For years, doctors have used lab-generated testosterone or infertile patients’ natural supply to show they have no chance of developing prostate cancer. But a new study suggests that patients who carry a mutation in the KRAS protein gene might catch more aggressive forms of the cancer.

The study used a mouse model of prostate cancer, and Kragojee and his colleagues found that KRAS mutations caused tumors to grow more slowly in mice with KRAS mutations. But they didn’t reveal evidence that KRAS mutations lead to more aggressive (also known as “super-aggressive”) prostate cancer, leading the team to conclude that KRAS mutations likely don’t increase cancer risk.

“As prostate cancer is increasingly recognized as an imperfect form of cancer that demonstrates the value of adding genetics to methodologies, we call our findings convincing evidence,” said study senior author Kim British, Ph.D., Osher Center at CAMH’s E. L. Steele Laboratories and professor of biological engineering in the School of Engineering & Applied Science. “This is not an argument for clinical use of KRAS mutations in prostate cancer, but it does suggest that KRAS mutations are not a major cancer risk factor.”

The KRAS gene, also known as the Cash1 gene, harnesses genetic changes that are normally not present in the normal brain. A mutation in the Cash1 gene estimates the basal levels of $315 in patients with malignant brain tumors. The genomic regions where KRAS proteins bind have been found to be more common in patients with a brain tumor and are suspected to increase cognitive loss. The Cash1 mutation was identified as a culprit in basal membrane-bound KRAS-driven prostate cancer, an aggressive form of non-Hodgkin lymphoma.

ER and non-ER using cell lines.

Researchers used a combination of in vitro and in vivo cell lines to screen for KRAS mutations. “Cell lines are a useful, inexpensive tool for studying cell behavior, adaptation, and cell differentiation. Cell lines are an excellent way to study cell proliferation, survival, and differentiation in cells,” said Kragojee, who also is Data Science & Data Science & Genomic Sciences Core Facility and a member of the Roche CellTech Center for Cancer Research & Precision Medicine and the Roche Oncology Data Sciences Center.

Gerard Koch, Ph.D., a postdoctoral fellow in study co-corresponding author, and colleagues found that KRAS mutations were erased from ER-positive (population-enriched) lymphomas, and cancer cells in ER-positive models were more aggressive. These results were validated in a mouse model of prostate cancer and in a sample of ER-positive Ewing sarcoma tumors, a rare type of non-HER2 breast cancer.

“ER and ER-positive lymphomas are characterized by nuclear accumulation of KRAS mutations in basal membrane positions along the cytosol membrane, but KRAS mutations have been found to be absent from ER-positive (high-TRIA)-positive ER+ (family) tumors,” said Gerardo Pérez, Ph.D., a postdoctoral fellow in the team. “Prostate cancer is one of the same sarcoma families that have ER mutations found in 60 percent to 80 percent of all patients with prostatitis pilaris and 120 percent to 180 percent of ER+ (no metastatic) patients.

“This suggests a novel etiologic role of KRAS mutations in prostate cancer,” said Pérez.

Different studies using different forms of prostate cancer revealed a different KRAS mutation pattern. ER-positive prostate cancer with reduced basophils (cells that detect changing hormones such as prostate acids) or without (lung cancer) had more KRAS mutations. In ER-positive highly lethal (ESMR) or ER-positive lung cancer, the KRAS mutation pattern correlated to the extent of cell damage (on average, KRAS mutations were more powerful). In the ER-positive GRK-resistant-SCA group, KRAS mutations correlated with greater and more aggressive prostate cancer.

“Our studies provide evidence supporting a heterogeneous KRAS mutation in the prostate cancer model. Based on these findings, we suggest a potential role for alterations in ER genetic diversity in the development of prostate cancer and ESRGV-A positive prostate cancer,” said Pérez.