Comprehensive Atlas of Genetic Architecture Compiled for Mutant RAS Genes in Cancers

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Researchers from the Johns Hopkins Kimmel Cancer Center, three other cancer centers and the Johns Hopkins Bloomberg School of Public Health have compiled a comprehensive atlas of the genetic architecture of mutant RAS genes in human cancers. Their four-year study of the RAS family – including the kras, NRAS and SARS genes that are mutated in about a third of all human cancers – found that the frequency of mutant RAS genes differs across different tumor types, age, sex, and racial groups, and patterns of co-mutation between RAS genes and other genes can potentially lead to different clinical outcomes or identify new areas for therapeutic intervention.

The book, published September 8 in Research against cancer, focused on next-generation targeted sequence data analyzes of more than 600,000 mutations from more than 66,000 tumors in 51 cancer types from the AACR (American Association for Cancer Research), which brings together generation sequence data from several academic institutions. Researchers from the Dana-Farber Cancer Institute in Boston, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center in Nashville, and Memorial Sloan Kettering Cancer Center in New York also contributed to this work. Study results are publicly available online at ras-hallmarks.jhmi.edu/ and through the AACR Project GENIE Registry.

This work has generated a comprehensive atlas of simultaneous and mutually exclusive mutations between RAS genes and other genes at unprecedented resolution. The results have immediate implications for how clinicians might be able to select patients for combination targeted therapies, such as KRAS-inhibiting drugs, and understand why some patients may not respond to certain therapies, says Dr. study senior author, Valsamo Anagnostou, MD, Ph.D., Director of the Molecular Oncology Laboratory and Thoracic Oncology Biorepository at Johns Hopkins Kimmel Cancer Center and Associate Professor of Oncology at Johns Hopkins University School of Medicine.

When treating patients with RAS mutant tumors, clinicians should consider clinical findings and tumor aggressiveness as well as co-mutations and patient characteristics such as gender, racial background, and ethnicity. age, explains Anagnostou. “Context matters,” she says. “Our study shows that you have to consider who the host is and what the genetic makeup of the tumor is, because RAS mutant tumors with different co-mutations have completely different profiles and clinical behavior.”

During the study, the researchers looked at several characteristics of RAS genes. They first looked at the distribution and heterogeneity, or variation, of mutant RAS across cancer types and co-occurring mutations. Led by Robert Scharpf, Ph.D., associate professor of oncology at Johns Hopkins Kimmel Cancer Center, the team developed new analytical frameworks to assess the prevalence and co-mutation patterns of RAS genes in the AACR Project registry. GENIUS. They studied the cancer type-specific prevalence of kras, NRAS and SARS mutant alleles (alternative forms of a gene) at codons (units of the genetic code) 12, 13 and 61 in the general population and stratified their results by patient age, race and sex.

The prevalence of RAS mutations varied according to cancer type: 74% in pancreatic cancers, 43.5% in colorectal cancers, 29.7% in non-small cell lung cancers, 25.3% in melanomas , 20.9% in cancers of unknown primary origin, 5.9% in precancerous cancers. blood and bone marrow diseases (myelodysplastic/myeloproliferative syndrome) and 1.5% in tumors of the central nervous system. Mutations were less common in prostate, breast and kidney cancer and in mesothelioma, with mutation rates affecting around 1% of individuals.

kras mutations occurred at higher frequency in gastrointestinal tumors, lung cancers, and gynecological malignancies, while NRAS was more frequently mutated in melanoma, thyroid cancer and hematological malignancies. SARS was globally less frequently mutated. Digging deeper, the researchers found that non-small cell lung cancers mostly harbored kras G12C mutations, whereas these mutations were present in approximately 10% of colorectal cancers and 1% of pancreatic cancers.

Mutations were found at different frequencies depending on the age, sex and gender of the patient. For example, RAS mutations were less common in younger patients with melanoma (11.8% less), cancer of unknown primary origin (12.5% ​​less), non-small cell lung cancer (11% less) and pancreatic cancer (14.6% less), but more common in younger patients with ovarian cancer (15.8% more) and leukemia /B lymphoblastic lymphoma (8.2% more) compared to the general population. Gender-based differences were also observed among RAS mutations, colorectal cancers (3.6% higher), and non-small cell lung cancer tumors (2.6% higher) in women more frequently harboring RAS mutations than men. In contrast, melanoma tumors in women had fewer RAS mutations (3.3% fewer) than in men.

Racial differences have also been observed among the mutations. For example, black people with colorectal cancers harbored a greater number of kras codon 12 mutations (6.5% higher) such as G12V, and kras codon 13 mutations (4.4% higher) such as G13D, than people of other racial groups. Codons are a DNA sequence that corresponds to a specific amino acid during protein synthesis. In non-small cell lung cancer, RAS mutations occurred less frequently in Asian patients (18.6% less). RAS mutations were also less common in black people with uterine cancers (9.6% less).

To assess co-occurring mutations, the team modeled dependencies between RAS genes and other genes across cancer types. RAS hotspot mutations co-occurred with mutations in genes AT M, KEAP1, MAX, NKX2-1, RBM10, STK11 and USF1 in non-small cell lung cancer, for example. The team also found some cases in which RAS mutations were less likely to coexist with other genetic mutations, such as with the BRAF Where RNF43 genes in colorectal cancers.

We have confirmed and validated co-occurring mutations known to us from previous studies, such as kras and STK11 in non-small cell lung cancer. However, we also found new co-mutations, such as kras and NTRK3which is very important, as these may represent potential therapeutic targets and may lead us to combination treatments. »


Robert Scharpf, Ph.D., Associate Professor of Oncology, Johns Hopkins Kimmel Cancer Center

The team also studied the genomic landscapes of RAS mutant tumors, examining all kras, NRAS and SARS mutant alleles and taking into account the co-occurrence with non-RAS mutations. The researchers found distinct patterns depending on the type of cancer and the patient’s age, sex and race.

Additionally, they examined how RAS co-mutations relate to cancer characteristics and expression profiles of cancer cells and the tumor microenvironment (the cells in and around tumors), evaluating sequence data from 9,258 Cancer Genome Atlas, a National Cancer Institute’s genomic database of more than 20,000 primary cancers covering 33 cancer types. These analyzes showed distinct gene expression programs in RAS mutant tumors with different co-mutations.

Finally, the team assessed the association between distinct genomic pathways of RAS mutant tumors and clinical outcomes. They evaluated 10,217 tumors from the Cancer Genome Atlas and assessed differences in overall survival among people with tumors harboring RAS co-mutations, with some notable results. Patients with lung cancer harboring kras G12C mutations and KEAP1, NTRK3, PIK3CA Where TP53 co-mutations, for example, had significantly shorter overall survival than those without kras co-mutations. Notable differences in outcomes with immunotherapy were also found in tumors with different kras mutations. For example, patients with non-small cell lung cancer harboring kras G12C/PIK3CA co-mutations had shorter overall survival, but patients with non-small cell lung cancer kras G12C and TP53 co-mutations achieved longer overall survival.

The team plans to extend this research to a platform that could be used to generate a map of co-mutations in all driver genes of human cancers, says Anagnostou.

Scientists who contributed to the work include Archana Balan, Jacob Fiksel, Christopher Cherry, Chenguang Wang, James White, Alexander Baras, Jordan Anaya, Blair Landon, Marta Majcherska-Agrawal and Paola Ghanem from Johns Hopkins. Other authors are from AACR Project Genie, Amgen, Dana-Farber Cancer Institute, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, and Memorial Sloan Kettering Cancer Center.https://www.hopkinsmedicine.org/”>

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