What it is & What we know
Genes and Gene Mutations
Our DNA is made up of thousands of genes which contain the instructions for how to make the proteins that regulate our bodies, telling our cells when to replicate, repair themselves, and/or destroy damaged cells.
Genes behave abnormally when they have mutated in some way and therefore cannot receive or send instructions properly.
Gene mutations can either be inherited or acquired (somatic). Inherited gene mutations are passed down from your mother and/or father, and are in every cell in your body when you are born. Acquired or somatic gene mutations occur after you are born and can result from environmental or lifestyle factors such as smoking, radiation, UV exposure, diet, etc.
Cancer is a disease that results in abnormal gene function.
While it has been believed that much of the time cancer is due to chance, as only 5-10% of cancers had known hereditary causes, we believe that much more of cancer risk is passed down from your parents. Our work at MiraKind is to discover the genetic markers for many more cancers, and to use this information to define the strategies and behaviors that may help reduce cancer risk.
The KRAS-variant is a good example of a new biomarker which provides a new explanation for the genetic cause of cancer for many more families with strong cancer histories. This mutation predicts an increased risk of breast (up from 1:8 to 1:4), ovarian (up from 1:74 to 1:12), and lung cancer, as well as multiple cancers in the same individual. The KRAS-variant is found in up to 25% of cancer patients, and is in 1/17 people in the general population, making it far more common that previously known mutations associated with cancer, such as BRCA1, which is found in only 5% of breast and ovarian cancer patients, and in 1/400 people overall.
Before the KRAS-variant
After the KRAS-variant
Hereditary cancer is caused by known inherited genetic mutations such as BRCA or CHEK2; familial cancer is cancer that occurs in families more often than would be expected by chance, although there has been no known genetic mutation identified to explain it; sporadic cancer is the term used to explain cancer that occurs in people who do not have a known strong family history or a known inherited genetic difference. The KRAS-variant is emerging as a hereditary explanation for a significant proportion of both familial and sporadic cancers that were previously unexplained.
What can the KRAS-variant tell me about my health?
The KRAS-variant was discovered in 2007, and MiraKind’s research studies are helping us learn more about its implications for health and cancer risk every day. However, we have already learned some important things about how individuals with the KRAS-variant may be able to use information about their KRAS-variant status to help them make decisions about their health. Learn more about the KRAS-variant if you have a family or personal history of cancer, have tested BRCA-negative, or are peri- or menopausal.
Getting tested for the KRAS-variant provides information that you and your doctor can use to make informed decisions about your health. If you do test positive, we are here to work with you and your physician—you can learn more about what your KRAS-variant test result means for your health in Understanding Your Results. As well, MiraKind’s community is available to provide ongoing support, communication, and education to you and your family members.
The KRAS-Variant and Cancer, including Family History of Cancer
The KRAS-variant is an inherited genetic mutation associated with a family history of cancer, especially breast,1 ovarian,2 lung,3 as well as other cancers,4,5 and multiple cancers in the same individual.6,7
While BRCA is the most well-known and commonly tested genetic mutation for Hereditary Breast and Ovarian Cancer (HBOC) families (i.e. those with multiple cases of breast and/or ovarian cancer on the same side of the family), it is also incredibly rare, found in only 0.25% of the population.
The KRAS-variant, in contrast, is found in 6-10% of the population, making it 20x more common than BRCA genetic mutations.
The biology of the KRAS-variant, an inherited genetic mutation, affords great promise for selecting the best treatment for the 20-25% of cancer patients who carry this biomarker.
In fact, recent research has shown that the KRAS-variant plays an important role in the body’s response to cancer therapies by affecting an individual’s immune system.
Specifically, studies have found that certain cancer medications are far more effective for KRAS-variant cancer patients, while others work poorly. The difference in taking the wrong versus the right cancer medicine if you are a KRAS-variant patient can lead to up to a 3-fold (300%) difference in your chance of survival. Research to determine which treatments work best for KRAS-variant patients have been conducted in breast,1 ovarian,2,3 colon,4-17 lung,18,19 and head and neck cancer.21-23 To read findings about specific types of cancers, please go here.
The KRAS-Variant and Menopause
Recent studies have found that continuing estrogen into menopause may help decrease cancer risk for certain individuals with an inherited genetic mutation known as the KRAS-variant.1,2,3
A recent MiraKind study showed that estrogen withdrawal, which occurs after oophorectomy (the removal of both ovaries), with the discontinuation of HRT, or at menopause, may increase cancer risk in women with the KRAS-variant.1 These findings indicate continuing estrogen with HRT may be beneficial for women with the KRAS-variant in these settings, if not otherwise contraindicated. It also suggests that KRAS-variant women may be a subgroup who are protected from cancer development through continued estrogen use.
