Gene expression has to withstand stochastic, environmental and genomic perturbations. For example, in the latter case, 0.5–1% of the human genome is typically variable between any two unrelated individuals. Such diversity might create problematic variability in the activity of gene regulatory networks, and ultimately, in cell behaviors. Using multigenerational selection experiments, we find that for the Drosophila proneural network, the effect of genomic diversity is dampened by miR-9a-mediated regulation of senseless expression. Reducing miR-9a regulation of the Senseless transcription factor frees the genomic landscape to exert greater phenotypic influence. Whole genome sequencing identified genomic loci that potentially exert such effects. A larger set of sequence variants, including variants within proneural network genes, exhibit these characteristics when miR-9a concentration is reduced. These findings reveal that microRNA-target interactions may be a key mechanism by which the impact of genomic diversity on cell behavior is dampened.
In the above article, we stated that our SNV mutations count included 5,379 silent, 3,901 missense, 831 nonsense, 360 splice-site, and 760 mutations resulting in a frame shift. One of these figures represents an error; the missense mutation count should read 13,901 and not 3,901. The underlying data as well as the rest of the text and figures reflect the correct mutation count (13,901).Cell 157, 753, April 24, 2014 ª2014 Elsevier Inc. 753
Background. The prognostic implication of wild type APC (APC-WT) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) is not well defined. Methods. APC prognostic value was evaluated retrospectively in two independent cohorts of patient with MSS mCRC with a confirmatory analysis from a public data set from Memorial Sloan Kettering Cancer Center (MSKCC). Results. In comparison to the APC-mutant (APC-MT) population (n=255), APC-WT patients (n = 86) tended to be younger (59% of age <40 vs 26% of age > 50), right-sided (41.7% vs. 27%), BRAF-V600E mutated (23.3% vs. 0.8%), and KRAS WT (65.1% vs. 49.8%). Alternative WNT pathway alterations, RNF43 and CTNNB1 were over-represented in the APC-WT vs APC-MT population (7% vs 0.4% and 4.7% vs 0.4%, respectively). APC-WT patients had a worse overall survival (OS) than APC-MT patients (22.6 vs 45.6 months, p<0.0001). Using a multivariate model correcting for primary tumor location, RAS and BRAF status, APC-WT was predictive of poor survival (APC-MT vs APC-WT, HR=0.62, 95%CI 0.44-0.86, P=0.0037). The prognostic implication of APC-WT on OS was confirmed further in a similar multivariate model of 934 stage IV patients from MSKCC public database (APC-MT vs APC-WT, HR=0.63, 95%CI 0.49-0.81, p<0.0001). Conclusion. APC-WT is associated with poor OS in MSS mCRC regardless of RAS and BRAF status. Compared with APC-MT mCRC tumors, APC-WT tumors were associated with other Wnt activating alterations, including RNF43 and CTNBB1. Our data suggest alternative therapy needs to be investigated in APC-WT patients. The Oncologist 2020;9999:• • Implications for Practice: MSS mCRC patients with APC-WT had a worse OS than patients with APC-MT regardless of RAS/ RAF status. APC status should be considered as a stratification factor in prospective trials and novel therapeutic strategies need to be developed for this subgroup of patients.
PURPOSE Older women with high-risk early breast cancer (EBC) benefit from adjuvant chemotherapy, but their treatment is frequently complicated by toxic side effects, resulting in dose reductions and delays. This makes it challenging for oncologists to maintain a relative dose intensity (RDI) ≥ 85%, as recommended for optimal curative-intent treatment. Understanding which women are at risk of receiving suboptimal RDI may inform treatment discussions and guide early, targeted supportive care or geriatric comanagement interventions. METHODS This was a prespecified secondary analysis of the HOPE trial, which enrolled women age ≥ 65 years with EBC initiating neoadjuvant or adjuvant chemotherapy. RDI was calculated as the ratio of delivered to planned chemotherapy dose intensity. The primary outcome was low RDI, defined as RDI < 85%. Multivariable logistic regression with stepwise selection was used to evaluate the association between baseline variables (demographic, clinical, and geriatric assessment) and low RDI. Survival probability was estimated using the Kaplan-Meier method, and the log-rank test was used to compare overall survival. RESULTS Three hundred twenty-two patients (median age at diagnosis, 70 years; range, 65-86 years) were included. The median follow-up was 4 years. Sixty-six patients (21%) had a low RDI. Age ≥ 76 years (odds ratio [OR], 2.57; 95% CI, 1.12 to 5.91; P = .03), lower performance status (OR, 4.32; 95% CI, 1.98 to 9.42; P < .001), and use of anthracycline-based or cyclophosphamide, methotrexate, and fluorouracil regimens (OR, 3.47; 95% CI, 1.71 to 7.05; P < .001) were associated with low RDI. The 5-year overall survival probability was 0.80 versus 0.91 in patients with RDI < 85 versus ≥ 85%, respectively (log-rank P = .02). CONCLUSION One in five older patients with EBC treated with standard chemotherapy received low RDI and had inferior survival outcomes. Older patients at risk for low RDI should be identified and targeted upfront before initiating chemotherapy.
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