The search for the cause of an inherited form of a rare, aggressive childhood lung cancer has uncovered important information about how the cancer develops and potentially sheds light on the development of other cancers.

“Prior research showed that the microRNA profiles of cancer cells are different from those of normal tissue, which pointed toward a possible role for DICER1 in cancer,” says senior author Paul Goodfellow, Ph.D., co-director of the Hereditary Cancer Core at the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis. “Very recently, other research found that reduced DICER1 gene expression in tumor cells is associated with worse outcomes in patients with ovarian, lung, breast and prostate cancers. Now we’ve shown that mutations in the DICER1 gene are directly linked to the development of PPB.”

“For years our large collection of cases of PPB and families has revealed the strong genetic component of this disease,” said Jack Priest, M.D., research director of the International PPB Registry in Minnesota. “We are thrilled that our colleagues Drs. Hill and Goodfellow uncovered an important mutation and have begun to understand the cellular mix-up which results in malignancy.” Current studies show around 40 percent of PPB cases occur in families with a history of the disease or certain other childhood cancers. In contrast, most pediatric cancers occur sporadically, without any familial patterns. This led scientists and doctors to suspect that the cancers were caused by an inherited genetic abnormality. To uncover the role of DICER1, the research team studied the genetic makeup of 11 extended families with two or more members having PPB or related childhood cancers.
The scientists say that finding this variant form of a gene in some PPB families is a first step to understanding why PPB and other conditions may occur in some families. But, because only a small number of families were studied it isn’t known whether DICER1 mutations explain all PPB cases, and much more needs to be learned before this information can be directly helpful to PPB families.
In collaboration with Drs. Hill and Goodfellow, and with Louis P Dehner, M.D., of Washington University St. Louis, who first described PPB in 1988, the International PPB Registry in Minnesota has collected and analyzed PPB cases from around the world for more than 20 years. More than 260 confirmed cases are being followed. The Registry is funded by Minneapolis/St. Paul-area foundations and is the only organization in the world focused exclusively on PPB.
Hill DA, Ivanovich J, Priest JR, Gurnett CA, Dehner LP, Desruisseau D, Jarzembowski JA, Wikenheiser-Brokamp KA, Suarez BK, Whelan AJ, Williams G, Bracamontes D, Messinger Y, Goodfellow PJ. Germline DICER1 mutations in familial pleuropulmonary blastoma.
Funding from the Siteman Cancer Center, Children’s Discovery Institute at St. Louis Children’s Hospital and Washington University School of Medicine, Hope Street Kids Foundation, Foundation of Children’s Hospitals and Clinics of Minnesota – Pine Tree Apple Tennis Classic, Washington University Department of Pathology, St. Louis Children’s Hospital Foundation and the Urological Research Foundation supported this research.
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.
Siteman Cancer Center is the only federally designated Comprehensive Cancer Center within a 240-mile radius of St. Louis. Siteman Cancer Center is composed of the combined cancer research and treatment programs of Barnes-Jewish Hospital and Washington University School of Medicine. Siteman has satellite locations in West County and St. Peters, in addition to its full-service facility at Washington University Medical Center on South Kingshighway.
Children’s National Medical Center, located in Washington, DC, is a proven leader in the development of innovative new treatments for childhood illness and injury. Children’s has been serving the nation’s children for more than 135 years. Children’s National is proudly ranked among the best pediatric hospitals in America by US News & World Report and the Leapfrog Group. For more information, visit www.childrensnational.org. Children’s Research Institute, the academic arm of Children’s National Medical Center, encompasses the translational, clinical, and community research efforts of the institution. Learn more about our research programs at www.childrensnational.org/research.

Serving as Minnesota’s children’s hospital since 1924, Children’s Hospitals and Clinics of Minnesota is the seventh-largest pediatric health care organization in the United States, with 332 staffed beds at its two hospitals in St. Paul and Minneapolis. An independent, not-for-profit health care system, Children’s of Minnesota provides care through more than 14,000 inpatient visits and more than 200,000 emergency room and other outpatient visits every year. Children’s is the only Minnesota hospital system to provide comprehensive care exclusively to children, and in 2008 was ranked among the best pediatric hospitals by U.S. News & World Report.