Because the KRAS-variant is primarily associated with cancer onset at or after menopause, learning whether you carry this inherited genetic mutation can help you make informed decisions about your health at many points in your life:
Determine whether higher-level breast cancer screening, such as breast MRI, is something to consider in addition to annual mammograms. If having a hysterectomy and you are peri-menopausal, discuss the pros and cons of ovary removal with follow-up hormone replacement therapy (HRT) with your physician.
Determine whether hormone replacement therapy at menopause could be protective against cancer if not otherwise contraindicated. Use the information to determine whether or not ovary removal makes sense for you at menopause.
Be aware that an increased risk of ovarian cancer increases the importance of ongoing gynecological care. Determine whether continuing on hormone replacement therapy may be beneficial.
Use your genetic information to ask for continued breast and gynecological screening. Determine whether continuing on hormone replacement therapy may be beneficial.
The KRAS-Variant and Autoimmunity
Recently, we have shown that the KRAS-variant, and other novel inherited mutations like it, appear to predict altered immunity, and possibly autoimmunity.
We first found that individuals with the KRAS-variant are immunosuppressed, resulting in unique responses to cancer therapy1, and likely explaining their increased cancer risk. We also are investigating the impact of the KRAS-variant on the flip-side of immunosuppression, which is autoimmunity, which is also associated with an increased risk of cancer.
Our findings with the KRAS-variant led us to investigate a large panel of genetic biomarkers like the KRAS-variant, which also disrupt microRNA signaling. We have now found that these biomarkers also predict altered immunity, as presented at American Society of Clinical Oncology (ASCO 2017).
Our first discovered biomarker was the KRAS-variant, which is:
- An inherited, genetic marker that has significant implications for women’s health
- A predictor of breast, ovarian and lung cancer
- A biomarker that identifies women who can be protected from cancer by staying on estrogen, and that identifies patients who will respond uniquely to cancer treatment
You can learn about what your KRAS-results mean on our Understanding Your Results page.
We have completed and now published our first study, "Estrogen Withdrawal, Increased Breast Cancer Risk and the KRAS-variant." Thank you to the over 1700 women that participated in this important study, confirming the indisputable importance of the biologically funcational KRAS-variant in breast cancer risk and biology.
Our first webinar with our preliminary results is in the video below.
Blog posts with more information on the KRAS-variant:
- Paranjape, T., Heneghan, H., Lindner, R., Keane, F., Hoffman, A., Hollestelle, A., Dorairaj, J., Geyda, K., Pelletier, C., Nallur, S., et al. (2011). A 3'-untranslated region KRAS variant and triple-negative breast cancer: a case-control and genetic analysis. Lancet Oncology 12, 377-386.
- Ratner, E., Lu, L., Boeke, M., Barnett, R., Nallur, S., Chin, L., Pelletier, C., Blitzblau, R., Tassi, R., Paranjape, T., et al. (2010). A KRAS-variant in Ovarian Cancer Acts as a Genetic Marker of Cancer Risk. Cancer Research 15, 6509-6515.
- Chin, L., Ratner, E., Leng, S., Zhai, R., Nullur, S., Babar, I., Muller, R., Straka, E., Su, L., Burki, E., et al. (2008). A SNP in a let-7 microRNA complementary site in the KRAS 3' untranslated region increases non-small cell lung cancer risk. Cancer Res 68, 8535-8540.
- Kazmi HR, Chandra A, Kumar S, Satyam LK, Gupta A, Nigam J, Srivastava M, Mittal B. (2016) A let-7 microRNA binding site polymorphism in the KRAS 3'UTR is associated with increased risk and reduced survival for gallbladder cancer in North Indian population. J Cancer Res Clin Oncol. 2016 Sep 12. [Epub ahead of print]
- Gutiérrez-Malacatt H, Ayala-Sanchez M, Aquino-Ortega X, Dominguez-Rodriguez J, Martinez-Tovar A, Olarte-Carrillo I, Martinez-Hernandez A, C CC, Orozco L, Cordova EJ. (2016) The rs61764370 Functional Variant in the KRAS Oncogene is Associated with Chronic Myeloid Leukemia Risk in Women. Asian Pac J Cancer Prev. 2016;17(4):2265-70.
- Pilarski, R., Patel, D., Weitzel, J., McVeigh, T., Dorairaj, J., Heneghan, H., Miller, N., Weidhaas, J., Kerin, M., McKenna, M., et al. (2012). A KRAS-variant is associated with risk of developing double primary breast and ovarian cancer. PLos ONE 7, e37891.
- McVeigh TP, Jung SY, Kerin MJ, Salzman DW, Nallur S, Nemec AA, Dookwah M, Sadofsky J, Paranjape T, Kelly O, Chan E, Miller N, Sweeney KJ, Zelterman D, Sweasy J, Pilarski R, Telesca D, Slack FJ, Weidhaas JB. (2015) Estrogen withdrawal, increased breast cancer risk and the KRAS-variant. Cell Cycle. 2015;14(13):2091-9. doi: 10.1080/15384101.2015.1041694. Epub 2015 May 11.