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A recent meta-analysis of 23 studies supported the empirically derived hypothesis that women who lack one of the four common minisatellite alleles at the HRAS1 locus are at increased risk of breast cancer. These studies relied on visual sizing of alleles on electrophoretic gels and may have underreported rare alleles. We determined whether this hyp...
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... was no evidence for deviation from Hardy-Weinberg equilibrium among case subjects, among control subjects, among total subjects (all P>.8), or among any group or subgroup defined by case subject/control subject status and/or fam- ily history status. Table 3 shows that the frequency of *Family history of breast cancer is defined as having a reported first-or second-degree female relative with breast cancer. Test of allele frequencies: family history (yes versus no)-case subjects only, P .1; ...
Citations
... Rare alleles of this minisatellite were shown to be associated with cancer risk [67,68], and it was proposed that altered expression of RASSF7 might contribute to the increased risk [69]. This generated a great deal of interest in the region; however, subsequent studies using improved technology failed to find a link [70,71] and the idea that rare alleles of the minisatellite are associated with cancer risk has fallen from favour. ...
The RASSF (Ras-association domain family) has recently gained several new members and now contains ten proteins (RASSF1-10), several of which are potential tumour suppressors. The family can be split into two groups, the classical RASSF proteins (RASSF1-6) and the four recently added N-terminal RASSF proteins (RASSF7-10). The N-terminal RASSF proteins have a number of differences from the classical RASSF members and represent a newly defined set of potential Ras effectors. They have been linked to key biological processes, including cell death, proliferation, microtubule stability, promoter methylation, vesicle trafficking and response to hypoxia. Two members of the N-terminal RASSF family have also been highlighted as potential tumour suppressors. The present review will summarize what is known about the N-terminal RASSF proteins, addressing their function and possible links to cancer formation. It will also compare the N-terminal RASSF proteins with the classical RASSF proteins and ask whether the N-terminal RASSF proteins should be considered as genuine members or imposters in the RASSF family.
... Each variant allele is derived from the common allele nearest to it in size [65]. The HRAS1 polymorphism was examined in 13 studies [66][67][68][69][70][71][72][73][74][75][76][77][78]. Positive odds ratios (ORs) were detected in all studies, five of which reached significance [66,71,75,76,78] with ORs of 2:7. ...
Breast cancer and endometrial cancer are the most common gynecologic malignancies of the postmenopausal period. As preventive medicine becomes the focus of interest, preventive oncology with special regard to these diseases will undoubtedly become a substantial part of the practicing oncologist's field of duties. The aim of this review is to summarize recommendations dealing with the risk assessment and prevention of breast and endometrial cancer. Obesity, the level of exercise and dietary factors are associated with breast cancer. The selective estrogen receptor modulators tamoxifen and raloxifen have both been shown to decrease the risk to the same extent. Patients at particularly high risk are being detected through the use of the Gail model, a well-known statistical model of risk. Other factors, such as breast density, the serum level of endogenous estrogen and the presence of single nucleotide polymorphisms, have to be taken into consideration.
... It is not clear why the length of this STR should influence serum levels. An association between rare alleles of a STR upstream of the HRAS gene and common cancers, including breast cancer, has been reported (86), but for breast cancer at least, this observation remains contentious (87,88). An in vitro study (89) reports that the length of a STR proximal to an enhancer element in the first intron of the EGFR gene influences transcription levels. ...