Cancer therapists are starting to meet that need, he said.

The study involved men who lived at least 10 years after a diagnosis of testicular cancer. And it found they had a substantially greater risk than the general population of having a cancer later in life, a risk that lasted for at least 35 years. The elevated risk was mostly due to the late side effects of treatment for the original cancer, according to the report published in the Sept. 21 issue of the Journal of the National Cancer Institute.

There have been other reports that reached similar conclusions, Lynch said, but “this is the largest cohort that has been put together looking at this, and one of the longest follow-ups.”

The study used data on 40,576 survivors of testicular cancer from 14 tumor registries in North America and Europe. It found a slightly higher risk of a second cancer among men who had only radiation therapy as compared to those who had only chemotherapy.

A significant finding was that more than 30 percent of men treated at age 35 developed second cancers over the next 40 years, compared to the 23 percent cancer risk of the general population.

The most common second cancers were of the bladder, colon, lung, pancreas and stomach, and they accounted for 60 percent of the additional risk.

Testicular cancer affects predominantly young men, and the survival rate is high, in the neighborhood of 95 percent. The most prominent testicular cancer survivor is 34-year-old Lance Armstrong of Texas, seven-time winner of the Tour de France bicycle race.

But the study results also apply to a growing number of people who survive other forms of cancer, Lynch said. Aside from particularly deadly forms of malignancy, such as lung tumors, cancer is increasingly treatable, he said.

“The clinical implications are growing now that many more people survive a first cancer and live to get a second one,” Lynch said. “These people can anticipate living for many years. The five-year survival rate for cancer is now over 50 percent.”

The study researchers focused “on treatment for the first cancer, particularly on radiotherapy and chemotherapy,” Lynch said. A problem with the newly reported research was a lack of information on exactly what treatments the survivors got — how much radiation, how much chemotherapy, he said.

But Lynch sees reason for hope. “The bottom-line message is that in general, the treatments we have been using are less toxic,” he said. “The second-cancer rates are going down. What we must do is find a cure for the first cancer but at minimum risk for second cancers.”

EARLY DETECTION

Even though it made treatment more tricky, Fiumara’s pregnancy enabled her to be diagnosed with ovarian cancer early. Ovarian cancer, which killed “Saturday Night Live” comedienne Gilda Radner, is called a silent killer because symptoms often don’t appear until the cancer is advanced. A week before Fiumara’s first chemotherapy in October, she had a chest X-ray. Doctors were surprised to see spots on her lungs. More tests followed. Doctors couldn’t tell for sure if the spots were cancer, but they worked under that assumption. Suddenly, Fiumara’s low-grade cancer had become more serious. Instead of two or three chemotherapy treatments, she was now scheduled for six. Her husband, 31, a civil engineer, accompanied his wife to each one. she’d sit in a chair while nurses hooked up intravenous lines to deliver several medicines. He’d sit nearby working on his laptop. The treatments lasted six or seven hours, and afterward, Fiumara would be sick and tired for days. While she recovered, Miller kept busy, painting the nursery and laying tile in the kitchen of their Huntersville home. Fiumara lost her hair, and wore a blue-jean cap to cover her bald head. Once in a while, she allowed herself an “ugly cry,” including the December day when they watched “Family Stone” at the movie theater. “Somebody should have warned us,” she said. “She dies from cancer!”But mostly, Fiumara kept a positive attitude and a sense of humor. “She’s a strong lady,” Millard said. “What’s impressive and special is her ability to keep her spirit up.”Stephenson said both Fiumara and Miller “came in with big smiles. They were always very optimistic.”By the end of January, when Fiumara had her final treatment, the drugs had shrunk the spots on her lungs. She had about four weeks before the baby was due. Doctors hoped that would give them both time for their immune systems to recover. But Fiumara went into labor just five days later. Millard, the obstetrician, decided to deliver the baby by Cesarian section to protect both mother and child. Hope Savannah Miller was born Feb. 4. Despite the doctor’s warning that she might be tiny and without hair because of chemotherapy, she weighed 6 pounds, 1 ounce, and has thick black hair. “She is vigorous and healthy,” Millard said. Soon after Fiumara and Miller took their daughter home, a wooden stork, made by a neighbor, showed up in their front yard, announcing Hope’s arrival. But the couple’s joy in their baby’s every squirm and squeal is dimmed by anticipation of what will come. A follow-up PET scan last week showed the spots in Fiumara’s lungs are indeed cancer, and it has spread to lymph nodes around her abdomen. After a biopsy of the lymph nodes, she and her doctors will talk about how to proceed. “It’s a little hard at the moment,” Fiumara said last week. “We just have to wait and see how much of a long road we have.”

