Abstract
KRAS is an independent negative predictor for anti-epidermal growth factor receptor (anti-EGFR) treatment in colorectal cancers (CRCs). However, 30% to 50% of CRC patients are KRAS-positive and do not benefit from anti-EGFR therapy. In this study, we investigated the mutational features and clinical significance of KRAS-positive Chinese CRC patients. A total of 139 Chinese CRC patients who received clinical KRAS testing (Sanger sequencing) were examined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Fifty KRAS-positive specimens were further detected by next-generation sequencing (NGS). The most prevalent mutation in KRAS was G12D (46%), followed by G12V (20%), and G13D (18%). In addition to KRAS, 72 unique alterations in another 12 genes were also detected. The most common mutated genes were TP53 (62%), APC (46%), and PIK3CA (22%). The proportion of HER2 amplifications in KRAS-positive CRC patients was 4.4%, which was lower than that in KRAS -negative CRC patients (14.3%). No relationship was found between HER2 amplification and KRAS status (p = 0.052). However, the odds ratio is very low (0.279). In addition, these gene mutations were not significantly associated with age, sex, tumor size, lymph node metastasis, mismatch repair–deficient, or tumor differentiation. However, TP53 mutations were more prevalent in colon cancer with KRAS mutations than in rectal cancer (75.0% vs 28.6%, respectively, p = 0.004). The negative predictive value of the IHC analysis for predicting HER2 amplification reached to 98.39%, while the positive predictive value reached only 50%. Overall, the mutation profiling of Chinese CRC patients with KRAS mutations is different from that of Western CRC patients. Our results will help us to understand the molecular features of Chinese CRC patients.
Highlights
In 2018, colorectal cancer (CRC) was the third most common malignancy worldwide[1]
After the comprehensive molecular characterization of colorectal cancer was reported by the TCGA22, an increasing amount of data have accumulated rapidly in different genetic or clinical backgrounds[25,26,27,28]
Molecular testing has become increasingly significant for the treatment of CRCs
Summary
In 2018, colorectal cancer (CRC) was the third most common malignancy worldwide[1]. In China, CRC was the fourth most commonly diagnosed cancer and the fifth leading cause of cancer-related death in 20152. A large number of cancer-relevant genes with specific clinical significance have been identified, such as epidermal growth factor receptor (EGFR), KRAS, ERBB2, BRAF, and PIK3CA4. Mutations in KRAS, NRAS, BRAF, and PIK3CA are important predictive and prognostic markers for anti-EGFR therapy[5,6,7]. Current guidelines have recommended that the mutation status of KRAS, NRAS, and BRAF should be tested when considering anti-EGFR treatment[8,9,10]. A few studies have reported the incidence rate of HER2 overexpression or amplification in CRC, it varies considerably, ranging from 0% to 83%18–22. Anti-HER2 therapy, like trastuzumab, may be a possible treatment option for CRCs with KRAS mutations[18]. The concordance between the results of IHC and FISH has yet to be verified
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