While mutations in the KRAS oncogene are amongst the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant tumor biology significantly contributes to the response to therapy. We hypothesized that presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS, EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy.
Constitutive heterochromatin is important for maintaining chromosome stability but also delays the repair of DNA double strand breaks (DSB). DSB repair in complex mammalian genomes involves a fast phase (2–6 hrs) where most of the breaks are rapidly repaired, and a slow phase (up to 24 hrs) where the remaining damages in heterochromatin are repaired. We found that p53 deficiency delays the slow phase DNA repair after ionizing irradiation. P53 deficiency prevents down regulation of histone H3K9 trimethylation at pericentric heterochromatin after DNA damage. Moreover, p53 directly induces expression of the H3 K9 demethylase JMJD2b through promoter binding. P53 activation also indirectly down regulates expression of the H3 K9 methytransferase SUV39H1. Depletion of JMJD2b or sustained expression of SUV39H1 delays the repair of heterochromatin DNA and reduces clonogenic survival after ionizing irradiation. The results suggest that by regulating JMJD2b and SUV39H1 expression, p53 not only controls transcription but also promotes heterochromatin relaxation to accelerate a rate-limiting step in the repair of complex genomes.
Sirolimus (SIR)/tacrolimus (TAC) is an alternative to methotrexate (MTX)/TAC. However, rational selection among these GvHD prophylaxis approaches to optimize survival of individual patients is not possible based on current evidence. We compared SIR/TAC (n=293) to MTX/TAC (n=414). The primary objective was to identify unique predictors of overall survival (OS). Secondary objective was to compare acute and chronic GvHD, relapse, non-relapse mortality, thrombotic microangiopathy (TMA), hepatic veno-occlusive disease (VOD/SOS), and acute kidney injury. Day 100 grades II-IV acute GvHD was significantly reduced in SIR/TAC vs MTX/TAC group (63 vs 73%, P=0.02). An interaction between GvHD prophylaxis groups and comorbidity index (hematopoietic cell transplantation (HCT)-CI) significantly impacted OS. Patients with HCT-CI⩾4 had significantly worse OS with MTX/TAC (HR 1.86, 95% CI 1.14-3.04, P=0.01) while no such effect was seen for SIR/TAC (HR 0.78, 95% CI 0.48-1.26, P=0.31). Other end points did not significantly differ between groups except TMA and VOD/SOS were increased in the SIR/TAC group, but excess death from these complications was not observed. We conclude, GvHD prophylaxis approach of SIR/TAC is associated with reduced grades II-IV acute GvHD, comparable toxicity profile to MTX/TAC, and improved OS among patients with HCT-CI⩾4.
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