Genotypes and Haplotypes in the AXIN2 and TCF7L2 Genes are Associated With Susceptibility and With Clinicopathological Characteristics in Breast Cancer Patients.

Background: Breast cancer is a multifactorial disease whose genetic susceptibility is related to polymorphic variants of cell proliferation and migration pathways. Variants in AXIN2 and TCF7L2 in the Wnt-ß catenin pathway have been associated with different types of cancer; however, little is known about its role in breast cancer. This study tests the hypothesis of links between AXIN2 rs1133683 and rs2240308, and TCF7L2 rs7903146 and rs12255372 variants in breast cancer. Methods: Peripheral blood samples were obtained from 404 women (202 patients and 202 control females). The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology was used to identify the gene variants. Results: The AXIN2 rs2240308 (C > T), and TCF7L2 rs7903146 (C > T) and rs12255372 (G > T) variants were associated with breast cancer and with age, TNM stage, and histologic-molecular subtype (p = 0.001). Likewise, the haplotype T-T in the TCF7L2 gene (rs7903146-rs12253372) was significantly related with breast cancer (OR = 2.66, 95%, CI = 1.64-4.30, p = 0.001). Conclusion: Our data show a link between AXIN2 rs2240308 and TCF7L2 rs7903146 and rs12255372 variants in breast cancer, and speculate this may be important in pathogenesis.

Protective role of +294 T/C (rs2016520) polymorphism of PPARD in Mexican patients with colorectal cancer.

PPARD encodes for peroxisome proliferator-activated receptor delta, which plays a significant role in controlling lipid metabolism, atherosclerosis, inflammation, cancer growth, progression, and apoptosis. Accumulated evidence suggests that the polymorphism rs2016520 in PPARD is associated with lipid metabolism, obesity, metabolic syndrome, and type 2 diabetes mellitus. The aim of this study was to determine whether the single nucleotide polymorphism +294T/C (rs2016520) in PPARD is associated with colorectal cancer (CRC) in the Mexican population. Genomic DNA from 178 CRC patients and 97 healthy blood donors was analyzed. The polymorphism was identified by the polymerase chain reaction-restriction fragment length polymorphism method. Results demonstrated that patients with the T/C genotype for the +294T/C (rs2016520) polymorphism present a protective role against CRC [odds ratio (OR) = 0.39; 95% confidence interval (CI) = 0.22-0.69; P = 0.0008]. This association was also evident for the T/C genotype in the stratified analysis by tumor-node-metastasis stages I+II (OR = 0.26, P = 0.0332) and III+IV (OR = 0.44, P = 0.0067). However, in the stratified analysis by tumor location, we observed an increased risk of rectal cancer (OR = 7.57, P = 0.0403) vs colon cancer (OR = 4.87, P = 0.234) in patients carrying the C/C genotype and under the dominant and recessive models of inheritance. In conclusion, for the first time, the association between the +294T/C (rs2016520) polymorphism and colorectal cancer has been studied in Mexican patients. Our results reveal that variations in PPARD may play a significant role in genetic susceptibility to colorectal cancer.

TCF7L2 and CCND1 polymorphisms and its association with colorectal cancer in Mexican patients.

Accumulative evidence suggests that alterations due to mutations or genetic polymorphisms in the TCF7L2 and CCND1 genes, which are components of the Wnt signaling pathway, contributes to carcinogenesis. The present study was designated to clarify whether common single nucleotide polymorphisms (SNPs) of the transcription factor 7- like 2 (TCF7L2) and cyclin D1 (CCND1) genes are associated with colorectal cancer risk in Mexican patients. A case-control study including 197 colorectal cancer patients and 100 healthy subjects was conducted in a Mexican population. Identification of polymorphisms was made by the polymerase chain reaction-restriction fragment length polymorphism methodology. The association was calculated by the odds ratio (OR) test. The results demonstrate that patients with the T/T genotype for the rs12255372 polymorphism of the TCF7L2 gene present an increased colorectal cancer risk (OR=2.64, P=0.0236). Also, the risk analysis for Tumor-Nodule-Metastasis (TNM) stage and tumor location showed association with this polymorphism under the over-dominant model of inheritance (OR=1.75, P=0.0440). A similar relation was observed for the genotype T/T of the rs7903146 polymorphism and the rectal location of cancer (OR=7.57, P=0.0403). For the rs603965 polymorphism of the CCND1 gene, we observed a protection effect for the colon cancer location under the dominant model (OR=0.49, P=0.0477). These results reveal a significant role of the analyzed polymorphisms in the TCF7L2 and CCND1 genes on the susceptibility or protection for developing colorectal cancer in the Mexican population.

