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Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. We show that the fitness landscape is rugged-the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context-and shows no evidence of diminishing-returns epistasis within variants of the same oncogene. These findings argue against a simple linear signaling relationship amongst these three oncogenes and imply a critical role for off-axis signaling in determining the fitness effects of inactivating tumor suppressors., (© 2023. Springer Nature Limited.)

Nasal polyposis (NP) is a chronic inflammatory disease in which several molecular and cellular interactions play important roles. Tumor necrosis factor-alpha (TNF-alpha) is a major pro-inflammatory cytokine with a key role in immune inflammatory responses in NP. Altered levels of TNF-alpha, which may occur due to polymorphisms in the TNF-alpha promoter region, may also be associated with NP susceptibility. Given these facts, we investigated the possible association of the TNF-alpha -308 G/A single nucleotide polymorphism (SNP) with NP. In this study, 97 consecutive adult patients with NP and 95 age- and gender-matched controls were recruited. For identification of SNP, restriction fragment length polymorphism analysis after polymerase chain reaction was carried out. The NP group had a significantly higher rate of polymorphism compared to controls (p = 0.015). Logistic regression analysis revealed that the presence of the TNF-alpha -308 G/A SNP is an independent risk factor for NP development (OR, 3.68; CI, 1.27-10.7; p = 0.016). The presence of a mutation failed to influence disease severity on the basis of resistance to medical and/or surgical treatment. This study suggests a possible linkage of a SNP in the TNF-alpha promoter with NP. These results need to be confirmed with multicentre studies for more precise interpretation and corroborative studies for investigating the influence of polymorphism on transcriptional activity.

More fibro-osseous lesions originate in the bones of the extremities than in the craniomaxillofacial bones, scapula, and ribs, which are rarely involved. Fibro-osseous lesions that decrease the quality of life should be treated surgically. We report the case of a fibro-osseous lesion that caused globus pharyngeus and dysphagia. We discuss the clinical, radiologic, and histopathologic features of this case as well as the removal of this unusual lesion by Doppler ultrasound-guided surgery. To the best of our knowledge, no other case of a fibro-osseous lesion in the retropharyngeal area has been reported in the literature.