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.
The finding by researchers at Washington University School of Medicine in St. Louis, the Children’s National Medical Center in Washington, D.C., the International Pleuropulmonary Blastoma Registry at Children’s Hospitals and Clinics of Minnesota and other collaborating institutions adds the final link to the chain connecting the gene DICER1 to cancer development — something that had been suspected but until now not definitively demonstrated.
The results were presented today at the American Association for Cancer Research 100th Annual Meeting 2009 in Denver, Colorado. The study shows that some children with the rare cancer pleuropulmonary blastoma (PPB) are born with a deleterious mutation in DICER1, a master controller gene that helps regulate expression of other genes. The children studied came from families with a history of PPB or related disorders.
“PPB is the first malignancy found to be directly associated with inherited DICER1 mutations, making the cancer an important model for understanding how mutations and loss of DICER1 function lead to cancer,” says lead author D. Ashley Hill, M.D., chief of pathology at Children’s National Medical Center. “Additionally, we now believe that PPB tumors arise from an unusual mechanism in which cells carrying mutations induce nearby cells to become cancerous without becoming cancerous themselves.”
Hill was principal investigator of the study, which was begun while she was on the Washington University faculty.
Only 50 to 60 cases of PPB are diagnosed each year around the world. Most children with PPB are under five years of age. The cancer progresses from air-filled lung cysts in the early stage to solid lung tumors in later stages. If detected in the earliest stage, 90 percent of patients appear to be cured when treated with surgery and sometimes chemotherapy. Overall survival drops to about 40 percent if the cancer is diagnosed in the latest stage.
The researchers found that all the children studied with PPB carried damaging mutations in one of their DICER1 genes, giving them one functional and one nonfunctional DICER1 gene in all their body’s cells. The researchers indicate that PPB lung tumors probably originate when one or more cells in the lung acquire a harmful mutation in their functional copy of the DICER1 gene.
The researchers also found that PPB lung tumors appear to result from a novel cancer induction mechanism not previously demonstrated. They discovered that loss of DICER1 protein specifically in lung airway cells appears to deregulate signals to nearby cells in which DICER1 itself still functions and somehow causes those cells to transform into malignant cells. However, the cells with the loss of DICER1 do not progress to malignancy.
DICER1 is so-named because its job is to chop up large molecules into smaller control molecules that help regulate the output of many of the 30,000 human genes. The short bits of genetic material it produces during its dicing activities are termed microRNAs.
Genetic Source of Rare Childhood Cancer Found; Gene is Implicated in Other Cancers
Cancer Survivors Face Future Risk
TUESDAY, Sept. 20 (HealthDay News) — The ever-improving treatments that are successfully helping cancer patients are also increasing the risk they will live long enough to develop second cancers, a study sponsored by the National Cancer Institute indicates.
The finding shows the need to develop effective cancer treatments that do less long-range damage, raising the possibility of a second cancer, said Dr. Charles F. Lynch, professor of epidemiology at the University of Iowa, and a member of the research team.
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.