It is well known that cigarette smoking is the major risk factor for lung cancer, showing up in about 90% of all cases. But what about that other ten percent?

For these, environmental causes are often proffered, the primary one being radon; but radon etiology is based on models utilizing the controversial linear no-threshold assumption, as it was applied to sketchy data on a small group of uranium miners more than 50 years ago. Asbestos exposure is surely a risk factor, but asbestos workers who also smoke have a risk that is 50 to 90 times greater than nonsmokers.

As to secondhand smoke, studies posit a 24% increased risk factor for these individuals, but figures on morbidity and mortality are mostly based on modeling-owing to the inherent difficulties of quantifying such concepts.

Beyond discerning the ten percent cohort, it has long been suggested that a strong genetic component also exists for lung cancer. For example, a widely-cited 2005 study from the Journal of the American Medical Association found that “Smokers with a family history of early-onset lung cancer in a first-degree relative had a higher risk of developing lung cancer with increasing age than smokers without a family history.”

The authors of that study added: “Family history assessment should be included when evaluating smokers or those presenting with symptoms consistent with lung disease.”

Family history, though, has some disadvantages. If smoking causes 90% of all lung cancer cases, and all your relatives smoked, and several did get lung cancer, what does that mean to you if you don’t smoke? Good question. A far better parameter than family history would be a genetic marker, of course. Imagine if you could be tested for a genetic predisposition to lung cancer!

Based on work recently published by University of Cincinnati researcher Marshall Anderson and his collaborators, a specific lung cancer susceptibility gene has been identified in humans. The paper, appearing in the April 15, 2009 issue of Clinical Cancer Research, is entitled “Fine Mapping of Chromosome 6q23-25 Region in Familial Lung Cancer Families Reveals RGS17 as a Likely Candidate Gene.”

The study applied the technique of “fine mapping” to biological samples collected from several multi-generational families, each with five or more members affected by lung cancer. Fine-mapping means that the search for a particular genetic element is confined to a smaller locus on the chromosome.

Harvard professor David Christiani, who was not directly involved in this effort, commented that:

“This study represents a significant contribution to our understanding of lung cancer susceptibility and is another step toward to the goal of preventive medicine. The authors undertook a daunting challenge of performing a family-based study of lung cancer in an effort to identify specific causal genes.”

Anderson himself noted that “Understanding of how the RGS17 gene impacts cancer development could change clinical diagnosis and treatment as radically as discovery of the breast cancer genes (BRCA1 and BRCA2) did. A proven genetic test could help us identify people at risk before the disease progresses.”

This is significant, when you consider that 25% percent of lung cancer patients experience no early symptoms, and are first diagnosed via routine chest X-rays or CT scans. Even more scary is that some people can progress into advanced stages of the disease, with few or no obvious symptoms.

Anderson added that: “What was most interesting is that this same gene was over-expressed in 60 percent of the samples from non-hereditary lung tumors. This suggests that perhaps epigenetic factors [regulation of the expression of gene activity without alteration of genetic structure] may be contributing to abnormal genetic development.”

The group plans to examine how environmental factors might affect familial cancer development.