As discussed in our previous Genetics series posts, the discovery of non-coding RNAs paved the way for changes in the Central Dogma and how we think about the flow of genetic information in our cells. The KRAS-variant is important because it interacts with a specific class of these non-coding RNAs, called microRNAs. Take a look at ourGenetics 102
Â and recall that microRNAs are the contractors of different biological projects in our cells. They determine the type and number of certain protein tools that are employed to assist in these projects.
How do microRNAs make these decisions and successfully regulate the cell?
They position themselves on a specific landing spot that is found in the 3 untranslated region (3 UTR) of growth and survival genes. KRAS is one of these genes, and the KRAS-variant is an irregularity or difference in a defined landing spot, which means that microRNAS cannot communicate with or control the KRAS gene in individuals with the KRAS-variant in the same way they can in people without this gene mutation.
Now that our understanding of microRNA signaling and the KRAS-variant has been refreshed, we can delve into a recent study conducted by members of Dr. Weidhaas lab at UCLA! Previous research has shown that KRAS-variant individuals exhibit a unique biology that not only increases their risk of developing certain types of cancers, but that can also be positively or negatively influenced based on external factors. Â For example, KRAS-variant individuals respond differently to significant decreases in estrogen as compared to patients without the KRAS-variant, and they also respond differently to specific cancer treatments as compared to their non-KRAS-variant counterparts. This finding seems to indicate that KRAS-variant individuals have fundamentally different baseline biology. Â Interested in this idea that the baseline biology of a KRAS-variant patient rather than just differences in a tumor they might develop is unique, researchers hypothesized that normal, non-cancerous cells with the KRAS-variant would also be biologically unique.
To test this hypothesis, the lab created and compared perfectly matched normal breast epithelial cells with the KRAS-variant versus those without. They were able to show that the KRAS-variant is responsible for a wide range of biological differences, even in normal cells. This confirms the global impact of the KRAS-variant on how cells grow, function, and regulate proteins and other cellular tools. As evidence of this impact, it was found that the KRAS-variant induced an epithelial-to-mesenchymal transition (EMT) in normal breast cells. EMT is recognized as an important marker of metastasis in tumors, the spread of cancerous cells beyond the primary cancer site. It remains to be determined what the impact of EMT in normal KRAS-variant cells is in general, and what if any impact this has on both tumor development and tumor behavior. This work is ongoing in the Weidhaas laboratory.
Why are these findings important?
Research on cancer has generally only focused on changes found in the tumor. While there are very few genetic differences that predict increased cancer risk, the few that are known, such as BRCA1 and BRCA2, generally do not predict different baseline cellular biology. Instead, patients with these mutations just repair DNA damage less effectively than those without, leading to a higher risk of developing cancer. The KRAS-variant is a new type of genetic marker of cancer risk, and its unique role in predicting cancer risk, as well as treatment response, is supported by these new findings – the presence of the KRAS-variant impacts baseline cell biology–the way in which our cells respond to external factors–in a powerful and meaningful way. These findings are important steps towards unraveling the best paths to both prevent cancer in KRAS-variant patients, as well as to find solutions for the best treatments.
This is one of the most intriguing articles I have ever read about cancer, and as a survivor I have read many! The fact that Dr. Weidhaas and staff have discovered that: “the presence of the KRAS-variant impacts baseline cell biology–the way in which our cells respond to external factors” is amazing to me. I have other health issues besides being in cancer remission, and I suspect that the Kras-variant has something to do with them – neurological system that is hypersensitive to pain; frequent migraine headaches; irregular-shaped cornea; exaggerated fatigue response to medications to name a few. I so look forward to reading about many new discoveries that will occur in Dr. Weidhaas laboratory.
Thank you so much Marie for the kind words!
I, too am fascinated with your advancing research, having been tested and declared positive for Kris-variant 10 years ago. Having 2 adult daughters-I am interested in how they can be tested. I was diagnosed with triple negative breast cancer in 2008.