Can a gene that causes dwarfism also confer major health benefits? Perhaps, according to a new study showing that a group of extremely short people in Ecuador get no diabetes, even though they are unusually obese.

The 22-year study of people living in villages on the slopes of the Andes mountains also found just one case of cancer in the 99 patients it tracked, many fewer than among non-dwarf relatives.

The absence of two of the worst diseases of aging was strong evidence that the mutation that causes what’s called “Laron syndrome” has an upside, says Valter Longo, a gerontologist at the University of Southern California, and the senior author on the new study. “If you talk to anybody in the field, there is no way you can have a population with increased obesity and no diabetes. What was particularly strange was having zero deaths from cancer with 22 years of direct monitoring.”

Unfortunately, the subjects did not outlive the comparison group of relatives, due to large numbers of accidents and other alcohol-related problems.

The Laron’s patients are descendants of “Conversos,” Jews who were forcibly converted to Catholicism in Spain after 1492, and who emigrated to Latin America to escape continued persecution. Laron’s syndrome is also found in Israel and several other Middle-eastern countries.

The root of Laron’s syndrome, AKA growth hormone receptor deficiency, is a genetic mutation that disables the growth-hormone receptor, says Arlan Rosenbloom, a professor emeritus of pediatric endocrinology at the University of Florida who has long studied the Ecuadorian group but was not involved with the current report. “Growth hormone binds to its receptor on cell surfaces to stimulate production of insulin like growth factor-I (IGF-I) which is the real ‘growth hormone,’” Rosenbloom says. “Failure of the growth-hormone receptor cuts growth after birth by 50 percent. The Ecuadorians with this condition, 99 living individuals, comprise upwards of one-third of all individuals in the world with growth-hormone receptor deficiency.”

Image: Mikael Häggström

Growth hormone, secreted by the pituitary gland, travels to the liver, where it stimulates the formation of insulin-like growth factor 1, which stimulates bone growth.

The genetic angle

The new comparison of genetic differences between Laron patients and their non-dwarf relatives emerged from what Rosenbloom calls “spectacular epidemiological observations” by first author Jaime Guevara-Aguirre, an Ecuadorian endocrinologist who treats the Laron’s patients.

Working with Rafael de Cabo, a collaborator at the National Institute on Aging, Priya Balasubramanian from Longo’s research group exposed human epithelial cells, where most human cancers originate, to blood serum from control and Laron subjects. Serum is the cell-free portion of blood. “We wanted to know how this would affect the expression of dozens of genes,” says Longo, who studies cellular changes in aging.

The springboard of modern aging research is caloric restriction, because a diet with roughly 65 percent of normal calories is the only life-extension technique that works in a vast range of organisms. Although a similar group of protective genes activate under caloric restriction in yeast, fruitflies and mice, “We did not expect that a lot of the genes we study in yeast would come out as the most affected” in patients with a broken growth-hormone receptor, Longo says. “Serum from the Laron patients caused changes that we and others have shown to be highly protective in simple systems [like yeast]. We hoped for this but never really expected that many of the same genes would be coming up.”

At the molecular level, a key mechanism of aging is “oxidative stress,” damage to proteins and DNA caused by reactive molecules and fragments containing oxygen. When the researchers exposed human cells to the oxidant hydrogen peroxide, far fewer DNA breaks appeared in cells bathed in serum from the Laron patients, suggesting that they were protected against cancer.

The study found a second critical difference: When the DNA was damaged, cells in Laron serum were much more likely to commit suicide through apoptosis. Because apoptosis is a major obstacle to cancer, this suggested that cells in a Laron patient that had started on the path toward cancer would be more likely to kill themselves before going rogue.

Combined, the two phenomenon seem to explain why during the 22-year study only one of the Laron’s patients being tracked had a cancer, which was successfully treated. About 17 percent of their normal-height relatives had cancer during the same period.

Growing more confident

The study illuminates the role of insulin-like growth factor-1 (IGF-1), a growth hormone that, while required during development, may cause problems later on. “Large population studies show that people with the highest levels of IGF-I are at increased risk for certain types of cancer,” says Rosenbloom.

Longo notes that the effects of IGF-1 may depend on whether it is formed in an individual organ or distributed in blood. “Our hypothesis is that we do not need a ton of circulating IGF-1,” Longo says. Laron patients have between 0 and 10 percent of the normal level of IGF-1, “but they are fine, several made it into their 80s.”

The Ecuadorian study was more evidence that IGF-1 formation requires a functioning growth-hormone system. A drug that blocks the growth-hormone receptor has been approved for treating acromegaly, or gigantism, which is caused by excessive production of growth hormone.

You don’t have to be a hypochondriac to wonder if such a drug could prevent cancer and diabetes in adults, but the new study shows correlation, not proof, and Longo advocates a more modest first step in clinical trials. Return to caloric restriction for a moment: Studies in mice show that fasting reduces IGF-1 and protects healthy cells — but not tumor cells — from damage during chemotherapy, and some cancer patients have begun fasting to reduce collateral damage during chemo. “I think that soon enough, we will start with a clinical trial of this growth-hormone receptor antagonist to protect cancer patients against chemotherapy toxicity,” Longo says.

The new study is further proof, that, up and down the line from yeast to mice to people, similar “conserved” biochemical mechanisms influence aging, cancer and diabetes, Longo says. “The conservation hypothesis is something I am very convinced of, but I did not expect what we saw. Maybe we would see major reductions in cancer and insulin resistance [a marker of diabetes], but to see not one case of diabetes, not one cancer death, and to see the genetic matches with the simple systems that we study, that was as good as we could hope for.”

