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Younger, Older Prostate Cancer Cases Marked by Distinct Expression Patterns

NEW YORK (GenomeWeb) – A new study suggests that the gene expression profiles present in prostate cancer tumors found in young men differ from those found in tumors from older prostate cancer patients, revealing potential differences in disease development and possible avenues for prostate cancer biomarkers in younger individuals.

Researchers from the US and the Netherlands used a combination of array-based gene expression profiling and small sequencing to track messenger RNA and microRNA patterns in matched tumor and normal samples from more than four dozen men with prostate cancer: 24 of whom were younger than 45 years old and 25 who were older than 70 years old.

Their results, published online this week in PLOS Genetics, indicated that younger patients were not only more prone to prostate cancer recurrence, but also typically showed higher expression of immune and inflammatory genes, including pathways involving the CTLA4 and IDO1/TDO2 genes.

"[O]ver-expression of CTLA4 and IDO1 was significantly associated with biochemical recurrence," senior author Susan Neuhausen, a population sciences researcher at the Beckman Research Institute of City of Hope in Duarte, California, and her co-authors wrote.

They noted that the results so far "provide clues on the mechanisms of tumor development and point to potential biomarkers for early detection and treatment for prostate cancer in young men."

A building body of evidence suggests that prostate cancer is becoming more common in men under the age of 45 or 50 years old, the team explained. And these cases tend to be more aggressive than those diagnosed in the elderly. To explore possible differences between samples from prostate cancer cases at either end of the age spectrum, the group brought together samples from individuals under 45 and over 70 years old who had similar tumor grade and differentiation level, based on Gleason scores.

Using Illumina Human Whole-Genome DASL arrays, the researchers assessed gene expression patterns in tumor and normal samples from 24 individuals between the ages of 38 and 45 years old and 25 individuals from an older group of prostate cancer patients who were 71 to 74 years old.

Along with comparisons of gene expression in tumor and normal samples from individuals within each age group, the team searched for genes with distinct expression profiles in samples from the younger and older patients.

For example, the researchers noted that 70 of the 121 genes found at higher levels in the younger prostate cancer patients came from pathways related to inflammation or immune pathways. On the other hand, the set of 62 genes with diminished expression in the younger age group included at least 21 metabolism-related genes.

With the help of gene-set enrichment analyses, the team found that expression was especially enhanced when it came to an immune pathway containing the immune checkpoint gene CTLA4 (what's missing?). And folding in miRNA patterns from the samples hinted that miRNAs targeting immune genes may also be dialed down in the younger prostate cancer patients.

The researchers noted that a handful of the same immune genes that were differentially expressed in the younger patients from their own analysis appeared to show age-related expression in prostate cancer samples considered for the Cancer Genome Atlas Project.

Meanwhile, for the 46 prostate cancer patients with available prostate-specific antigen data available after surgery, the team saw evidence of biochemical disease recurrence in five individuals from the young prostate cancer group and two older prostate cancer patients. Again, inflammation and immune-related genes — particularly CTLA4 and IDO1 — appeared to be upregulated in the younger patients with potential recurrence.

"[E]ven when matching Gleason score and tumor grade, there are differences in gene expression in prostate tumors from young and older men," the authors wrote, though they cautioned that "[i]t may be that these younger men have less indolent disease, and if not caught early, would have progressed to a higher grade and Gleason score in several years."

Even so, they explained, "[w]e have identified genes and associated pathways that may explain some of the age differences, and that may provide urologists with important information to treat the increasing number of young men with prostate cancers."