Genetic variation of acquired structural chromosomal aberrations

Human malignancies are often hallmarked with genomic instability, which itself is also considered a causative event in malignant transformation. Genomic instability may manifest itself as genetic changes in the nucleotide sequence of DNA, or as structural or numerical changes of chromosomes. Unrepaired or insufficiently repaired DNA double-strand breaks, as well as telomere shortening, are important contributors in the formation of structural chromosomal aberrations (CAs). In the present review, we discuss potential mechanisms behind the formation of CAs and their relation to cancer. Based on our own studies, we also illustrate how inherited genetic variation may modify the frequency and types of CAs occurring in humans. Recently, we published a series of studies on variations in genes relevant to maintaining genomic integrity, such as those encoding xenobiotic-metabolising enzymes, DNA repair, the tumour suppressor TP53, the spindle assembly checkpoint, and cyclin D1 (CCND1). While individually genetic variation in these genes exerted small modulating effects, in interactions they were associated with CA frequencies in peripheral blood lymphocytes of healthy volunteers. Moreover, we observed opposite associations between the CCND1 splice site polymorphism rs9344 G870A and the frequency of CAs compared to their association with translocation t(11,14). We discuss the functional consequences of the CCND1 gene in interplay with DNA damage response and DNA repair during malignant transformation. Our review summarizes existing evidence that gene variations in relevant cellular pathways modulate the frequency of CAs, predominantly in a complex interaction. More functional/mechanistic studies elucidating these observations are required. Several questions emerge, such as the role of CAs in malignancies with respect to a particular phenotype and heterogeneity, the formation of CAs during the process of malignant transformation, and the formation of CAs in individual types of lymphocytes in relation to the immune response

<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

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

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

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