Genetic Markers Identify Probability of Lung Cancers Recurrence

Genetic alterations in tumors and tissue taken from early-stage lung cancer patients are clear pointers to which cancers might recur. Researchers say the findings could change the approach to treating even the smallest lung cancers—the size of a pea—which are known to recur within five years in 30 to 40 percent of patients.

"This is DNA forensics for cancer," says Malcolm Brock, M.D., associate professor of surgery at Johns Hopkins. "While there may be no trace of cancer that we can spot after surgery with a microscope, the DNA evidence from these tumors may have been left at the scene, especially in lymph nodes."

The research team from Johns Hopkins Kimmel Cancer Center identified methyl groups that connect with the DNA structure of a gene. The development of cancers signals cells to switch certain genes on or off, and methylation is a common phenomenon in this process. Disruption to these signals may create abnormal proteins that lead to cancer or its recurrence.

In the study, Brock and his team checked more than 700 surgical samples from 167 early stage non-small lung cancer patients, looking for specific methylation patterns linked o cancer. For 51 patients, whose cancers recurred within 40 months, tumor and lymph node tissue was compared with samples from the remaining 116 patients whose cancer did no recur. The scientists tested all the samples for methylation on seven genes linked to the development of lung cancer. Four of them—p16, H-cadherin, APC and RASSF1A—showed the highest amounts of methylation in patients who had a recurrence of the cancer.

For many of the genes, the study revealed a twofold difference in methyl marks between recurrent cancers and those that did not return.

"The DNA evidence we see for many of the recurring cases suggests it may be wise if our work is confirmed to reclassify such cancers as advanced disease instead of early stage," says Brock.

Higher than normal methylation, combining two genes known as p16 and H-cadherin located in both tumor tissue and a lymph node remote from the tumor area, meant that cancers returned faster than average in 11 patients. For 8 of them this methylation pattern had cancers returning within a year; for the remaining 3 it took 30 months for the cancers to recur.

When analyzing the results to quantify the odds on a patient’s cancer returning, they noted a 5 to 25-fold in risk depending on the particular methylation pattern. While the small sample size meant that some of the gene markers lacked statistical significance, they believed that odds predictions were valid for p16 and H-cadherin.

Kimmel Cancer Center medical oncologist James Herman, M.D. says if these results are confirmed, it may lead doctors to consider treating high-risk patients more aggressively with chemotherapy after surgery. He also believes that therapies which target these gene patterns by stripping off methyl groups hold promise as well. "These marks of aggressive disease also are themselves targets for therapy."

The study appeared in the March 13 issue of the New England Journal of Medicine.

New Breast Cancer Gene HMMR Found

Researchers have found a new gene called HMMR that, when mutated, may lead to a significantly greater chance of developing breast cancer. The study was a collaboration of international researchers from Spain, Israel, and several U.S. organizations.

The HMMR gene is mutated in about 10% of the population, while two other genes related to breast cancer, BRCA1 and CRCA2, are mutated in only about 0.3% of the popuation. According to the study’s authors, it’s important to identify more common breast cancer-related genes so that targeting the gene for early detection will have a greater impact.

The method of identifying the HMMR gene began with computer modeling to identify genes that impact cancer development and to see how they interact with other genes. Starting with four known breast cancer-related genes (BRCA1, BRCA2, ATM and CHEK2), researchers then showed that alterations of either BRCA1 or HMMR can lead to genetic instability and interfere with cell division.

To specifically understand whether variations in HMMR increased breast cancer risk, 923 women with breast cancer and similar women without breast cancer were analyzed in a study led by Gadi Rennert, M.D., director of the CHS National Cancer Control Center in Haifa, Israel. The results indicated that women in the study under 40 years of age with the HMMR variant (even after accounting for mutations in the BRCA1 or BRCA2 genes), had a 2.7 times greater risk of developing breast cancer than women without the variation.

The study was conducted among a population of Ashkenazi Jewish women, who have a higher risk of breast cancer than other groups.