We reviewed all English-language articles on associations among circulating levels of the insulin-like growth factors (IGF) and their binding proteins (IGFBP), polymorphisms in their genes, and breast cancer risk. In premenopausal women, five of eight IGF-I studies and four of six IGFBP-3 studies of circulating levels found that women in the highest quantile had more than twice the risk of developing breast cancer of those in the lowest, although in some this effect was only apparent at young ages. In postmenopausal women, however, there was no consistent effect. A simple sequence length polymorphism 1 kb 5' to IGF-I was examined in relation to circulating levels of IGF-I (12 studies) or breast cancer risk (4 studies), but there was no convincing evidence of any effect. For an A/C polymorphism 5' to IGFBP-3, all three studies were consistent with a modest effect on circulating levels, but no evidence of a direct effect on breast cancer risk was seen in the only relevant study. Variation within the reference range of IGF-I and IGFBP-3 may confer only modest increases in breast cancer risk, and any single polymorphism may only account for a small proportion of that variation. Nevertheless, population attributable fractions for high circulating levels of IGF-I and IGFBP-3 and for common genetic variants could be substantial. Further large studies, or combined analysis of data from existing studies, are needed to quantify these effects more precisely.
... 18 A meta-analysis by Krontiris et al., 1 showed that in studies that used Southern-blot based analysis the frequency of rare alleles was 9%. Recent studies on non-Hodgkin lymphoma, lung, breast and ovarian cancer using PCR-based methodologies, report rare allele frequencies ranging from 13-17% in the control population [15][16][17][18] which is similar to our results. In 2 of these studies fluorescent primers and size fractionations were used and detection was carried out on an automated sequencer. ...
... In 2 of these studies fluorescent primers and size fractionations were used and detection was carried out on an automated sequencer. 17,18 These techniques may be even more accurate in detecting rare alleles than the PCR-based long-gel electrophoretic assay. The distribution of common and rare alleles in our control population, however, was not different from theirs. ...
... Some studies using PCR-based methods observed fewer a3 and a4 common alleles, but a greater number of rare alleles close in size to a3 and a4 than Southern-blot based methods. 17 Preferential amplification of shorter alleles has been a concern with PCR-based methods. 21 If such a problem existed, an increased number of the short a1 and a2 alleles would be expected and not an excess of the long rare alleles in the a3 and a4 size range. ...
The HRAS1 variable number of tandem repeats (VNTR) polymorphism, 1 kb downstream from the HRAS1 gene, has been reported to be associated with risk of various cancers. To examine whether individuals with rare HRAS1 VNTR alleles are at increased risk of bladder cancer we carried out a case control study with 230 bladder cancer cases and 203 hospital-based controls frequency-matched on ethnicity, gender and age. For genotyping we used a PCR-based long-gel electrophoretic assay that provides precise allele size discrimination. We did not find evidence of a strong overall effect of the HRAS1 VNTR on bladder cancer risk. Genotype data for whites and blacks were analyzed separately, but the number of black subjects was too small to estimate meaningful odds ratios. Compared to white subjects with 2 common alleles, the odds ratio (OR) for white subjects with 1 rare allele was 0.9 (95% confidence interval (CI) = 0.5-1.4) and for those with 2 rare alleles OR = 1.7 (95% CI = 0.6-5.4). HRAS1 genotype may be related to the prognosis of bladder cancer, however, because incident cases, i.e., newly diagnosed cases had a higher frequency of rare alleles than did prevalent cases, i.e., cases already existing at the time of recruitment. Repeating the analyses with incident cases only (n = 53), the OR for subjects with 1 rare allele was 1.2 (95% CI = 0.6-2.4) and for those with 2 rare alleles 3.2 (95% CI = 0.8-13.7). The number of incident cases was too small to draw firm conclusions on a possible association with a subgroup of tumors with a poor prognosis. Published 2002 Wiley-Liss, Inc.
... 27 Linkage analysis in two large German breast cancer families, with negative lod scores for the BRCA1 and BRCA2 locus, showed a multipoint lod score of 3.30 at two other markers, localised between the two markers in the French study, on chromosome 8p. 28 In studies focusing on chromosome 8p, LOH 14 Rare allele carriers, Total 13 Rare allele carriers 131 12 Rare allele carriers 130 11 Rare allele carriers 129 10 Rare allele carriers 128 9 Rare allele carriers 127 8 Rare allele carriers 126 7 Rare allele carriers 125 6 Rare allele carriers 124 5 Rare allele carriers 123 4 Rare allele carriers 122 3 Rare allele carriers 121 2 Rare allele carriers 120 1 ...
