Our Susceptibility to Cancer: Lessons from My Father's Death
Recently,
my father passed away after suffering from lung cancer. The loss of a
parent is always hard, but the loss of a parent who was extraordinarily
kind is even harder. Meanwhile, I couldn't help wondering how he could
have avoided developing this disease, because my dad strove to live a
long life and help others. He was inspired by the longevity of some
people and their ability to survive. He always took care of himself,
abstaining from alcohol and cigarettes, and led a healthy lifestyle, as
did my whole family.
My dad's unexpected death set off an alarm
concerning elevated risks of cancer our siblings and our next
generation face, because we knew that my grandmother on my dad's side
died of colon cancer. There may be a combination of genetic and
non-genetic factors in familial cancers. My siblings and I talked about
this at the dinner table and over the phone, and asked ourselves many
questions, such as, What events in my dad's life might have
contributed to his disease? Are we susceptible to cancer? How could
this affect the future of our next generation?
Maybe you
too have similar questions. You might even wonder what your chances are
of developing cancer. Sometimes answers cannot be easily found, for
cancer is not a single disease, even when it arises in the same
organ/tissue. In order to understand cancer, it is helpful to draw a
picture of what happens at the cellular and genetic level.
Good genes gone bad: Cancer is a disease of damaged genes
As
you may know, a gene is the basic unit of heredity and a segment of DNA
in our bodies. One powerful insight provided by all research is that
cancer is a disease of damaged genes. Essentially, there are two
classes of genes involved in cancer development:
Oncogenes (echoing the Greek word onkos, meaning a lump or mass) are capable of driving cancer growth without limits and tumor suppressor genes, which, in contrast to oncogenes, work to stop cancer progress.
Also,
humans carry a set of latent cancer genes called "proto-oncogenes". A
proto-oncogene has the potential of converting itself into a potent
oncogene under proper conditions. These genes are also targets for
carcinogenic attacks, leading to their conversion into potent
oncogenes.
The act of driving a car can illustrate how
oncogenes and tumor suppressor genes work with respect to malignant
cell growth. The proto-oncogenes operate like the accelerator pedal in
a car. Mutant oncogenes, due to activated function, may result in
pedals that become stuck to the floor. Conversely, the tumor suppressor
genes work like brakes. When these genes are functionally inactivated
or destroyed, a defective braking mechanism takes place. If mutation is
the engine that drives relentless cancerous growth, stuck accelerators
and defective brakes conspire to create the malignancy. As a
consequence, normal cells, like a car without brakes racing on the
highway, start their runaway cell growth.
The joint
involvement of these growth-controlling genes plays a central role in
the generation of a variety of cancers. To date, it has been
demonstrated in bladder, lung, brain, colon, prostate, and breast
cancers. Although oncogenes and tumor suppressor genes participating in
breast cancer are largely different from those encountered in colon
cancer, a common theme exists: the malignant growth of the human cancer
cell derives from the activation of oncogenes and the inactivation of
tumor suppressor genes.
Answers to the puzzle of hereditary cancers
Hereditary
cancers refer to ones in which an alteration in a single major gene
strongly contributes to the development of cancer or cancer-related
conditions within the family. About 10% of cancers have a strong
hereditary component. Cancers, such as breast, ovarian, prostate, and
colon, frequently run in families, including close relatives,
particularly over two or more generations.
To understand
hereditary cancers, it is necessary to understand almost all genes in
our cells are present in two redundant copies: one deriving originally
from our mother's gene, the other from our father's. This redundancy
represents a universal mechanism for preventing the onset of cancers in
the body. In the case of tumor suppressor genes, this two-copy system
offers a measure of protection to the cell. If one copy of a tumor
suppressor gene is accidentally lost, the remaining gene copy serves as
a perfectly adequate backup. Returning to the car analogy for a moment,
half a brake lining is as good as a whole one in slowing down cell
growth.
