ILLUSTRATIONS: RAFAEL LOPEZ
What’s in your DNA?
Studying nature and nurture links to cancer risk
“He’s got your blue eyes.”
“She inherited your mom’s button nose.”
“He got his dad’s curly hair.”
Anyone attending a parent-child night at school can quickly see the role genes and inheritance play in human physical traits. Ear shape, skin color, height — these and so many other obvious features are passed along from mother and father to son or daughter.
Yet just as people inherit their parents’ physical features, they also inherit their less-noticeable genetic characteristics. Human DNA preserves the blueprints for astounding capabilities developed over hundreds of generations, such as sight, walking upright and higher reasoning. However, those inherited genes may also include some that are not so helpful — and some that may be downright harmful — including genes that increase the risk of cancer and other diseases.
Today, researchers at City of Hope are investigating just how these not-so-obvious genes increase cancer risk. They also seek ways to identify who is at increased risk of disease so they can take steps to prevent it or catch it early. Some also look beyond the genetic make-up of individuals — looking instead at bigger groups — to learn how cultural, genetic and social differences may contribute to risk and survival among various ethnic populations.
What links within
Each cell in the human body contains 25,000 to 35,000 genes. Genes line up in structures called chromosomes. The nucleus of human cells contains 23 pairs of chromosomes — half inherited from the mother, the other half from the father.
When genes are altered or mutated, they may cause disease. Sometimes parents pass along altered forms of genes to their children. Sickle cell anemia, for example, arises in children due to genetic mutations inherited from their parents.
Other mutations in genes come not from parents, but from genetic hiccups that can happen during the course of a lifetime. Genes can become altered due to exposures to toxins in the environment, such as asbestos, chemicals and second-hand smoke, for example. Personal lifestyle habits and other factors, including sun exposure, lack of exercise and a poor diet, also may contribute.
Possessing an inherited mutation is like a baseball player starting out with one strike against him before he even steps up to the plate. Sometimes it does not take many more mutations to advance a cell to a cancerous stage. More than 100 known genes are thought to increase a person’s risk of cancer or other diseases, including breast, ovarian and colon cancer and endocrine disorders, said Theodore Krontiris, M.D., Ph.D., executive vice president of Medical and Scientific Affairs, director of City of Hope Comprehensive Cancer Center and professor of Molecular Medicine.
Mutations can lead to cancer in a few ways. They can prevent the repair of DNA damage, which can then lead to a buildup of defects, some of which overstimulate cell growth. Some turn off controls for cell maturation, while others keep damaged cells from preventively self-destructing before they go awry. Each cancer has its own combination of mutations that give rise to it and keep it going — even cancers that are found in the same tissue type.
Krontiris and his colleagues have studied genes associated with an increased risk of prostate cancer by looking at the DNA from men with prostate cancer whose brothers also had the disease. They identified a new mutation that appears to only increase the risk of prostate cancer when a man inherits the mutation from both parents. The finding could eventually lead to new tests for prostate cancer risk.
That mutation may illuminate the significance of introns, small sections of DNA that were thought to be extra, unused genetic bits — a sort of filler in the genetic code. Krontiris and his colleagues are studying introns to understand how they affect the function of active genes around them. They are finding that introns act indirectly and might contribute to cancer, diabetes, hypertension and neurodegenerative disorders.
“It’s still too early to understand how they work,” Krontiris said. “While we think we know what the genes do, we’re not sure how gene variations cause elevated risks of cancer.”
Most people who develop cancer do not have an inherited genetic mutation. Instead, they accumulate mutations from environmental exposures, lifestyle and the passing of years. But for the 5 to 10 percent of people who have genes known to increase cancer risk, the odds can loom particularly large.
“While the risk of getting cancer from having inherited cancer genes for the total population is small, the risk for people who carry these genes is much higher,” said Jeffrey Weitzel, M.D., director of the Department of Clinical Cancer Genetics and associate professor in the Division of Medical Oncology & Therapeutics Research. For example, women without a genetic predisposition for breast cancer have about a 2 percent risk of developing cancer by age 50. But, women who carry a mutation in one of the BRCA genes — mutations known to be linked to breast and ovarian malignancy — have a 20 percent risk of developing breast cancer by age 40. That rises to a 50 percent chance by age 50, and as much as an 85 percent risk over their entire lifetimes.
“That points out the need to identify who is carrying the genes, so they may be screened and consider preventive therapies to help reduce their risk,” Weitzel added.
The family tree
Genetic screening is not for everyone, noted Weitzel. Experts say prime candidates for the testing include those who have several close relatives with a certain type of cancer, as well as women or men who develop a gender-specific cancer but who do not have enough relatives of that gender to determine if the disease runs in the family.
Testing even after cancer diagnosis can help patients prevent future cancers, Weitzel said. In a study published in 2003, he and his colleagues found that when women newly diagnosed with breast cancer underwent genetic testing to determine their inherited risk, they were more likely to select treatment that reflected that risk. The seven women in the study whose tests indicated they had a high risk of recurrence all chose to have bilateral mastectomies rather than more conservative treatment.
