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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
PIK3CA mutations frequently coexist with RAS and BRAF mutations in patients with advanced cancers
Filip Janku1, J Jack Lee, Apostolia M Tsimberidou
1Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Background:
Oncogenic mutations of PIK3CA, RAS (KRAS, NRAS), and BRAF have been identified in various malignancies, and activate the PI3K/AKT/mTOR and RAS/RAF/MEK pathways, respectively. Both pathways are critical drivers of tumorigenesis.
Methods:
Tumor tissues from 504 patients with diverse cancers referred to the Clinical Center for Targeted Therapy at MD Anderson Cancer Center starting in October 2008 were analyzed for PIK3CA, RAS (KRAS, NRAS), and BRAF mutations using polymerase chain reaction-based DNA sequencing.
Results:
PIK3CA mutations were found in 54 (11%) of 504 patients tested; KRAS in 69 (19%) of 367; NRAS in 19 (8%) of 225; and BRAF in 31 (9%) of 361 patients. PIK3CA mutations were most frequent in squamous cervical (5/14, 36%), uterine (7/28, 25%), breast (6/29, 21%), and colorectal cancers (18/105, 17%); KRAS in pancreatic (5/9, 56%), colorectal (49/97, 51%), and uterine cancers (3/20, 15%); NRAS in melanoma (12/40, 30%), and uterine cancer (2/11, 18%); BRAF in melanoma (23/52, 44%), and colorectal cancer (5/88, 6%). Regardless of histology, KRAS mutations were found in 38% of patients with PIK3CA mutations compared to 16% of patients with wild-type (wt)PIK3CA (p = 0.001). In total, RAS (KRAS, NRAS) or BRAF mutations were found in 47% of patients with PIK3CA mutations vs. 24% of patients wtPIK3CA (p = 0.001). PIK3CA mutations were found in 28% of patients with KRAS mutations compared to 10% with wtKRAS (p = 0.001) and in 20% of patients with RAS (KRAS, NRAS) or BRAF mutations compared to 8% with wtRAS (KRAS, NRAS) or wtBRAF (p = 0.001).
Conclusions:
PIK3CA, RAS (KRAS, NRAS), and BRAF mutations are frequent in diverse tumors. In a wide variety of tumors, PIK3CA mutations coexist with RAS (KRAS, NRAS) and BRAF mutations.
Insights
Oncogenic mutations in PIK3CA, RAS (KRAS, NRAS), and BRAF genes are common in many cancers. These mutations often coexist, suggesting potential therapeutic targets in diverse tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Oncogenic mutations in PIK3CA, RAS (KRAS, NRAS), and BRAF genes are frequently observed in various malignancies.
- These mutations activate critical cancer-driving pathways, including the PI3K/AKT/mTOR and RAS/RAF/MEK pathways.
Purpose of the Study:
- To investigate the frequency and co-occurrence of PIK3CA, RAS (KRAS, NRAS), and BRAF mutations in a diverse cohort of cancer patients.
- To identify specific cancer types with high prevalence of these mutations.
Main Methods:
- Tumor tissues from 504 patients with diverse cancers were analyzed.
- Polymerase chain reaction-based DNA sequencing was employed to detect mutations in PIK3CA, KRAS, NRAS, and BRAF genes.
Main Results:
- PIK3CA mutations were found in 11% of patients, KRAS in 19%, NRAS in 8%, and BRAF in 9%.
- High mutation frequencies were observed in specific cancers: PIK3CA in cervical, uterine, breast, and colorectal cancers; KRAS in pancreatic, colorectal, and uterine cancers; NRAS in melanoma and uterine cancer; BRAF in melanoma and colorectal cancer.
- PIK3CA mutations significantly co-occurred with RAS (KRAS, NRAS) and BRAF mutations (47% vs. 24%, p=0.001), and vice versa (28% vs. 10% for KRAS, p=0.001).
Conclusions:
- Mutations in PIK3CA, RAS (KRAS, NRAS), and BRAF are prevalent across a wide spectrum of tumors.
- A significant co-occurrence of PIK3CA mutations with RAS (KRAS, NRAS) and BRAF mutations was observed in diverse tumor types.
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