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. 2011;6(7):e22769.
doi: 10.1371/journal.pone.0022769. Epub 2011 Jul 29.

PIK3CA mutations frequently coexist with RAS and BRAF mutations in patients with advanced cancers

Filip Janku  1 , J Jack Lee, Apostolia M Tsimberidou, David S Hong, Aung Naing, Gerald S Falchook, Siqing Fu, Rajyalakshmi Luthra, Ignacio Garrido-Laguna, Razelle Kurzrock
Affiliations

PIK3CA mutations frequently coexist with RAS and BRAF mutations in patients with advanced cancers

Filip Janku et al. PLoS One. 2011.

Abstract

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Frequency of mutations in tested tumors with 95% confidence intervals (CI).
A. PIK3CA mutations. B. KRAS mutations. C. NRAS mutations. D. BRAF mutations.
Figure 2
Figure 2. Proportion (numbers) of mutation types.
A. PIK3CA mutations (n = 54). B. KRAS mutations (n = 69). C. NRAS mutations (n = 19). D. BRAF mutations (n = 31).
Figure 3
Figure 3. Simultaneous PIK3CA and RAS (KRAS, NRAS) or BRAF mutations.
Wild-type RAS (KRAS, NRAS) or BRAF (blue bar) and mutant RAS (KRAS, NRAS) or BRAF (red bar) in: A. All tumor types (tested, n = 436); B. All cancers excluding colorectal cancers (tested, n = 332); C. Colorectal cancers (tested, n = 104); D. Ovarian cancers (tested, n = 50).
Figure 4
Figure 4. Simultaneous PIK3CA and KRAS mutations.
Wild-type KRAS (blue bar) and mutant KRAS (red bar) in: A. All tumor types (tested, n = 367); B. All cancers excluding colorectal cancers (tested, n = 270); C. Colorectal cancers (tested, n = 97); D. Ovarian cancers (tested, n = 46).
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