“If a woman is a BRCA carrier, the chance she’ll develop another cancer in the next 10 years is 40 percent, and most women have no desire to go through surgery, radiation and chemotherapy again. It gives them a chance to practice both therapy and prevention,” Weitzel said. And if women who know their genetic risk share that information with family members, they can encourage family members who also may be at higher risk to be vigilant about getting screened, he added.
Recent research indicates that mutations in more than 500 genes may be involved in human cancers, and about 120 of them actually drive cancer development. According to cancer genome researchers, mutations in 1 percent of all human genes are linked to cancer. Of these, about 20 percent can be inherited, while the rest can be acquired through environmental or other exposures. (About 10 percent can either be inherited or acquired.) As researchers comb through the human genome, the list of known cancer-linked genes will continue to grow.
Garry Larson, Ph.D., associate research scientist in the Division of Molecular Medicine, Weitzel and others at City of Hope are working to develop tests for such gene mutations in breast cancer. By comparing genetic material from tumors from sisters with breast cancer, they hope to find more inherited breast cancer gene mutations.
These discoveries change lives.
When 45-year-old City of Hope breast cancer patient Merry Rogers was diagnosed with the disease, she did not believe family history could be to blame. Since her mother did not develop breast cancer, she thought, genetics could not be playing a role.
But Rogers later learned that her father’s mother and several other relatives
Most people who develop cancer do not have an inherited genetic mutation. Instead, they accumulate mutations from environmental exposures, lifestyle and the passing of years.
on her father’s side had died of breast cancer. She got tested for BRCA genes.
When results confirmed she had the BRCA1 gene mutation, she felt relieved.
“It sounds silly, but I was really happy to know that I had the gene, because then I could explain to myself why I got cancer,” Rogers said. She shared the results with her two sisters and brother, and encouraged them to be tested, as well.
“I’m happy because I think I’m leaving a legacy for my nephews, so that three or four generations from now, they can be more aware of the risk,” Rogers said.
Based on the results, she decided to have a more radical surgery to nearly eliminate her risk of breast cancer.
“I used to think that I’d die of cancer — that it would eventually come back,” she said. “Now I think I’d be really surprised if I got it again. I think I’ll live to be 90.”
Extended families
While parents contribute their offspring’s genetic traits, their race and ethnicity tie their children to those larger groups, too. Those ancestral histories can influence risk, as researchers have found that certain cancers occur more often or are more lethal in certain groups. Gene mutations that occurred early in the history of certain races and ethnic groups are passed on, so many members of those populations now carry them.
For instance, studies show descendents of Ashkenazi Jews are more likely to carry BRCA gene mutations, which increase the risk of breast cancer in both women and men. Ashkenazi Jews trace their heritage to the medieval Jewish communities that lived near the Rhine river in Germany.
Weitzel’s lab also has found a previously unrecognized gene linked to people of Mexican descent that is a variation on the Jewish genes. He suspects its origins may stretch back to Jewish people who fled to Mexico during the Spanish Inquisition.
This finding may explain in part why certain Latinas are at higher risk of breast cancer, despite Latinas’ overall lower risk compared to whites.
Researchers found that 31 percent of Latinas with breast cancer who were screened between 1998 and 2004 at City of Hope had genetic mutations that increased their risk of breast cancer. Other races and ethnicities have different mutations that similarly increase the risk of breast cancer.
Race and ethnicity also influence survival rates in patients with life-threatening diseases. Smita Bhatia, chair of the Division of Population Sciences and associate director of the Cancer Control and Population Sciences Program, is researching the influence of race and ethnicity, as well as socioeconomic status, on the survival of children treated for leukemia.
Eighty percent of children diagnosed with acute lymphoblastic leukemia — the most common form of childhood leukemia — live at least five years after treatment, depending on the severity of their disease. However, children in certain ethnic groups appear to have a better chance of surviving and avoiding recurrence than others. Children of Asian descent had the highest rates of survival at five years, with no relapse in 75 percent of those studied, followed by whites and Latinos. Blacks had the lowest rates of survival without relapse, at about 62 percent.
The difference, Bhatia said, might be genetic or physiologic. Social factors also come into play. Possible reasons include differences in the way children of different ethnicities respond to drugs, varying levels of access to health care that could lead to later-stage diagnoses, or differences in how well the children and their parents are able to comply with taking medication and receiving care. Researchers must perform rigorous studies to separate true genetic factors from environmental and social ones.
Bhatia recently began a five-year study to determine which of those factors influence survival. She will analyze blood drawn from children and young adults up to age 22 to see how well their bodies metabolize therapeutic drugs. In addition, researchers will survey children’s pill-taking habits and provide “smart” pill bottles that record each time they are opened to record compliance.
“It’s important for the children to take their drugs as prescribed. If they don’t, it really increases their chance of recurrence,” Bhatia said. “But if they’re taking them, and it’s not helping them as much, this will help us to understand what is going on physically to create that difference.”
Understanding those connections between social, family and genetic predispositions to cancer and other diseases is the first step in finding better ways of treating them, and eventually preventing them.