Coaltered Ras/B-raf and TP53 Is Associated with Extremes of Survivorship and Distinct Patterns of Metastasis in Patients with Metastatic Colorectal Cancer

Abstract

We aimed to investigate genomic correlates underlying extremes of survivorship in metastatic colorectal cancer and their applicability in informing survival in distinct subsets of patients with metastatic colorectal cancer. Experimental Design: We examined differences in oncogenic somatic alterations between metastatic colorectal cancer cohorts demonstrating extremes of survivorship following complete metastasectomy: 2-year (n ¼ 17) and 10-year (n ¼ 18) survivors. Relevant genomic findings, and their association with overall survival (OS), were validated in two independent datasets of 935 stage IV and 443 resected stage I-IV patients. Results: In the extremes-of-survivorship cohort, significant co-occurrence of KRAS hotspot mutations and TP53 alterations was observed in 2-year survivors (P < 0.001). When validating these findings in the independent cohort of 935 stage IV patients, incorporation of the cumulative effect of any oncogenic Ras/B-raf (i.e., either KRAS, NRAS, or BRAF) and TP53 alteration generated three prognostic clusters: (i) TP53-altered alone (median OS, 132 months); (ii) Ras/B-raf-altered alone (65 months) or Ras/ B-raf-and TP53 pan-wild-type (60 months); and (iii) coaltered Ras/B-raf-TP53 (40 months; P < 0.0001). Coaltered Ras/B-raf-TP53 was independently associated with mortality (HR, 2.47; 95% confidence interval, 1.91-3.21; P < 0.001). This molecular profile predicted survival in the second independent cohort of 443 resected stage I-IV patients. Coaltered Ras/B-raf-TP53 was associated with worse OS in patients with liver (n ¼ 490) and lung (n ¼ 172) but not peritoneal surface (n ¼ 149) metastases. Moreover, coaltered Ras/B-raf-TP53 tumors were significantly more likely to involve extrahepatic metastatic sites with limited salvage options. Conclusions: Genomic analysis of extremes of survivorship following colorectal cancer metastasectomy identifies a prognostic role for coaltered Ras/B-raf-TP53 and its association with distinct patterns of colorectal cancer metastasis.

Clinical Implication of Concordant or Discordant Genomic Profiling between Primary and Matched Metastatic Tissues in Patients with Colorectal Cancer

“…When a random forest model was applied, the metastatic sites were predicted by the conditions of several genes frequently found in CRC. Datta et al [28] reported that metastatic CRC tumors harboring co-occurring RAS/BRAF and TP53 alterations were significantly more likely to involve extrahepatic metastatic sites compared with tumors that were RAS/BRAF-altered or TP53-altered only. This analysis considered the synergistic effects of the three genes, and the results for key genes were similar to our findings.…”

Genetic Alterations of Metastatic Colorectal Cancer

“…Datta and coworkers explored a large group of 935 patients with metastatic CRC and showed that co-alteration of oncogenic TP53 with either KRAS , NRAS , or BRAF mutations was associated with significantly worse survival compared to alterations in either gene group alone [ 59 ]. Interestingly, RAS/BRAF-TP53 co-mutated CRCs were associated with worse survival in patients with liver and lung, but not with peritoneal surface metastases Moreover, co-altered BRAF/RAS-TP53 were significantly associated with the development of extra-hepatic metastatic sites [ 59 ].…”

“…Datta and coworkers explored a large group of 935 patients with metastatic CRC and showed that co-alteration of oncogenic TP53 with either KRAS , NRAS , or BRAF mutations was associated with significantly worse survival compared to alterations in either gene group alone [ 59 ]. Interestingly, RAS/BRAF-TP53 co-mutated CRCs were associated with worse survival in patients with liver and lung, but not with peritoneal surface metastases Moreover, co-altered BRAF/RAS-TP53 were significantly associated with the development of extra-hepatic metastatic sites [ 59 ]. Similar conclusions were reached by Kawaguchi et al who analyzed the possible relationship between somatic gene mutation profile and outcome in 507 metastatic CRC patients who underwent CLM resection: BRAF , RAS , TP53 , and SMAD4 mutations were significantly associated with overall survival, coexisting mutations in RAS , TP53 , and SMAD4 were associated with negative outcome (reduced OS and RFS) than coexisting mutations in any two of these genes and mutations in one or more of these genes [ 60 ].…”

Genomic and Prognostic Heterogeneity Among RAS/BRAFV600E/TP53 Co-Mutated Resectable Colorectal Liver Metastases

“…In primary CRC, the prognostic value of RAS has been suggested to be limited to MSS cancers and to depend on the consensus molecular subtypes (34). In patients with resectable CRLM, the prognostic value may depend on co-occurring TP53 mutations (12,13) or TP53/SMAD4 mutations (14).…”

“…Mutations in RAS have consistently been associated with a poor prognosis among patients with resectable colorectal liver metastases (CRLM) (7)(8)(9), and it has been suggested that surgical treatment is less bene cial in patients with RAS mutations (10). However, the prognostic effect size is modest (11) and it was recently proposed that the effect is limited to tumors with co-occurring TP53 mutations (12,13), or co-occurring TP53 and SMAD4 mutations (14). BRAF V600E mutations have a stronger prognostic effect size, but the prognostic value is limited by the low prevalence of this marker among patients with resectable CRLM (15).…”