XRCC1 polymorphisms and haplotypes in Mexican patients with acute lymphoblastic leukemia.

We examined the influence of the Arg194Trp, Arg280His, and Arg399Gln polymorphisms of XRCC1 (X-ray repair cross-complementing group 1) on the development of childhood acute lymphoblastic leukemia (ALL) in 120 ALL patients and 120 controls in Mexico. All of them were genotyped for these polymorphisms, using polymerase chain reaction. No significant differences in allele and genotype frequencies for any polymorphism were observed between patients and controls. Estimation of haplotypes showed the eight expected haplotypes (A-H), seven of which were found in both patients and controls; haplotype A (Arg-Arg-Arg) was the most common, whereas haplotypes F and G were absent in patients and controls, respectively. Haplotype B (Trp-Arg-Arg) was found to be associated with an increased risk of ALL (odds ratio (OR) = 1.95, 95% confidence interval (CI) = 1.13-3.37; P = 0.016), particularly in males (OR = 2.65, 95%CI = 1.25-5.63; P = 0.01). Individually, the 194Trp, 280His, and 399Gln alleles were not associated with significantly increased risk for ALL in these Mexican children.

[Diseases caused by triplet expansion]. / Enfermedades causadas por expansión de tripletes.

INTRODUCTION: Today we know of a group of mutations caused by the expansion of nucleotide triplets, which are very unstable in meiosis and mitosis. Four types of triplets have the capacity for pathogenic expansion in human beings (CGG/ GCC, CAG/GTC, CTG/GAC and GAA/CTT) and maybe located both in coding sequences (bulbospinal muscular atrophy, Huntington's disease and certain spinocerebellar ataxias) and non-coding sequences (fragile X syndrome, Friedreich's ataxia, myotonic dystrophy). Trinucleotide expansion may lead to gains or losses in gene functioning and seems to be associated to a variety of factors, some of which are directly related with the expansive process (cis-acting) and others whose interaction with the triplets helps to make them increasingly more unstable (trans-acting). Medium-sized expansions (pre-mutations), although clinically silent, do show a marked tendency to expand into complete mutations during the transition along the germinal line. The models that have been proposed to explain triplet expansion involve gene recombination and replication processes; however, they have not fully succeeded in explaining the phenomena related to mutation or phenotypic expression in these diseases. DEVELOPMENT: This work examines the most recent concepts related to the dynamic mutation processes that give rise to human diseases; it also reviews the most important clinico-biological aspects observed in those diseases. CONCLUSIONS: Dynamic mutation processes represent a new concept in the molecular biology of gene mutations. An ever increasing number of pathologies are caused by this type of DNA alterations, which, as a whole, display very interesting clinico-biological characteristics.

Nine independent F9 mutations in the Mexican hemophilia B population: nonrandom recurrences of point mutation events in the human germline.

The factor IX gene (F9) is a valuable model for studying germ-line mutations. Nine mutations were detected in nine Mexican patients with hemophilia B by direct sequencing using genomic amplification with transcript sequencing (GAWTS): six single base changes, one micro-deletion, and two large deletions. Germline origins of mutations were found in three of six families with sporadic cases. Curiously, the four independent single base substitutions which were not at CpG dinucleotides occurred at only two different nucleotide positions (17,678 and 17,747) one transition and one transversion at each. The two remaining substitutions were identical changes at a CpG dinucleotide, but were determined to be independent by germline origin analysis. A statistical analysis suggests that the independent recurrence of mutations at these locations may reflect an unusual aspect of F9 mutagenesis in the Mexican population. These data raise the possibility of population-specific differences in human germline mutations.

