Molecular epidemiology and diagnostics of KRAS mutations in human cancer

Abstract

RAS mutation is the most frequent oncogenic alteration in human cancers. KRAS is the most frequently mutated followed by NRAS. The emblematic KRAS mutant cancers are pancreatic, colorectal, lung adenocarcinomas and urogenital cancers. KRAS mutation frequencies are relatively stable worldwide in various cancer types with the one exception of lung adenocarcinoma. The frequencies of KRAS variant alleles appears cancer type specific, reflecting the various carcinogenic processes. In addition to point mutation KRAS, allelic imbalances are also frequent in human cancers leading to the predominance of a mutant allele. KRAS mutant cancers are characterized by typical, cancer-type-specific co-occurring mutations and distinct gene expression signatures. The heterogeneity of KRAS mutant primary cancers is significant, affecting the variant allele frequency, which could lead to unpredictable branching development in metastases. Selection of minute mutant subclones in the primary tumors or metastases during target therapies can also occur frequently in lung or colorectal cancers leading to acquired resistance. Ultrahigh sensitivity techniques are now routinely available for diagnostic purposes, but the proper determination of mutant allele frequency of KRAS in the primary or metastatic tissues may have larger clinical significance.

Keywords: Diagnostics; Epidemiology; Human cancer; KRAS mutation; Tumor progression.

Fig 1.

Mutation incidence of the RAS family genes in human cancers (5–7). Data are expressed in %. cervCA cervical cancer, choCA cholangial cancer, CRC colorectal cancer, endomCA endometrial cancer, hematop hematopoietic malignancies, LUAD lung adenocarcinoma, mel malignant melanoma, ovCA ovarian cancer, pancCA pancreatic cancer, proCA prostate cancer

Fig. 2.

KRAS exon2 mutant allele incidences in various cancers. Data are expressed in %. LUAD lung adenocarcinoma, n = 579, 2nd Department of Pathology, SU; CRC colorectal cancer, n = 560, 2nd Department of Pathology, SU; PCA pancreatic cancer, n = 2661 (Ref. 14); choCA cholangial cancer, n = 255 (Ref. 13); ovVA ovarian cancer, n = 410 (Ref. 13); endomCA endomatrial cancer, n = 306 (Ref. 13).