AUTHOR=Ottaiano Alessandro , Santorsola Mariachiara , Circelli Luisa , Perri Francesco , Cascella Marco , Sabbatino Francesco , Capuozzo Maurizio , Granata Vincenza , Zappavigna Silvia , Lombardi Angela , Scrima Marianna , Petrillo Nadia , Ianniello Monica , Casillo Marika , Gualillo Oreste , Nasti Guglielmo , Caraglia Michele , Savarese Giovanni 

TITLE=Hypertension, type 2 diabetes, obesity, and p53 mutations negatively correlate with metastatic colorectal cancer patients’ survival

JOURNAL=Frontiers in Medicine

VOLUME=10

YEAR=2023

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2023.1091634

DOI=10.3389/fmed.2023.1091634

ISSN=2296-858X

ABSTRACT=<sec><title>Introduction</title><p>We studied the predictive and prognostic influences of hypertension (HT), type 2 diabetes (T2D), weight, and <italic>p53</italic> mutations in metastatic colorectal cancer (CRC) patients.</p></sec><sec><title>Patients and methods</title><p>T2D was diagnosed according to the ADA criteria. HT was classified according to the ACC/AHA guidelines. BMI (body-mass index) was calculated and classified according to the WHO criteria. TruSigt™Oncology 500 kit was applied to construct the genomic libraries for Next Generation Sequencing (NGS) analysis. The Illumina NovaSeq 6000 technological platform and the Illumina TruSight Oncology 500 bioinformatics pipeline were applied to analyze results. Overall survival (OS) was calculated through Kaplan-Meier curves. Univariate and multivariate analyses were performed to assess the relationships between clinical and/or molecular covariates. Associations between HT, T2D, BMI, p53, and clinical variables were evaluated by the χ2 test. <italic>P</italic> &lt; 0.05 were considered statistically significant.</p></sec><sec><title>Results</title><p>Two-hundred-forty-four patients were enrolled. One-hundred-twenty (49.2%), 110 (45.1%), and 50 (20.5%) patients were affected by overweight, HT, and T2D, respectively. DC (disease control) was achieved more frequently in patients without T2D (83.1%) compared to the diabetic ones (16.9%) (<italic>P</italic> = 0.0246). DC, <italic>KRAS</italic> mutational status, T2D, BMI, and concomitant presence of T2D, BMI, and HT associated with survival (<italic>P</italic> &lt; 0.05). At multivariate analysis, age (≥65 vs. &lt;65 years), response to first-line chemotherapy (DC vs. no DC), and concomitant presence of T2D, BMI, and HT (HR: 4.56; 95% CI: 2.40–8.67; <italic>P</italic> = 0.0217) emerged as independent prognostic variables. <italic>P53</italic> was mutated in 31/53 analyzed cases (60.4%). The most frequent gene variants were p.Arg175His and p.Cys135Tyr. High BMI (&gt;25 kg/m<sup>2</sup>) associated with occurrence of <italic>p53</italic> mutations (<italic>P</italic> &lt; 0.0001). <italic>P53</italic> mutated patients presented a worse prognosis compared to the wild-type ones (HR: 3.21; 95% CI: 1.43–7.23; <italic>P</italic> = 0.0047).</p></sec><sec><title>Conclusion</title><p>Diabetic, hypertensive and overweight metastatic CRC patients are a negative prognostic subgroup deserving specific therapeutic strategies. <italic>P53</italic> mutations associate with prognosis and BMI unrevealing complex and unexplored connections between metabolism and cancer occurrence.</p></sec>