Gene Signature May Predict Recurrence of Liver Cancer

Researchers have enhanced a genetic technique for studying chemically preserved tissue samples and used it to discover a gene signature that may identify patients with liver cancer who are at risk of a recurrence. Their findings also suggest that some late recurrences (more than 2 years after the initial disease) may not be recurrences at all, but rather new primary tumors that develop in a liver damaged by environmental factors such as infection by a hepatitis virus or cirrhosis.

In the study, published online October 15 in the New England Journal of Medicine (NEJM), Dr. Todd Golub of the Dana-Farber Cancer Institute and his colleagues first overcame a technical challenge. Genome-wide expression profiling studies, which are large-scale surveys of gene activity in cells, have led to new classifications of cancers and diagnostic tools, but they can only be performed on frozen samples. Vast stores of patient samples, including specimens with long-term clinical follow-up, have been preserved with the chemical formalin rather than by freezing, and therefore are unavailable for genomic analyses.

To address this problem, scientists at Illumina, Inc., recently developed a technique for profiling several hundred genes in formalin-fixed samples. In this study, Dr. Golub and his colleagues modified the technique to profile approximately 6,000 genes. They obtained useful information from 90 percent of the 2,000 patient samples they examined, including some collected 24 years ago.

Next, the researchers profiled liver tumors, but failed to detect a survival signature. They then hypothesized that tissues surrounding the liver tumor - rather that the tumor itself - might harbor a genetic signature associated with recurrence. This adjacent tissue is frequently abnormal in patients who have experienced infection or cirrhosis.

Using a set of 106 patients, the team identified a 186-gene signature based on the activity of genes in tissues adjacent to tumors. They validated it using samples from patients in other parts of the world. If confirmed by future studies, the signature could identify at-risk patients who might benefit from intensive treatments and preventive measures.

The ability to survey the entire genome in an unbiased manner was essential, noted Dr. Golub, who also directs the cancer program at the Broad Institute. "We never would have discovered this signature if we had only been profiling several hundred genes," he said. A commerical tool is now available for genome-wide analyses of formalin-fixed samples.

One in Four Teenage Girls Receives HPV Vaccine

One in four teenage girls has begun the process of vaccination against human papillomavirus (HPV) with the three-shot series of Gardasil, according to the 2007 National Immunization Survey-Teen. In March 2007 the Advisory Committee on Immunization Practices (ACIP) recommended that all girls age 11 or 12 be routinely vaccinated with three doses of quadrivalent HPV vaccine. The new survey was the first official government report on compliance.

The vaccination series can be started as young as age 9. The ACIP also advises females aged 13 to 26 to obtain "catch-up" vaccinations, even though Gardasil is preventive, not therapeutic, and they may have already been exposed to HPV. The quadrivalent vaccine protects against HPV types 6, 11, 16, and 18, which account for up to 70 percent of cervical cancers and 90 percent of genital warts.

The 25.1 percent vaccination rate drawn from the sample group suggests that 2.5 million of the 10 million teenage girls in the United States were vaccinated. However, the survey was completed by telephone interview in 5,474 households where a teen boy or girl aged 13 to 17 lived, and results were confirmed from medical records for only 2,947 of those teens. Furthermore, the vaccination schedule calls for three shots over the course of 6 months; thus those surveyed as having received one dose of the vaccine may not complete the full, three-shot series. Finally, some structural aspects of the survey methodology and health care provider histories could make it difficult to generalize these results either to the entire population or to specific groups, such as Latina teens.

The results were published October 10 in the Morbidity and Mortality Weekly Report, as part of a report on recommended vaccinations for adolescents. It also included compliance reports for several other ACIP-recommended vaccines indicated for adolescents.

Smoking in Middle Age Decreases Quality of Life in Old Age

It is well established that smoking shortens life expectancy, but smoking in midlife also results in a poorer quality of life in old age, according to a study published October 13 in Archives of Internal Medicine.

Researchers in Finland examined the relationship between long-term cigarette smoking and health-related quality of life (HRQoL) among 1,658 men participating in the Helsinki Businessmen Study. All the men were healthy at baseline in 1974 with a mean age of 47.8 years. The health status of 1,131 (87.9 percent) of those men alive in 2000 was re-evaluated using the RAND 36-Item Health Survey, a widely used measure of HRQoL. The researchers found that participants who never smoked lived, on average, 10 years longer than heavy smokers and had the highest (i.e., best) scores on the RAND scales.

"The differences were greatest between never smokers and heavy smokers, ranging from 4 points on the scale of social functioning to 14 points on the physical functioning scale," the scientists reported. The physical component summary score showed a graded deterioration of HRQoL as the number of cigarettes smoked daily increased.

Compared with heavy smokers, never smokers "enjoyed significantly better health status in late life, which was equal to an age difference of 10 years in the general population," the researchers noted. "From a prevention point of view, our findings of the smoking/HRQoL relationship add to the view of the burden of smoking on society. The argument of better quality of life may be especially meaningful for the aging smoker but, as our results show, for the best HRQoL [smoking] should not be started at all."

More Evidence for Role of ALK in Neuroblastoma

In August 2008, researchers identified germline mutations in the anaplastic lymphoma kinase (ALK) gene in the vast majority of families with the inherited form of neuroblastoma. They also found somatic ALK mutations in 12 percent of high-risk, spontaneous (not inherited) tumor samples. An additional four studies published in the October 16 Nature have now confirmed a role of ALK in neuroblastoma.

In the first study, investigators found three different germline mutations in ALK in eight families affected by hereditary neuroblastoma, and somatic ALK mutations in 8.4 percent of samples from spontaneous tumors and 35.7 percent of neuroblastoma cell lines. In the second study, researchers found germline ALK mutations in two out of six families, and discovered that gene number alterations and gene changes in ALK in spontaneous tumors occurred mainly in two regions on the gene.

The third study also found ALK mutations in 6.1 percent of primary tumors and 33 percent of neuroblastoma cell lines. The fourth study identified five different ALK mutations in 8 percent of neuroblastoma samples; three were somatic and two were germ-line mutations.

Importantly, these mutations appear to increase the activity of the ALK protein; the studies showed that the mutant ALK protein was overexpressed and continually activated other proteins in downstream cell-signaling pathways, which can lead to aberrant cell growth and division. Inhibiting the mutant ALK genes, either with RNA interference or with targeted drugs, decreased the proliferation of neuroblastoma cells or caused cell death in all of the studies.

"Neuroblastoma is the most common childhood cancer diagnosed before the age of one, and accounts for some 15 [percent] of all cancer deaths in children," says Dr. Charis Eng from the Cleveland Clinic in an accompanying editorial. Although further studies will be needed to define how ALK might be targeted for treatment or for genetic testing in families affected by inherited neuroblastoma, she explains, "The long-awaited discovery of a major non-syndromic neuroblastoma gene is indeed a welcome advance."