Fusobacterium nucleatum associates with stages of colorectal neoplasia development, colorectal cancer and disease outcome.

Commensal bacteria in the colon may play a role in colorectal cancer (CRC) development. Recent studies from North America showed that Fusobacterium nucleatum (Fn) infection is over-represented in disease tissue versus matched normal tissue in CRC patients. Using quantitative real-time polymerase chain reaction (qPCR) of DNA extracted from colorectal tissue biopsies and surgical resections of three European cohorts totalling 122 CRC patients, we found an over-abundance of Fn in cancerous compared to matched normal tissue (p < 0.0001). To determine whether Fn infection is an early event in CRC development, we assayed Fn in colorectal adenoma (CRA) tissue from 52 Irish patients. While for all CRAs the Fn level was not statistically significantly higher in disease versus normal tissue (p = 0.06), it was significantly higher for high-grade dysplasia (p = 0.015). As a secondary objective, we determined that CRC patients with low Fn levels had a significantly longer overall survival time than patients with moderate and high levels of the bacterium (p = 0.008). The investigation of Fn as a potential non-invasive biomarker for CRC screening showed that, while Fn was more abundant in stool samples from CRC patients compared to adenomas or controls, the levels in stool did not correlate with cancer or adenoma tissue levels from the same individuals. This is the first study examining Fn in the colonic tissue and stool of European CRC and CRA patients, and suggests Fn as a novel risk factor for disease progression from adenoma to cancer, possibly affecting patient survival outcomes. Our results highlight the potential of Fn detection as a diagnostic and prognostic determinant in CRC patients.</p

Genotype and Haplotype Analyses of <i>TP53</i> Gene in Breast Cancer Patients: Association with Risk and Clinical Outcomes

<div><p>Variations in the <i>TP53</i> gene have been suggested to play a role in many cancers, including breast. We previously observed an association between <i>TP53</i> haplotypes based on four polymorphisms (rs17878362, rs1042522, rs12947788, and rs17884306) and the risk of colorectal and pancreatic cancer. Based on these results, in the present study, we have investigated the same polymorphisms and their haplotypes in 705 breast cancer cases and 611 healthy controls in relation to the disease risk, histopathological features of the tumor and clinical outcomes. In comparison to the most common haplotype A₁-G-C-G, all the other identified haplotypes were globally associated with a significantly decreased breast cancer risk (P = 0.006). In particular, the A₂-G-C-G haplotype was associated with a marked decreased risk of breast cancer when compared with the common haplotype (P = 0.0001). Moreover, rs1042522 in patients carrying the GC genotype and receiving only the anthracycline-based chemotherapy was associated with both overall and disease-free survival (recessive model for overall survival HR = 0.30 95% CI 0.11–0.80, P = 0.02 and for disease-free survival HR = 0.42 95% CI 0.21–0.84, P = 0.01). Present results suggest common genetic features in the susceptibility to breast and gastrointestinal cancers in respect to <i>TP53</i> variations. In fact, similar haplotype distributions were observed for breast, colorectal, and pancreatic patients in associations with cancer risk. Rs1042522 polymorphism (even after applying the Dunn-Bonferroni correction for multiple testing) appears to be an independent prognostic marker in breast cancer patients.</p></div

OS and DFS in relation to haplotype distributions (Cox regression).

<p>^aLoci rs17878362, rs1042522, rs12947788, rs17884306.</p><p>^b Number of alleles are reported. Because each individual has two alleles, the total number of alleles is twice the total number of individuals. Individuals with missing haplotype data were not included in the analyses.</p><p>^cAllele A₂ carries the 16-bp insertion within intron 3</p><p>HR, hazard ratio; 95% CI, confidence interval. Significant results in bold.</p><p>OS and DFS in relation to haplotype distributions (Cox regression).</p

<i>TP53</i> haplotype distribution between BC patients and controls.

<p>^aLoci rs17878362, rs1042522, rs12947788, rs17884306.</p><p>^bNumber of alleles are reported. Because each individual has two alleles, the total number of alleles will be twice the total number of individuals. Individuals with missing haplotype data were not included in the analyses.</p><p>^cAdjusted for age.</p><p>^dAllele A₂ carries the 16-bp insertion within intron 3</p><p>OR, odds ratio; CI, confidence interval. Significant P-values are in bold.</p><p><i>TP53</i> haplotype distribution between BC patients and controls.</p

Kaplan-Meier disease-free survival curves for <i>TP53</i> rs17878362 polymorphism in patients receiving only the hormonal therapy (log-rank for recessive model).

<p>Numbers of patients at risk are indicated in the lower part of the plot.</p

OS and DFS in relation to SNP distributions in patients treated with anthracycline-based chemotherapy (Cox regression).

<p>The SNP rs17884306 was monomorphic in cases, thus not presented.</p><p>HR, hazard ratio; 95% CI, confidence interval. Significant results in bold; significant differences after Dunn–Bonferroni correction (P<0.02) are marked with an asterisk.</p><p>OS and DFS in relation to SNP distributions in patients treated with anthracycline-based chemotherapy (Cox regression).</p

Overall (OS) and disease-free (DFS) survival in relation to SNP distributions (Cox regression).

<p>The SNP rs17884306 was monomorphic in cases, thus not presented.</p><p>HR, hazard ratio; 95% CI, confidence interval. Significant results in bold.</p><p>Overall (OS) and disease-free (DFS) survival in relation to SNP distributions (Cox regression).</p