascular supply.
Tumors require sustenance in the form
of nutrients and oxygen, as well as an
ability to evacuate metabolic waste
products and carbon dioxide. This
entails the development of new blood
vessels, which is termed angiogenesis
Fig. Angiogenesis, invasion and metastasis. A For any cancer to grow
beyond 1 mm3 it must evoke a blood supply. B New vessel formation
results from the release of angiogenic factors by the tumour cells and
loss of inhibition of the endothelial cells. C The loss of cellular adhesion
and disruption of the extracellular matrix allow cells to extravasate into
the blood stream and metastasise to distant sites.

14. 6-Metastasis
 Metastasis - ability to move to other tissues
 Cancer cells are invasive and can infiltrate
surrounding tissues by breaking down the
intercellular matrix. In addition, cancer
cells can detach from the primary tumor
and move to other sites in the body,
forming new malignant tumors. This
process is called metastasis (see Figure).
The ability to invade new tissues results
from new mutations in cancer cells.

15. Case
Julie, a 23-year-old with a family history of breast cancer, sought counseling at the cancer risk assessment clinic. She had been
visiting her local breast center to be treated for fibrocystic breast disease. After her last mammogram, she requested an operation to
remove her breasts. Julie came to the counseling session with a maternal aunt who had undergone the surgery several years earlier. The
genetic counselor explored the factors that had prompted Julie’s request for surgery and reviewed her family history. Three of Julie’s six
maternal aunts had breast cancer in their late 30s or early 40s. One maternal first cousin had been diagnosed with breast cancer in her
30s. Julie’s mother was in her 50s and had no history of cancer. Julie told the counselor that women in her family believed that the only
way to avoid the disease was to have their healthy breasts removed before cancer developed. Julie went on to say that her mother’s
breasts had been removed at age 34, and the aunt attending the session had had surgery the previous year, when she turned 40. The
aunt told stories of caring for her dying sisters. She also stated, “It would be the same as a death sentence not to do this.” This led the
remaining aunts to seek surgery, and now Julie was being encouraged to take the same step. The genetic counselor explained that the
maternal aunts could take a genetic test to determine if a mutant gene was contributing to the development of breast cancer in the family.
The counselor explained that if her aunts carried such a mutation, Julie could be tested for the same mutation. If Julie had the mutant
gene, surgery could be a reasonable option. However, if Julie did not inherit the mutation, her risk for breast cancer would be the same as
that of the general population (10%), and breast removal would be unnecessary. One of Julie’s aunts with cancer was tested, and it was
found that she carried a mutation for a predisposition to breast cancer. Julie and her mother were tested, and neither of them had the
mutation. Julie continues to be followed by the local breast center for fibrocystic breast disease; however, she has decided not to have
surgery.

16. REFERNCES:
 Human Heredity - Principles and Issues 9th Edition
 Helen_M._Kingston_ABC_of_Clinical_Genetics_3rd_Book
 ‫وما‬ ‫مالها‬ ‫الوراثة‬‫عليها‬_‫عريض‬ ‫سالم‬ ‫شيخة‬ ‫الدكتورة‬
 2016 How the Immune System Works
 Davidsons Principles and practice of medicine_22Ed