PubMed · 8751424
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R G Bristow, S Benchimol, R Hill. 1996-07-15. p53 protein expression or protein function?. https://doi.org/10.1016/0360-3016(96)85887-1
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Next-generation sequencing data is fundamentally changing the clinical management of patients with cancer. The most frequent genomic alterations in malignancy are mutations and amplifications, with a subset of tumors having multiple amplifications - "amplificators". We sought to understand the molecular correlates of high tumor amplification burden in a pan-cancer context. Using both national registries and a single-institution dataset, our results demonstrate that cancers with TP53 mutations (as compared to those with wild-type TP53) exhibited significantly higher tumor amplification burden across all datasets. Amplifications, generally associated with overexpression, may be potentially actionable secondary consequences of TP53 mutations.
BACKGROUND: While 2-4% of lung cancers possess alterations in BRAF, little is known about the immune responsiveness of these tumours. METHODS: Clinical and genomic data were collected from 5945 patients with lung cancers whose tumours underwent next-generation sequencing between 2015 and 2018. Patients were followed through 2020. RESULTS: In total, 127 patients with metastatic BRAF-altered lung cancers were identified: 29 tumours had Class I mutations, 59 had Class II/III alterations, and 39 had variants of unknown significance (VUS). Tumour mutation burden was higher in Class II/III than Class I-altered tumours (8.8 mutations/Mb versus 4.9, P < 0.001), but this difference was diminished when stratified by smoking status. The overall response rate to immune checkpoint inhibitors (ICI) was 9% in Class I-altered tumours and 26% in Class II/III (P = 0.25), with median time on treatment of 1.9 months in both groups. Among patients with Class I-III-altered tumours, 36-month HR for death in those who ever versus never received ICI was 1.82 (1.17-6.11). Nine patients were on ICI for >2 years (two with Class I mutations, two with Class II/III alterations, and five with VUS). CONCLUSIONS: A subset of patients with BRAF-altered lung cancers achieved durable disease control on ICI. However, collectively no significant clinical benefit was seen.
BACKGROUND: Although pathologic level of invasion and histologic grade are helpful in predicting the clinical outcome of transitional cell carcinoma of the bladder, they also create uncertainty. Immunohistochemical staining for p53, MIB-1, epidermal growth factor receptor (EGFR), c-erb B-2, and bcl-2 have shown promise as prognostic factors when evaluated singly, although multivariate analyses that include histologic grade and the interactive effects of these markers have not been studied extensively. The authors have initiated a prospective study to determine whether these markers add prognostic information to that provided by level of invasion and histologic grade. This initial report details how these five markers relate to invasion of the bladder after controlling for the effects of histologic grade. METHODS: The authors evaluated 229 transitional cell carcinomas in 229 patients using the World Health Organization grading schema and immunohistochemical staining with antigen retrieval for p53, MIB-1, EGFR, c-erb B-2, and bcl-2, and they related these markers to invasion after controlling for grade with a multivariate logistic regression model. RESULTS: Although Grades 2 and 3 were the most important for predicting invasion, Grade 2 tumors that stained for either MIB-1 or p53 indicated a significantly greater probability of invasion than suggested by grade alone. bcl-2 and p53 had an opposing and interactive effect: when p53 was absent, the presence of bcl-2 implied less probability of invasion; but when both bcl-2 and p53 were present, the protective effect of bcl-2 was no longer observed. Although neither EGFR nor c-erb B-2 were as important as the other three markers in determining the risk of invasion, Grade 3 tumors that stained for one, and especially both, of these markers were less likely to be invasive. CONCLUSIONS: These five markers sort into three interactive pairs: MIB-1 and p53, bcl-2 and p53, and EGFR and c-erb B-2. MIB-1 and p53 together imply a greater probability of invasion. bcl-2 appears to have a dual role, which depends on the presence of accumulated p53. Finally, EGFR and c-erb B-2 related closely to each other and in Grade 3 tumors imply a lesser probability of invasion. It is likely that combinations of markers, or correlations between markers and grades, will yield prognostic information that is more powerful than what histologic grade alone can provide.