Woman With Cancer Faces a Hard Choice: Risking Chemotherapy During Pregnancy
Two years after a miscarriage and eight weeks into her second pregnancy, Kristina Fiumara relaxed when the ultrasound detected her unborn baby’s heart beat _ strong and steady. But when she shifted, for a different view on the monitor, the fetus disappeared and darkness filled the screen. “That’s not supposed to be there,” the technician said. The grapefruit-size mass appeared to be a benign cyst, doctors said. To be safest for the baby, they waited until she was 12 weeks pregnant to operate. The surgery on Aug. 24 was supposed to last one to two hours. Fiumara’s husband, Dan Miller, was still waiting _ and worried _ when doctors came to see him three hours later. The mass had looked cancerous, they said. A rapid biopsy confirmed low-grade ovarian cancer. “I felt like somebody had smacked me in the face with a dead fish,” Miller said. When she got home from the hospital, Fiumara, 32, a recruiter for an executive search firm in Charlotte, went to the Internet to find more about cancer during pregnancy. By the time her doctors at Carolinas Medical Center recommended chemotherapy, she knew that a growing number of studies show anti-cancer drugs do not damage a fetus if they’re given after the first 12 weeks of pregnancy. She also knew that having cancer during pregnancy is rare _ about 1 in 1,000. Fiumara’s obstetrician, Dr. Devin Millard, and her maternal-fetal specialist, Dr. Courtney Stephenson, had each seen only one other case of ovarian cancer in pregnancy in their careers. Her oncologist, Dr. Jim Hall, said he sees one or two cases a year. “Even the oncologists had to huddle and come up with a plan,” Millard said, “because there is no standard treatment.”Ten years ago, pregnant women with cancer would face a dramatic choice: Terminate your pregnancy, or risk your life and the life of your baby. Doctors believed high doses of cancer-fighting drugs would damage the unborn child or that the stress of pregnancy itself would reduce a woman’s chances for survival. But as more research has become available, doctors now believe chemotherapy can be delivered safely _ to mother and fetus _ after the first trimester of pregnancy, after the fetal organs have developed. There’s no data on how babies of chemotherapy patients fare into adulthood. But registries kept by doctors in Oklahoma, New Jersey, Houston and Toronto are tracking the progress of pregnant women diagnosed with cancer and their children who were exposed to chemotherapy drugs in utero. Dr. Elyce Cardonick, a maternal-fetal specialist at Cooper University Hospital in Camden, N.J., began collecting cases in 1996 after becoming involved with three cancer patients who were told they should terminate their pregnancies to get treated. The patients, who had Hodgkin’s disease, breast cancer and melanoma, eventually received treatment after the first trimester without damage to their babies. Cardonick realized other doctors and patients needed to know this.”No physician wanted to be the first person to treat a (pregnant) patient with cancer,” she said. “No one person had a lot of experience because it was rare.”Cardonick’s registry includes 200 women. With other cases reported in medical journals, she’s found about 400 cases since 1966. Most had breast or cervical cancer.
Some Good News In The Fight Against Lung Cancer
According to American Cancer Society estimates for 2008, 215,020 new cases of lung cancer in the U.S. will be diagnosed and 161,840 deaths due to the disease will occur. The National Cancer Institute figures that approximately one out of every 14 men and women in the U.S. will be diagnosed with cancer of the lung or airways at some point in their lifetime.
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.”
Smokers’ Urine May Give Cancer Alert Early Enough to Save Lungs
April 19 (Bloomberg) — Smokers with high levels of two chemicals in their urine were more likely than others in a study to get lung cancer, a finding that may lead to a new test to predict risk in time to prevent or treat the disease.
High levels of these chemical byproducts of tobacco smoke in the urine were linked to lung-cancer rates as much as 8.5 times higher than those of other smokers, said Jian-Min Yuan, the study leader and an associate professor of public health at the University of Minnesota in Minneapolis. He spoke in Denver today at the American Association for Cancer Research meeting.
Lung tumors are the most lethal form of cancer in the U.S., spurring 161,840 deaths and 215,020 new cases in 2008, according to the American Cancer Society, based in Atlanta. While there are about 60 possible carcinogens in tobacco smoke, pinpointing byproducts, or metabolites, that may spur the malignancies may help prevention, Yuan said.
“If we can identify a smoker with a high level of metabolites, and down the road they have a higher risk of lung cancer, public health workers can get them motivated to quit smoking,” Yuan said in an April 16 telephone interview. “If they can’t quit, we can do more intensive screening to find very small lung cancers that can be treated.”
Yuan analyzed varying levels of metabolites in the urine of about 500 smokers drawn from the Shanghai Cohort Study and the Singapore Chinese Health Study, funded by the U.S. National Cancer Institute in Bethesda, Maryland. Dividing smokers into those having high, medium and low levels of the two chemicals, the researchers followed lung cancer diagnoses for 10 years.
Risk Factors
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