Dataset Information

Prognostic impact of ATM mutations in patients with metastatic colorectal cancer.

ABSTRACT: Tumors bearing homologous recombination deficiency are extremely sensitive to DNA double strand breaks induced by several chemotherapeutic agents. ATM gene, encoding a protein involved in DNA damage response, is frequently mutated in colorectal cancer (CRC), but its potential role as predictive and prognostic biomarker has not been fully investigated. We carried out a multicenter effort aimed at defining the prognostic impact of ATM mutational status in metastatic CRC (mCRC) patients. Mutational profiles were obtained by means of next-generation sequencing. Overall, 35 out of 227 samples (15%) carried an ATM mutation. At a median follow-up of 56.6 months, patients with ATM mutated tumors showed a significantly longer median overall survival (OS) versus ATM wild-type ones (64.9 vs 34.8 months; HR, 0.50; 95% CI, 0.29-0.85; P = 0.01). In the multivariable model, ATM mutations confirmed the association with longer OS (HR, 0.57; 95% CI, 0.33-0.98; P = 0.04). The prognostic impact of ATM mutations was independent from TP53 mutational status and primary tumor location. High heterogeneity score for ATM mutations, possibly reflecting the loss of wild-type allele, was associated with excellent prognosis. In conclusion, we showed that ATM mutations are independently associated with longer OS in patients with mCRC.

SUBMITTER: Randon G

PROVIDER: S-EPMC6393680 | biostudies-other | 2019 Feb

REPOSITORIES: biostudies-other

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Prognostic impact of ATM mutations in patients with metastatic colorectal cancer.

Randon Giovanni G Fucà Giovanni G Rossini Daniele D Raimondi Alessandra A Pagani Filippo F Perrone Federica F Tamborini Elena E Busico Adele A Peverelli Giorgia G Morano Federica F Niger Monica M Antista Maria M Corallo Salvatore S Saggio Serena S Borelli Beatrice B Zucchelli Gemma G Milione Massimo M Pruneri Giancarlo G Di Bartolomeo Maria M Falcone Alfredo A de Braud Filippo F Cremolini Chiara C Pietrantonio Filippo F

Scientific reports 20190227 1

Tumors bearing homologous recombination deficiency are extremely sensitive to DNA double strand breaks induced by several chemotherapeutic agents. ATM gene, encoding a protein involved in DNA damage response, is frequently mutated in colorectal cancer (CRC), but its potential role as predictive and prognostic biomarker has not been fully investigated. We carried out a multicenter effort aimed at defining the prognostic impact of ATM mutational status in metastatic CRC (mCRC) patients. Mutational ...[more]

PMID: 30814645

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Project description:BACKGROUND:Colorectal cancer (CRC) is the second most common cause of cancer-specific death in both sexes in Western countries. KRAS mutations occur in about 50% of metastatic CRCs (mCRCs). The prognostic value of specific KRAS mutations still remains unexplored and unclear. METHODS:Two hundred and forty KRAS wild-type and 206 KRAS/NRAS mutant consecutive unresectable mCRC patients with PS Eastern Cooperative Oncology Group (ECOG) 0 or 1, aged < 80 years, and with a life expectancy >3 months entered into this study. DNA was extracted from paraffin-embedded formalin-fixed tumour tissues, and it was sequenced with the Oncomine Solid Tumour DNA kit (Thermo Fisher Scientific, Waltham, MA, USA). Data were analysed using the Torrent Suite Software v5.0 (Thermo Fisher Scientific). The primary outcome was the analysis of the prognostic role of different KRAS mutations in terms of overall survival (OS). RESULTS:There were no significant differences among the most prevalent mutations (p.G12D, p.G12V, p.G13D, p.G12A, p.G12C, and p.G12S) in terms of age (<65 vs. ?65 years), gender (male vs. female), grading (G1/G2 vs. G3), side of primary tumour (left vs. right), pT, and pN. At the median follow-up of 25.6 months, there were 77 deaths in KRAS-mutated patients and 94 in wild-type patients. Three homogeneous prognostic groups were identified: wild-type patients (group A, median survival: 27.5 months), p.G13D/p.G12A/p.G12V/p.G12D mutants (group B, median survival: 17.3 months), and p.G12C/p.G12S mutants (group C, median survival: 5.0 months, p < 0.0001 according to Log Rank test). Upon multivariate analysis, metastatic involvement and p.G12C/p.G12S KRAS mutation group C (vs. other mutations) emerged as independent prognostic variables for survival. CONCLUSIONS:We show that mutant KRAS is a negative prognostic factor and that p.G12C/p.G12S variants present the worst clinical courses. This information suggests a clear difference among KRAS mutations, and it will be useful to test potentiated and/or innovative therapeutic strategies in p.G12C/p.G12S metastatic CRC patients.