Now let me explain the heredity of human cancer by
showing you a snapshot of colon cancer. One type of colon cancer is
familial polyposis, in which hundreds of polyps are present in the
colon and later become malignant. It is caused by mutations in the
adenomatous polyposis coli (APC) gene (a tumor suppressor gene). The
APC gene is present in the genomes of normal cells but absent or
functionally inactive in those of cancer cells. The loss of the APC
gene is a two-step process involving the successive elimination of two
gene copies. To create an inborn susceptibility to cancer, defective
versions of the APC gene are passed from parents to offspring via sperm
or egg. In affected families, these individuals carry a particular
hereditary mutation in every cell of their body. At some point, a
child's cell in the colon will lose its surviving intact copy of the
APC gene and then launch forth into uncontrolled growth.
In
sporadic cancers (i.e., those as a result of mutation occurring after
conception rather than inheritance), the inactivation of one copy of
the APC gene is the first step in the multi-step process of colon
cancer development. For example, this inactivation may be caused by
carcinogenic attacks. Only when the other copy of the APC gene is lost,
will the cells march on their way to becoming cancerous.
On
the other hand, individuals inheriting a defective copy of the APC gene
have already taken the initial step, as all of their colonic cells
already carry a mutant gene copy and can directly proceed to the next
step — elimination of the remaining intact APC gene. Sadly, tumor cells
usually resort to a more tactical way of eliminating the second copy of
a tumor suppressor gene. In these people, the process of polyp
formation and ultimately cancerous growth is, undoubtedly, exceedingly
accelerated. Familial polyposis accounts for 1% of all colorectal
cancer cases, yet individuals with this condition have a nearly 100%
chance of developing cancer by age 50.
When repair becomes disrepair
Cancer is a complex, multi-step process that can take decades to a lifetime to develop, during which the human body usually places a myriad of roadblocks in the path of a cell intent on forming cancer. The immune system, though not a focal point here, certainly stands as a line of defense against it. Fortunately, DNA repair, a clever strategy to erase the damage created by mutation or miscopying, serves as one of the obstacles that hold down fatal malignancies to a very low rate.
Just as you or I may make inadvertent mistakes when we make a hand-written copy of an original, the process of DNA replication also creates inadvertent mistakes. However, just as we can also correct the writing error with an eraser, the DNA repair machinery can instantly correct gene copy errors. We now know that several kinds of familial cancers are caused by inherited defects in DNA repair. Imagine the consequence that this defect would lead to if mistakes during DNA replication were no longer fixed properly. Let's again look at the example of colon cancer, this time from the perspective of DNA repair.
Hereditary Non-Polyposis Colorectal Cancer (HNPCC) is an inherited disorder. It is characterized by the absence of polyp formation and attributed to hereditary mutation in a DNA repair gene. An individual suffering from HNPCC inherits a defective version of one of the four critical DNA repair genes. Therefore, in their cells, many of the DNA copying mistakes will remain uncorrected and be passed on as mutations to the daughter cells following cell division. As a result, over many cycles of growth and division, the cells of HNPCC patients accumulate mutations at an alarming rate.
Once again, the fundamental difference between this type of cancer and those sporadic (or non-inherited) cancers is the rate at which affected genes undergo mutations. In the colonic cells of an HNPCC patient, the absence of competent DNA repair machinery leads to a greatly accelerated rate of genetic mutation, and thus cancer development.
There is good news, however. The possibility of preventing or curing most colorectal cancer is now feasible; that is why it is imperative to promote broader public awareness and screening strategies among those with increased risks. HNPCC accounts for up to 5-6% of all colorectal cancer cases. Individuals with HNPCC have a lifetime risk of 70-80% for developing colorectal cancer, and women with HNPCC have a lifetime risk of 30-60% for developing uterine cancer, although the underlying mechanism remains unclear. It is also important to know that while the presence of a faulty gene can increase the risk of cancer, some people who inherit a defective gene never go on to develop cancer.