The findings were verified in two other studies conducted in New York–one among another group of Ashkenazi Jewish women with a family history of breast cancer but no identified BRCA1 or BRCA2 mutations, and a third study of Jewish women with and without breast cancer in New York. Overall, 2,475 women with breast cancer and 1,918 healthy women were studied in Israel and New York.

The findings indicated that incidence of breast cancer was 23% higher in women who had one copy of the genetic variant, and 46% higher in women who had two copies of the variant. Researchers also concluded that HMMR may be associated with early-onset breast cancer, as the women with the HMMR variant were diagnosed about one year earlier than the control group.

"Identifying genes involved in cancer in the general population is important, because not all of the causes of breast cancer have been found. Through discoveries such as this, someday we might be able to more precisely estimate a person’s risk of cancer based on their genes," says study author Laura Rozek, Ph.D., a postdoctoral research fellow at the University of Medical School.

The study was funded by the National Cancer Institute, the National Institutes of Health, the Breast Cancer Research Foundation, the Niehaus, Southworth, Weissenbach Foundation, and the Koodish Foundation.

Sources: Nature Genetics, doi:10.1038/ngxxxx and University of Michigan

Genes Linked to Multiple Sclerosis (MS)

Researchers have published their discovery linking two genes with multiple sclerosis (MS).
Multiple sclerosis is an inflammatory disorder in which the immune cells infiltrate the brain and spinal cord.

Surrounding and protecting some brain and spinal cord cells is a fatty layer known as the myelin sheath. Myelin sheath is important for conducting electrical impulses along the nerves and maintaining the health of the nerves.
In multiple sclerosis, inflammation causes the myelin to degenerate and eventually disappear, causing the impulses that travel along the nerves to decelerate.

The researchers conducted a study using DNA technology that enabled them to screen the genetic blueprint of close to 3,000 people, 931 of whom had the disease.

The data revealed 174 nucleotide differences called single nucleotide polymorphisms (SNPs) that may be associated with the risk of multiple sclerosis. They then analyzed 110 out of the 174 SNPs in a second set of subjects which number close to 5,000 people. In their final combined analysis, the scientists cited several genes that showed significant association with the risk of multiple sclerosis, two of which are implicated in the regulation of the immune response–interleukin-2 receptor alpha gene (IL2RA) and interleukin-7 receptor alpha gene (IL7R).

Other associated genes include KIAA0350, RPL5, DBC1, CD58, ALK, FAM69A, ANKRD15, EVI5, KLRB1, CBLB and PDE4B.
The research was published in the August 2007 issue of the New England Journal of Medicine.

Gene Link Found for Type 1 Diabetes

A research team, from the Children’s Hospital of Philadelphia and McGill University in Montreal has identified a single gene that may be a trigger for Type 1 diabetes.

The gene variant, called KIAA0350, greatly raises a child’s chances of developing the disease.
The study is published in the journal Nature.

Breast Cancer Genes Don’t Lower Survival Rate

Breast-cancer patients carrying two well-known genes linked to the disease have the same survival chances as noncarriers of the genes who develop the disease, according to a study by Israeli and Canadian researchers.

The study was aimed in part at shedding light on whether breast-cancer treatment should be tailored differently for women with the two gene mutations, known as BRCA1 and BRCA2. The results provided no decisive answers on that question, but could provide some comfort to carriers who might feel the odds stacked against them.

Gene Linked to Childhood Asthma

A recent study reports that scientists have found a gene that is strongly associated with an increased risk of asthma in children.
The study, published in the journal Nature, encompassed more than 2,000 children, and found that a gene called ORMDL3 was found at higher levels in the blood cells of children with Asthma.
Though the study did not determine how the gene was specifically related to increased risk of asthma, it indicated that the genes are found in primitive organisms such as yeast. The scientists opined that ORMDL3 may be a component of ancient immune mechanisms.

Source: BBC (7/4/2007)