BRAF, PIK3CA, and HER2 Oncogenic Alterations According to KRAS Mutation Status in Advanced Colorectal Cancers with

Soo Kyung Nam1, Sumi Yun1,2, Jiwon Koh2

  • 1Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.

Plos One
|March 19, 2016
PubMed
Abstract

Insights

In advanced colorectal cancer (CRC), KRAS mutations occur in 54.5% of patients. Identifying PIK3CA, BRAF, and HER2 alterations alongside KRAS status aids in managing advanced CRC.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Anti-EGFR therapy is crucial for advanced colorectal cancer (CRC).
  • Mechanisms of resistance to anti-EGFR therapy involve KRAS, BRAF, PIK3CA mutations, and HER2 amplification.
  • Understanding the frequency and clinical impact of these genetic alterations is vital for CRC management.

Purpose of the Study:

  • To investigate the frequencies of KRAS, BRAF, PIK3CA mutations, and HER2 amplification in advanced CRC.
  • To determine the clinical implications of these genetic alterations.
  • To evaluate the association between these mutations/amplifications and patient prognosis.

Main Methods:

  • Genotyping of KRAS, BRAF, and PIK3CA mutations using real-time PCR and Sanger sequencing.
  • Assessment of microsatellite instability (MSI) and HER2 amplification via fragmentation assay and silver in situ hybridization, respectively.
  • Analysis of 191 advanced CRC patients with distant metastasis.

Main Results:

  • KRAS mutations were identified in 54.5% of patients, PIK3CA in 13.1%, BRAF in 3.1%, and HER2 amplification in 8.4%.
  • PIK3CA mutations were more common in KRAS-mutant CRC (18.3%) than KRAS wild-type (6.9%).
  • BRAF mutations or HER2 amplifications in KRAS wild-type patients correlated with a worse prognosis (P=0.004).

Conclusions:

  • KRAS mutations are prevalent in 54.5% of advanced CRC cases.
  • Subgrouping patients based on PIK3CA, BRAF, and HER2 status, in addition to KRAS, improves management strategies for advanced CRC.
  • These genetic markers are important for predicting treatment response and patient outcomes.

Related Concept Videos

The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
7.5K
Tumor Progression02:07

Tumor Progression

Tumor progression is a phenomenon where the pre-formed tumor acquires successive mutations to become clinically more aggressive and malignant. In the 1950s, Foulds first described the stepwise progression of cancer cells through successive stages.
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
7.8K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
5.0K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
6.2K