Since cancer cells carry mutated genes, the next question that arises is: how have good genes gone bad?
How good genes go bad
Our world is like a field with our bodies springing up from that field like plants, so our body needs nourishment and a healthy environment to grow and prosper. At the same time, we are surrounded by weeds — viruses, X-rays, radiation, tobacco, alcohol, and toxic chemicals in our food, water, and air. These weeds or a toxic environment can lead to the demise of the plant. Incredibly, every human cell sustains thousands of mutagenic attacks everyday!
Carcinogens (i.e. cancer-causing agents, like X-rays, tobacco, toxic chemicals, or viruses) can enter our cells and bond with diverse target molecules inside. They can bond with DNA, and somehow alter DNA sequence, eventually damaging it. Once genes in a cell are damaged, the cell is no longer normal. This mutant cell will begin to grow uncontrollably within the body, sooner or later yielding a mass of descendant cells. The result: a tumor is created. Evidently, breathing in secondhand smoke caused damage to my dad's body that contributed partially to his lung cancer, since he used to work closely with a heavy smoking colleague for a decade or so.
All of us are equally vulnerable to cancer
Surely, the passing of a set of mutant genes through sperm or egg creates a hereditary susceptibility to cancer. Keep in mind, however, that the same genes, when mutated by random genetic accidents occurring throughout one's life, generate unpredictable cancers in more than 90% of the population. According to the National Cancer Institute, over 1 million individuals in the United States will have been diagnosed with cancer in 2009. Over half-a-million Americans die of cancer each year. Tragically, many of those cases would have been preventable.
In summary, all humans carry genes that affect their predisposition to various types of cancer. While the roots of cancer lay deep in our genes and in our cells, cancer's ultimate causes really originate far outside the individual cell, in the environment where we live, in the food we ingest, and in the air we breathe. It has become abundantly clear that these factors, as reflected in our lifestyle, considerably influence cancer progression. We must address these ultimate causes of cancer before we can significantly lower the cancer incidence.
My father's death has taught me that, while we try to enjoy our lives, we need to be more vigilant about cancer risk factors, both obvious and subtle ones. Furthermore, of critical importance in cancer prevention is a healthy lifestyle, which played a fundamental role in my father's prosperous life journey, and over which an individual can take control.
The ending can be a happy one: caring for our younger generations
Finally, as I contemplate the generations to come, it reminds me of how my dad loved and cared for not only his own children and grandchildren, but also other kids, including those of strangers.
Nearly 40 years ago when my dad had to take sick leave for his tuberculosis, he was able to spend more time with us and other kids in the neighborhood. One day he noticed a skin problem on a little girl who was brought to our neighborhood by her big sister to socialize with her classmates. My dad, being a doctor, urged her parents through the sister, to take care of her skin ailment. It appeared to be a peculiar ringworm (tinea in medical term). The girl's mom had already given up hope because all the doctors they had visited said that it was incurable. My dad, however, didn't give up. He went ahead, spending his own money despite our limited funds, and purchased the necessary medication for this little girl at the best hospital in the city. He then instructed her family in the method of topical treatment for the girl. After a period of time, the little girl's skin was completely healed. Her mom was very touched.... Needless to say, our two families, who didn't know each other before, became good friends resulting from my dad's genuine care for a stranger's girl.
References:
1. Offit, K., Brown K. (1994) Quantitating familial cancer risk: A resource for clinical oncologists. Journal of Clinical Oncology 12:1724-36.
2. Fearon E.R. (1997) Human cancer syndromes: Clues to the origin and nature of cancer. Science 278:1043-50.
3. Weinberg, R.A. (1998) One renegade cell: How cancer begins. published by Basic Books.
4. Garber, J.E., Offit, K. (2005) Hereditary cancer predisposition syndromes. Journal of Clinical Oncology 23(2):276-92.