High recurrence of recombinants in a family with pericentric inversion of chromosome 18.

We report a family in which the father carries a pericentric inversion involving two third of the chromosome 18 (p11.2q22). Of his three children, the proposita and her youngest brother show partial duplication of the short arm and partial deficiency of the long arm; the oldest sister shows the other recombinant (partial duplication of the long arm and partial deficiency of the short arm). In the literature, we found only one family in which both recombinants of a parental pericentric inversion were present in the same offspring and none with three affected and both kinds of recombinants. A review of the reported familial cases reveals that the risk of aneusomy of recombination, at least for chromosome-18 inversion carriers, may be close to 20% and no only 5-10% as previously reported.

A familial syndrome with hypotonia, mental retardation and dysmorphic features resembling Cohen syndrome.

Since its original description (2), many new cases of Cohen syndrome have been reported, most of them showing a quite variable expressivity. Autosomal recessive inheritance is widely accepted (MIM : 216550) (11), however, multiple instances of sporadic cases are observed. From a literature review (52 cases), we could determinate, in order of frequency, the most important clinical traits of the Cohen syndrome. We report here a father and two sons with dysmorphic features resembling Cohen syndrome and transmitting by an autosomal dominant mode.

Molecular characterization of the fragile-X syndrome in the Mexican population.

The fragile X (fra-X) syndrome is the most frequent form of inherited mental retardation. Facial dysmorphism, macroorchidism and a folate-sensitive fragile site on Xq27.3 are commonly associated features. The gene causing this disorder, designated as FMR1, is X-linked and shows an unusual inheritance mode. A multistep amplification of the CGG repeats at the 5' end of the FMR1 gene has been recently identified as the cause of the fra-X syndrome. Different numbers of repeats define three gene forms (normal, premutated and mutated), whose ranges show little variation in the populations studied so far. We analyzed 18 Mexican individuals with the fra-X syndrome, 40 of their relatives (first and second degree), and 76 healthy individuals without antecedents of mental retardation. Southern blot and PCR permitted the assessment of the number of CGG repeats and the methylation state of the FMR1 gene for the normal, premutated, and mutated alleles. The results showed no statistical differences when compared with those from other populations. No cytogenetic expression of the Xq27.3 fragile site in 50% of the affected males and in all the affected and carrier females was observed. This finding emphasizes the necessity of a molecular analysis in fra-X cases and their relatives in order to provide a more adequate genetic counseling.

Translocation 4;13 with adjacent 1 and 3-1 segregations leading to complementary segmental trisomies 13.

A familial 4;13 translocation showed three different segregations and two kinds of imbalances: two brothers had a distal trisomy 13 [46,XY,-4,+der 4, t(4;13)(q35;q14)mat] and their maternal uncle had a proximal trisomy 13 [47, XY,+der13,t(4;13)(q35;q14)mat]. A relative excess of abortions was observed in this family, probably related to a lethal variety of segregation.

[Effect of gene dosage on the glyceraldehyde-3-phosphate dehydrogenase enzyme (GAPD) in partial 12p13.3 pter trisomy]. / Efecto de dosis génica para la enzima gliceraldehído-3-fosfato deshidrogenasa (GAPD) en trisomía parcial 12p13.3 pter.

A family with three brothers presenting 12p trisomy due to an adjacent-1 segregation of a paternal translocation (1;12) (q44;p12.2) is described. The patient's phenotype was compatible with the chromosomal imbalance including the gene dosage effect of the glyceraldehyde-3-phosphate dehydrogenase. The importance of the genetic counseling in these families is stressed.