Acquired genetic characteristics of acute lymphoblastic leukemia (ALL) cells are used to individualize therapy, whereas germ line genetic characteristics generally are not. We determined whether ALL outcome was related to 16 genetic polymorphisms affecting the pharmacodynamics of antileukemic agents. Of 246 children, 116 were treated on the lowerrisk (LR) and 130 on the higher-risk (HR) arms of a St Jude protocol. Patients in the HR group with the glutathione S -transferase (GSTM1) nonnull genotype had greater risk of hematologic relapse (P ؍ .03), which was further increased by the thymidylate synthetase (TYMS) 3/3 genotype (P ؍ .03). These genotypes remained predictive in multivariate analyses (P < .001 and .003, respectively). No genotypes were predictive in the LR arm. Expression of these 2 genes in ALL blasts was lower in those with low-activity genotypes. For central nervous system relapse, among the HR group, the vitamin D receptor start site (P ؍ .02) and intron 8 genotypes (P ؍ .04) predisposed, whereas for LR patients the TYMS 3/3 genotype predisposed (P ؍ .04). The GSTM1 nonnull and TYMS 3/3 genotypes are plausibly linked to drug resistance.
It has been proposed that human colorectal tumors can be classified into two groups: one in which methylation is rare, and another with methylation of several loci associated with a "CpG island methylated phenotype (CIMP)," characterized by preferential proximal location in the colon, but otherwise poorly defined. There is considerable overlap between this putative methylator phenotype and the well-known mutator phenotype associated with microsatellite instability (MSI). We have examined hypermethylation of the promoter region of five genes (DAPK, MGMT, hMLH1, p16INK4a, and p14ARF) in 106 primary colorectal cancers. A graph depicting the frequency of methylated loci in the series of tumors showed a continuous, monotonically decreasing distribution quite different from the previously claimed discontinuity. We observed a significant association between the presence of three or more methylated loci and the proximal location of the tumors. However, if we remove from analysis the tumors with hMLH1 methylation or those with MSI, the significance vanishes, suggesting that the association between multiple methylations and proximal location was indirect due to the correlation with MSI. Thus, our data do not support the independent existence of the so-called methylator phenotype and suggest that it rather may represent a statistical artifact caused by confounding of associations.
Hereditary breast cancer (HBC) accounts for 5-10% of breast cancer cases and it significantly increases the lifetime risk of cancer. Our objective was to evaluate the sociodemographic variables, family history of cancer, breast cancer (BC) screening practices and the risk profile of cancer affected or asymptomatic at-risk women that undergo genetic counseling for hereditary breast cancer in public Brazilian cancer genetics services. Estimated lifetime risk of BC was calculated for asymptomatic women using the Gail and Claus models. The majority of women showed a moderate lifetime risk of developing BC, with an average risk of 19.7% and 19.9% by the Gail and Claus models, respectively. The average prior probability of carrying a BRCA1/2 gene mutation was 16.7% and overall only 32% fulfilled criteria for a hereditary breast cancer syndrome as assessed by family history. We conclude that a significant number of individuals at high-risk for HBC syndromes may not have access to the benefits of cancer genetic counseling in these centers. Contributing factors may include insufficient training of healthcare professionals, disinformation of cancer patients; difficult access to genetic testing and/or resistance in seeking such services. The identification and understanding of these barriers is essential to develop specific strategies to effectively achieve cancer risk reduction in this and other countries were clinical cancer genetics is not yet fully established.