The evolution of a cancer

Genetically, cancer is a mess. Tumor cells don’t do the work of a healthy cell, but they are awfully good at making sloppy copies of themselves. Removed from the normal restraints and error-checking that keep healthy cells honest, cancer cells can change over time as they evolve to fight the immune system and cancer drugs.

 

Chart: NIH

The new study in Nature tracks the evolution of a breast cancer, a diagnosis that becomes more common with age.

Until now, getting a picture of these genetic changes has been an insurmountable task. Just “reading” the normal DNA in one person cost billions and took about a decade. But now, techniques for hyperspeed DNA sequencing are starting to produce libraries of genetic data, raising the hope of unraveling the varying genetics of cancer.

Nature is now reporting the most thorough study of evolution in a single patient’s breast cancer. “This week, for the first time, we have looked in detail at the evolution of a cancer genome over time,” says Samuel Aparicio, a professor at the BC [British Columbia] Cancer Research Center and the paper’s senior author. The study compared the cancer’s genes before and after it had spread, nine years later.

One disease, or many?

The ability to look in detail at cancer genes raises the prospect of eventually understanding the cause of the many diseases we call cancer. Cancer is a curious beast, and its genetics can get more bizarre with time. In the Aparicio study, the tumor cells nine years after diagnosis showed 32 significant mutations, only five of which were common in the original tumor.

Understanding these early and late mutations could shed light on the origin and spread of cancer.

 

From original graphic by DOE

Understanding the genetics of cancer could help in prevention and in treatment.

High-speed sequencing could eventually help doctors select treatments based on the genetics of the cells in the tumor, and Aparicio says his team has already begun tracking patient’s genes. “We will be able to build up our idea of what mutations might be conferring resistance or sensitivity to drugs. Eventually, we can ask, ‘did this or that genome respond better to this drug?’”

Making treatment decisions could be complicated, however, as even the original tumor showed genetic weirdness that is not found in healthy tissue. This genetic diversity is important, Aparicio says. “When one considers developing a therapeutic strategy, we tend to regard the cancer genome as a single entity. Cancer biologists have known this for decades, but we just have not had the means to see it.”

Moral of the story: Weapons against a “single” cancer are actually confronting multiple foes, which have — or may evolve — multiple genetic tricks for evading cancer-killing medicines and the immune system.

 

From graphic by NIH

Sequencing DNA relies upon matching pairs of components that have specific preferences for partners. If you know the sequence on one strand, you can predict the sequence of the other.

Consequential sequencing system

Scientists have wanted to understand the changing genetics of cancer for decades, but this study was only possible due to phenomenal advances in sequencing speed that are meanwhile causing the cost to drop, some say, faster than the price of computers.

Ultra-speed “synthesis DNA sequencing” relies on DNA’s ladder-shaped, double-stranded structure. The molecule is built of pairs of components called “bases” that are picky about partners: The base nicknamed “A” will only link to “T”. Likewise, “G” is specific to “C.”

Any time you see a C, you know it’s got to be linked to a G. So knowing the sequence on one strand tells you the sequence on its complementary strand.

Technicians start synthesis sequencing by splitting the DNA ladder lengthwise and anchoring millions of short strands to a sample plate. The sequencing machine then introduces new bases and watches as they complete the anchored strands. Because each base will only link to its complementary pair member, the process of attachment shows the structure of the DNA fragments that were originally attached to the plate.

Synthesis sequencing is just catching on, and the current study looked at one tumor, from one patient. To understand which mutations are most dangerous, “one really has to … look at multiple cancers,” Aparicio says.

However, one mutation that already seems portentous is HAUS3, which causes defects in proteins that organize the chromosomes as they undergo the delicate process of uncoiling, duplicating, and recoiling during cell division, Aparicio says. “We know from other studies that if we deplete those proteins, cell division becomes error-prone, which leads to instability in the genome, so conceivably mutations in those genes might have been involved in the early stages of cancer.”

 

Graphic: National Cancer Institute

The secondary cancer, called a metastasis, is more likely to cause death than the primary tumor.

A first look

As an early look into the tangled genomics of cancer, the study is a good first step, says Michael Gould, an oncologist at the University of Wisconsin-Madison School of Medicine and Public Health. “In this data from one patient, the original tumor had a lot fewer meaningful mutations than previous reports on breast cancer cell lines. If this holds up for other solid tumors, and I believe it will, there will not be a huge catalog of mutations in any individual [primary] tumor, and that’s good.”

However, Gould adds that compared to a previous study of the blood cancer leukemia, the British Columbia study also found more genetic change over time. “In leukemia, the primary and metastatic tumors had the same spectrum of mutations, and people concluded there was not necessarily genetic evolution going on, that maybe when the cancer first comes up, you either have a metastatic mutation or you don’t. In this [breast cancer] study, and maybe it’s generalizable to other solid tumors, there is some evolution going on between the primary and metastatic tumor.”

As Aparicio says, the treatment goal of this type of genomic analysis is already beginning, as researchers try to correlate different genetics with treatment outcomes. But learning about gene damage in the primary tumor may also identify the original cause of the cancer. Whether that cause resides in the environment or the patient, such insights should become the basis for better cancer prevention.

David J. Tenenbaum