KRAS mutant allele-specific imbalance in lung adenocarcinoma

Abstract

The significance of KRAS mutant allele-specific imbalance (MASI) in lung adenocarcinomas is unknown. KRAS MASI was defined as predominance of the mutant allele over the wild-type allele. We assessed the frequency of KRAS MASI by comparing peak heights of mutant and wild-type alleles on sequencing electropherograms and by KRAS fluorescence in situ hybridization (FISH). A review of sequencing electropherograms of 207 KRAS-mutated lung adenocarcinomas demonstrated 23 (11%) cases with the mutant allele peak higher than the wild-type allele peak and 15 (7%) cases with the mutant allele peak equal to the wild-type allele peak. Of 17 cases with the mutant allele peak higher or equal to the wild-type allele peak, 8 (47%) showed KRAS amplification by FISH. KRAS FISH analysis of 36 KRAS-mutated lung adenocarcinomas with the mutant allele peak lower than the wild-type allele peak, 21 KRAS and EGFR wild-type and 16 EGFR-mutated adenocarcinomas showed no KRAS amplification. KRAS MASI was associated with selective amplification of the KRAS mutant allele (Po0.001). Patients with KRAS MASI showed worse overall survival. The cumulative proportion surviving at 17 months for KRAS MASI group was 35% compared with 84.1% for patients with KRAS mutant allele peak lower than wild-type allele peak (P ¼ 0.012). The adverse prognostic significance of KRAS MASI was independent of clinical stage and was maintained among stage I patients. The detection of KRAS MASI in lung adenocarcinomas by sequencing electropherograms may identify patients with more aggressive disease.

Multiparametric molecular characterization of pulmonary sarcomatoid carcinoma reveals a nonrandom amplification of anaplastic lymphoma kinase (ALK) gene

“…In particular, relevant issues are to unravel if ALK gene is silenced by genetic or epigenetic mechanisms or there are posttranscriptional adjustments of the protein. The lack of ALK protein despite gene amplification, its occurrence in tumors with adenocarcinoma lineage only (as also confirmed by the absence of p40) [30], and the lack of any clinicopathologic correlations, including tumor stage and mutational status, made ALK amplification unlikely to be an early phenomenon contributing alone to the maintenance of a subset of PSC or the progression toward metastasis, as at variance demonstrated for EGFR [35] or KRAS [36] amplification in lung adenocarcinoma mutated for the relevant genes, but rather pointed to additional genetic co-alterations or mechanisms, such as c-MET or FGFR2 polysomy or amplification, which are recurring in PSC in up to 18% of PSC [22]. In particular, ALK and c-MET seemed to be strictly co-amplified, with significant differences with the control group of lung adenocarcinoma [37].…”

EGFR and KRAS Mutations in ALK-Positive Lung Adenocarcinomas: Biological and Clinical Effect

“…Strikingly, these cases demonstrated a concomitant point mutation and amplification of the EGFR (case #1) or KRAS gene (#4 and #5). The preferential amplification of the EGFR mutant allele has already been reported by other authors and is considered to be one of the main mechanisms leading to MASI30 . Interestingly, MASI of the KRAS gene was identified in 11% of lung ADCs.…”

“…Interestingly, MASI of the KRAS gene was identified in 11% of lung ADCs. This subset of tumors is correlated to a worse clinical outcome with respect to KRAS-mutated cancers without gene amplification10,30 .The combination of molecular and in situ results may facilitate the speculation concerning the existence of different pathogenetic mechanisms in DP ADC. The genetic pattern observed in case #1, showing EGFR amplification in all the tumor cells, 100% of EGFR mutant allele and ALK rearrangement in 25% of the cells, strongly suggests that the EGFR mutation occurs as the first event, and subsequently the EGFR-mutated allele undergoes gene amplification.Therefore, ALK rearrangement could be a secondary event in tumor progression, and the two alterations co-exist in the same cells.…”

Intratumor Heterogeneity of KRAS Mutation Status in Pancreatic Ductal Adenocarcinoma Is Associated With Smaller Lesions

“…Amplification of mutant KRAS was previously reported in carcinomas of the colon, lung, and pancreas. [30][31][32] In pancreatic adenocarcinoma, KRAS mutant allele amplification was reported in 18.4% of cases in 1 cohort. 31 Interestingly, mutant KRAS amplification was associated with the presence of undifferentiated carcinoma, suggesting a more advanced disease.…”