In-Depth Look at RAS Mutations Highlight Age-Related Molecular Differences in CRC

PHILADELPHIA (August 19, 2019) – A new study by researchers at Fox Chase Cancer Center provides more evidence that colorectal cancers diagnosed in younger patients may be distinct from those diagnosed in older patients.

Joshua E. Meyer, MD, of the Department of Radiation Oncology at Fox Chase, and colleagues including Ilya Serebriiskii, PhD, Sanjeevani Arora, PhD, Elizabeth Handorf, PhD, and Erica Golemis, PhD, recently conducted an in-depth analysis of the mutational profile of the three RAS oncogenes – KRAS, NRAS, and HRAS -- genes that, when mutated, are associated with worse survival outcomes in colorectal cancer.

Their analysis identified a greater incidence of a specific KRAS mutation – G12 – in patients who were younger than 40 years. In contrast, older patients had more frequent incidence of a separate mutation –Q61. 

“The discovery of this [Q61] mutation lends support to the idea that, while we have always thought of colorectal cancer as one group, or a couple of groups, or diseases, we need to continue to split them up into smaller and smaller boxes in order to optimize treatment paradigms for patients,” Meyer said.

The paper, “Comprehensive characterization of RAS mutational profile in colon and rectal cancers, and in older versus young patients” was published in Nature Communications.

In recent years, the American Cancer Society has reported that colorectal cancer incidence in adults younger than 55 has been increasing since the mid-1990s. Additionally, a growing body of data indicates that colorectal cancer mortality rates in adults younger than 55 have begun to increase in the last decade after multiple decades of decline.

Mutations in the RAS pathway, particularly KRAS and NRAS, occur in about 40% to 50% of colorectal cancers, and are known to drive tumor progression and influence the efficacy of cytotoxic and targeted therapies for the disease. 

In order to further characterize RAS mutations in colon and rectal cancers, Meyer, Fox Chase colleagues, and collaborators at Foundation Medicine analyzed 13,336 colorectal cancer samples and compared the frequency of specific mutations based on age of diagnosis, microsatellite instability (MSI) status, and tissue subsite.

Looking specifically at those patients with microsatellite stable or MSI-low disease, they found that the number of KRAS alterations significantly increased with age, while the frequency of variants in NRAS remained constant.

Unexpectedly, some specific mutations in RAS had association with sex as well as age.  For example, Q61 mutations were identified as occurring at more than twice the frequency among patients 40 and older compared with younger patients, with certain variants of the mutation occurring only among older patients. Additionally, the Q61K codon substitution was found only in samples from colon tumors and not in rectal tumors, and Q61K mutations occurred more frequently in females than in males.

Meyer believes this study by itself will not change clinical practice, but makes clear the need for additional investigations of colorectal cancer in younger patients.

“Because patients with colorectal cancers younger than age 50 represent only about 10 percent of newly diagnosed patients, they are a difficult group to study in isolation,” he said. “The more information like this that we have, that shows that [colorectal cancer] is a different disease in specific patient subgroups, the easier it will be for us to really delve into each patient population and try to develop a better treatment paradigm for them.”

This work was supported by an NCI Core Grant P30 CA006927, NIG R01 DK108195, NIH R01 CA229259-01, by a subsidy of the Russian Government to support the Program of Competitive Growth of Kazan Federal University, a grant from the Colorectal Cancer Alliance to study young onset colorectal cancer, and a Department of Defense Career Development Award.

Fox Chase Cancer Center (Fox Chase), which includes the Institute for Cancer Research and the American Oncologic Hospital and is a part of Temple Health, is one of the leading comprehensive cancer centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase is also one of just 10 members of the Alliance of Dedicated Cancer Centers. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence six consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

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