Project description:BackgroundKRAS is one of the most frequently mutated oncogenes in colorectal cancer (CRC). Recently, a novel therapy targeting KRAS G12C mutation has demonstrated promising activities for corresponding advanced solid tumors, including metastatic CRC (mCRC). However, the prognostic impact of the KRAS G12C mutation remains unclear in patients with mCRC.Materials and methodsWe retrospectively reviewed medical records of patients with mCRC who received first-line chemotherapy between January 2005 and December 2017 at four large oncology facilities in Japan. Survival outcomes were compared between patients with KRAS G12C and those with non-G12C mutations.ResultsAmong 2,457 patients with mCRC, 1,632 met selection criteria, and of these, 696 had KRAS exon 2 mutations, including 45 with KRAS G12C mutation tumors. Patient characteristics were not significantly different between the KRAS G12C and non-G12C groups. At a median follow-up of 64.8 months, patients with the KRAS G12C mutation showed significantly shorter first-line progression-free survival (PFS; median, 9.4 vs. 10.8 months; p = .015) and overall survival (OS; median, 21.1 vs. 27.3 months; p = .015) than those with non-G12C mutations. Multivariate analysis also showed that KRAS G12C mutation was significantly associated with shorter PFS (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.04-1.96, p = .030) and OS (HR, 1.42; 95% CI, 1.01-2.00; p = .044).ConclusionWe demonstrate that, compared with non-G12C mutations, KRAS G12C mutation is significantly correlated with shorter first-line PFS and OS. These findings indicate the relevance of a stratified treatment targeting KRAS G12C mutation in mCRC.Implications for practiceAmong patients with KRAS exon 2 mutated metastatic colorectal cancer (mCRC), median progression-free survival (PFS) and overall survival (OS) were 9.4 and 21.1 months, respectively, for G12C mutation and 10.8 and 27.3 months, respectively, for patients with non-G12C mutations, indicating significantly shorter PFS (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.08-2.01; p = .015) and OS (HR, 1.50; 95% CI, 1.08-2.08; p = .015) in patients with G12C mutation than in those with non-G12C mutations. Furthermore, multivariate analysis showed that KRAS G12C mutation was independently associated with shorter first-line PFS and OS. Thus, these findings underscore the relevance of a stratified treatment targeting KRAS G12C mutation in mCRC.

Project description:Background:The prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer (CRC) varies with microsatellite instability (MSI) status. The gene expression-based consensus molecular subtypes (CMSs) of CRC define molecularly and clinically distinct subgroups, and represent a novel stratification framework in biomarker analysis. We investigated the prognostic value of these mutations within the CMS groups. Patients and methods:Totally 1197 primary tumors from a Norwegian series of CRC stage I-IV were analyzed for MSI and mutation status in hotspots in KRAS (codons 12, 13 and 61) and BRAF (codon 600). A subset was analyzed for gene expression and confident CMS classification was obtained for 317 samples. This cohort was expanded with clinical and molecular data, including CMS classification, from 514 patients in the publically available dataset GSE39582. Gene expression signatures associated with KRAS and BRAFV600E mutations were used to evaluate differential impact of mutations on gene expression among the CMS groups. Results:BRAFV600E and KRAS mutations were both associated with inferior 5-year overall survival (OS) exclusively in MSS tumors (BRAFV600E mutation versus KRAS/BRAF wild-type: Hazard ratio (HR) 2.85, P?<?0.001; KRAS mutation versus KRAS/BRAF wild-type: HR 1.30, P?=?0.013). BRAFV600E-mutated MSS tumors were strongly enriched and associated with metastatic disease in CMS1, leading to negative prognostic impact in this subtype (OS: BRAFV600E mutation versus wild-type: HR 7.73, P?=?0.001). In contrast, the poor prognosis of KRAS mutations was limited to MSS tumors with CMS2/CMS3 epithelial-like gene expression profiles (OS: KRAS mutation versus wild-type: HR 1.51, P?=?0.011). The subtype-specific prognostic associations were substantiated by differential effects of BRAFV600E and KRAS mutations on gene expression signatures according to the MSI status and CMS group. Conclusions:BRAFV600E mutations are enriched and associated with metastatic disease in CMS1 MSS tumors, leading to poor prognosis in this subtype. KRAS mutations are associated with adverse outcome in epithelial (CMS2/CMS3) MSS tumors.

Dataset Information

Prognostic impact of ATM mutations in patients with metastatic colorectal cancer.

Publications

Prognostic impact of ATM mutations in patients with metastatic colorectal cancer.

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