The acquired genetic characteristics of acute lymphoblastic leukemia (ALL) blasts are often used to guide the intensity of therapy, whereas the germline host genetic characteristics of the patient generally have not been considered. Multiple common, functionally important polymorphisms affect genes whose products determine the pharmacokinetics and pharmacodynamics of antileukemic agents. It is not yet known how genetic polymorphisms may interact to affect the outcome of antileukemic therapy. Combining classification and regression tree with failure time analysis, we assessed whether 16 genetic polymorphisms, alone or in combination, predicted relapses in 246 children with ALL, 116 of whom were treated on the lower-risk (LR) and130 on the higher-risk (HR) arms of the St Jude protocol Total XIIIB. Genotyping was performed for the following polymorphic loci: CYP3A4*1B and CYP3A5*3; GSTP1 313A>G, GSTM1 and GSTT1 deletions; MDR1 exon 21 (2677G>T/A) and MDR1 exon 26 (3435C>T); MTHFR 677C>T and MTHFR 1298A>C; NR3C1 1088A>G; SLC19A1 80G>A; TPMT 238G>C, 460G>A and 719A>G; TYMS enhancer repeat; UGT1A1 promoter repeat polymorphism; VDR intron 8 G>A and VDR FokI (start-site) T>C. In all children with available RNA in their diagnostic ALL blasts, gene expression levels of prognostic genotypes were analyzed using the Affymetrix genechip array HG_U95Av2. Among the HR group, the glutathione S-transferase M1 (GSTM1) non-null genotype was associated with the risk of hematological relapse (5-year cumulative incidence, 17.1%±4.5% compared to 5.1%±2.9% for GSTM1 null genotype, p = 0.03), and among the non-null genotypes, the thymidylate synthetase (TYMS) 3/3 genotype was associated with a further increase in hematologic relapse risk (5-year cumulative incidence, 29.2%±9.5% compared to 10.9%±4.7% for TYMS 2/3 or 2/2 genotypes, p = 0.02). Increased expression levels of these two target genes (p < 0.0001 and p = 0.09, respectively) were consistent with resistance to the drugs interacting with these gene products. For central nervous system relapse, among the HR group, the vitamin D receptor (VDR) start site (p = 0.02) and intron 8 genotypes (p = 0.04) predisposed, whereas for LR patients the TYMS 3/3 genotype predisposed (p = 0.04). The genotypes associated with outcome have pharmacologic plausibility: e.g., high GST activity (GSTM1 non-null) could cause anticancer drug resistance; high TYMS activity (TYMS 3/3) would be less inhibited by antifolates. In conclusion, germline polymorphisms influence the outcome of antileukemic therapy, and therefore represent determinants of response that can be used to optimize therapy.
This article outlines and discusses Brazil's new regulations on the use of human biological materials for research, specifically, Resolution CNS 441/11, enacted by the National Health Council of Brazil in May 2011, and the National Guidelines for Biorepositories and Biobanks (Ordinance No. 2201) published by the Ministry of Health in September 2011. The authors examine the differences between sample collections for single studies and large-scale collections for multiple studies (e.g., the National Tumor Bank at the Brazilian National Cancer Institute and the A. C. Camargo Hospital Biobank). Also discussed are the ethical and operational implications, i.e.,informed consent process, strategies for sample collection, custodianship, access to samples, and rules for disposal. Insights gained may be useful for developing national biobanking regulations in other countries in Latin America.
In Brazil, genetic counseling is usually available in university-affiliated medical genetics services located in tertiary centers that provide cancer diagnosis and treatment. The present study aims to describe the structure and characteristics of three cancer genetic services in Brazilian public health care hospitals and discuss alternatives for the identification and prevention of hereditary cancer syndromes in developing countries. The three services presented here are similar in their structure, routine procedures for cancer risk estimation and criteria for the indication of genetic testing. They all demand that genetic counseling be an essential part of the cancer risk evaluation process, before and after cancer predisposition testing. However, when high-risk patients are identified, all services describe difficulties in the access and continuity of genetic and medical services to the patient and his/her at-risk relatives. The services differ in the type of population served, reflecting distinct referral guidelines. This study emphasizes the importance of the creation of new cancer genetic services in other Brazilian regions and the necessity for establishing a collaborative network to facilitate the diagnosis and research of cancer genetic syndromes.
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