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Clinical outcomes and correlates of TP53 mutations and cancer.

ABSTRACT: The initial observation that p53 accumulation might serve as a surrogate biomarker for TP53 mutation has been the cornerstone for vast translational efforts aimed at validating its clinical use for the diagnosis, prognosis, and treatment of cancer. Early on, it was realized that accurate evaluation of p53 status and function could not be achieved through protein-expression analysis only. As our understanding of the p53 pathway has evolved and more sophisticated methods for assessment of p53 functional integrity have become available, the clinical and molecular epidemiological implications of p53 abnormalities in cancers are being revealed. They include diagnostic testing for germline p53 mutations, and the assessment of selected p53 mutations as biomarkers of carcinogen exposure and cancer risk and prognosis. Here, we describe the strengths and limitations of the most frequently used techniques for determination of p53 status in tumors, as well as the most remarkable latest findings relating to its clinical and epidemiological value.

SUBMITTER: Robles AI

PROVIDER: S-EPMC2829964 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Clinical outcomes and correlates of TP53 mutations and cancer.

Robles Ana I AI Harris Curtis C CC

Cold Spring Harbor perspectives in biology 20100301 3

The initial observation that p53 accumulation might serve as a surrogate biomarker for TP53 mutation has been the cornerstone for vast translational efforts aimed at validating its clinical use for the diagnosis, prognosis, and treatment of cancer. Early on, it was realized that accurate evaluation of p53 status and function could not be achieved through protein-expression analysis only. As our understanding of the p53 pathway has evolved and more sophisticated methods for assessment of p53 func ...[more]

PMID: 20300207

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Project description:BackgroundColorectal cancer (CRC) has been ranked as the second most deadly cancer and the third most diagnosed cancer cases for the year 2020. Specifically for Romania, the number of CRC-related deaths in 2019 was estimated at 6307 people, with a standardized mortality rate of 33.8 per 100,000 inhabitants. Although the tumor protein 53 (TP53) gene is intensively studied, there are few data on TP53 mutations in Romanian CRC. Furthermore, since genetic alterations may show geographical differences, our study aimed to analyze the clinical status and TP53 somatic variation in Romanian CRC patients.Subjects and methodsDNA from 40 randomly selected cases of CRC was extracted from formalin-fixed paraffin-embedded tissues and sequenced using direct Sanger sequencing techniques, and variants were annotated according to the recommendations of the Human Genome Variation Society. Novel variants were analyzed using MutationTaster2021 to predict their effects.ResultsThe mean age was 63.6 years (range 33-85 years) with a male to female ratio of 2.3. More than 45% (18/40) had an advanced cancer stage (≥ stage III). Mutations were found in 21/40 cases (52.5%), with one case having two mutations, giving a total of twenty-two mutations in the TP53 coding DNA. These mutations include 3 (13.6%) insertion-deletion mutations, two of which are novel frameshift mutations: c.165delT (in exon 4) and c.928_935dup (in exon 9), both of which are predicted to lead to nonsense-mediated mRNA decay and are classified as deleterious. The remaining 19 (86.36%) were substitution mutations: 1 nonsense and 18 (81.8%) missense mutations, with G > A (n = 7/19; 36.8%) and C > T (n = 6/19; 31.5%) transitions being the most common. The G > T transversion was found in 21.05% (4/19) of the substitution mutations.ConclusionWe have described two novel frameshift mutations in TP53. The discovery of novel mutations following the efforts of The Cancer Genome Atlas and other large-scale cancer genome sequencing projects may be further evidence of the heterogeneous nature of mutations in cancer and may indicate that the identification of carcinogenic mutations is not yet saturated. Further sequencing is therefore needed, especially in less studied populations. Importantly, consideration of their geographical environment will shed light on population-specific carcinogenesis.

Dataset Information

Clinical outcomes and correlates of TP53 mutations and cancer.

Publications

Clinical outcomes and correlates of TP53 mutations and cancer.

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