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Comparative Analysis of Gene Correlation Networks of Breast Cancer Patients Based on Mutations in TP53.

ABSTRACT: Breast cancer is one of the most prevalent cancers in females, with more than 450,000 deaths each year worldwide. Among the subtypes of breast cancer, basal-like breast cancer, also known as triple-negative breast cancer, shows the lowest survival rate and does not have effective treatments yet. Somatic mutations in the TP53 gene frequently occur across all breast cancer subtypes, but comparative analysis of gene correlations with respect to mutations in TP53 has not been done so far. The primary goal of this study is to identify gene correlations in two groups of breast cancer patients and to derive potential prognostic gene pairs for breast cancer. We partitioned breast cancer patients into two groups: one group with a mutated TP53 gene (mTP53) and the other with a wild-type TP53 gene (wtTP53). For every gene pair, we computed the hazard ratio using the Cox proportional hazard model and constructed gene correlation networks (GCNs) enriched with prognostic information. Our GCN is more informative than typical GCNs in the sense that it indicates the type of correlation between genes, the concordance index, and the prognostic type of a gene. Comparative analysis of correlation patterns and survival time of the two groups revealed several interesting findings. First, we found several new gene pairs with opposite correlations in the two GCNs and the difference in their correlation patterns was the most prominent in the basal-like subtype of breast cancer. Second, we obtained potential prognostic genes for breast cancer patients with a wild-type TP53 gene. From a comparative analysis of GCNs of mTP53 and wtTP53, we found several gene pairs that show significantly different correlation patterns in the basal-like breast cancer subtype and obtained prognostic genes for patients with a wild-type TP53 gene. The GCNs and prognostic genes identified in this study will be informative for the prognosis of survival and for selecting a drug target for breast cancer, in particular for basal-like breast cancer. To the best of our knowledge, this is the first attempt to construct GCNs for breast cancer patients with or without mutations in the TP53 gene and to find prognostic genes accordingly.

SUBMITTER: Park B

PROVIDER: S-EPMC9313229 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHeterozygous germline TP53 gene mutations result in Li-Fraumeni Syndrome (LFS). Breast cancer (BC) is the most frequent tumor in young women with LFS. An important issue related to BC in the Mexican population is the average age at diagnosis, which is approximately 11 years younger than that of patients in the United States (U.S.) and Europe. The aim of this study was to determine the prevalence of germline mutations in TP53 among young Mexican BC patients.MethodsWe searched for germline mutations in the TP53 gene using targeted next-generation sequencing (NGS) in 78 BC patients younger than 45 years old (yo) who tested negative for BRCA1/2 mutations. A group of 509 Mexican women aged 45yo or older without personal or family BC history (parents/grandparents) was used as a control.ResultsWe identified five patients with pathogenic variants in the TP53 gene, equivalent to 6.4% (5/78). Among patients diagnosed at age 36 or younger, 9.4% (5/55) had pathogenic TP53 mutations. Three of these variants were missense mutations (c.844C > T, c.517G > A, and c.604C > T), and the other two mutations were frameshifts (c.291delC and c.273dupC) and had not been reported previously. We also identified a variant of uncertain clinical significance (VUS), c.672G > A, which causes a putative splice donor site mutation. All patients with TP53 mutations had high-grade and HER2-positive tumors. None of the 509 patients in the healthy control group had mutations in TP53.ConclusionsAmong Mexican BC patients diagnosed at a young age, we identified a high proportion with germline mutations in the TP53 gene. All patients with the TP53 mutations had a family history suggestive of LFS. To establish the clinical significance of the VUS found, additional studies are needed. Pathogenic variants of TP53 may explain a substantial fraction of BC in young women in the Mexican population. Importantly, none of these mutations or other pathological variants in TP53 were found in the healthy control group.

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.

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Comparative Analysis of Gene Correlation Networks of Breast Cancer Patients Based on Mutations in TP53.

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