... 118 The HRAS1 polymorphism was examined in 13 studies. [119][120][121][122][123][124][125][126][127][128][129][130][131] Positive ORs were detected in all studies (fig 1), five of which reached significance 119 124 128 129 131 with ORs of 2-7. Combining the studies showed an association between rare HRAS1 alleles and breast cancer (OR=2.03, ...
This review focuses on genes other than the high penetrance genes BRCA1 and BRCA2 that are involved in breast cancer susceptibility. The goal of this review is the discovery of polymorphisms that are either associated with breast cancer or that are in strong linkage disequilibrium with breast cancer causing variants. An association with breast cancer at a 5% significance level was found for 13 polymorphisms in 10 genes described in more than one breast cancer study. Our data will help focus on the further analysis of genetic polymorphisms in populations of appropriate size, and especially on the combinations of such polymorphisms. This will facilitate determination of population attributable risks, understanding of gene-gene interactions, and improving estimates of genetic cancer risks.
... The reason for the association between TTTA tandem repeat polymorphism in the intronic region and breast cancer risk is unclear. It is reported that the genetic variation in the tandem repeats in the intronic region of the H-ras1 gene is also associated with cancer risk (Krontiris et al., 1985(Krontiris et al., , 1993, although this observation has failed to be confirmed by the recent study (Firgaira et al., 1999). It is still possible, however, that a variable number of tandem repeats in the intron 4 might affect the expression of the CYP19 gene. ...
Screening of the entire coding and major promoter regions of the CYP19 gene identified two novel polymorphisms at codon 39 (Trp to Arg) and codon 408 (silent) in addition to those reported previously at codon 264 (Arg to Cys) and intron 4 [tetranucleotide (TTTA) simple tandem repeat]. A case-control study was conducted in order to see whether or not these polymorphisms were associated with breast cancer risk in Japanese women. Homozygous and heterozygous carriers of the variant allele Arg at codon 39 showed a significantly decreased risk of breast cancer (OR=0.39, 95%C.I.=0.17–0.89). On the other hand, homozygous carriers of the allele with 10 or more TTTA repeats at intron 4 showed a trend toward an increase (OR=1.80, 95%C.I.=0.97–3.36) in breast cancer risk. Other polymorphisms were found not to be associated with breast cancer risk. These results suggest that the CYP19 polymorphisms at exon 39 and intron 4 would be useful for selecting Japanese women at a high risk of breast cancer. Int. J. Cancer 89:325–328, 2000. © 2000 Wiley-Liss, Inc.
... The carriers of a certain class of rare alleles of the minisatellite locus are proposed to be at increased risk of breast cancer, the relative risk being approximately twofold (Krontiris et al. 1993). However, two most recent studies using a more accurate method for allele sizing found no overall association and it seems that the earlier results are false due to misclassification of alleles resulting from methodological reasons (Firgaira et al. 1999, Tamimi et al. 2003. These findings suggested that the putative associations of HRAS1 minisatellite alleles and breast cancer need to be re-evaluated with the new method of sizing alleles. ...
Breast cancer has been recognized for over 100 years as having a familial component.1 More recently, a number of epidemiological investigations have attempted to quantify the risks of breast cancer associated with a positive family history. Attempts have also been made to examine whether the pattern of related individuals with breast cancer are consistent with the effects of a single gene of large effect, shared environmental effects, many genes acting in an additive manner or, more likely, a combination of two or more of these effects. In addition to this statistical and observational evidence for the role of genes in the development of breast cancer, a number of specific genes have been identified as playing a role. Perhaps the most notable of these genes are BRCA1 and BRCA2, which were identified through genetic linkage studies and localized to the long arms of chromosomes 17 and 13, respectively.2,3 Because BRCA1 and BRCA2 have been extensively studied, they are the subjects of a separate chapter (Chapter 19) in this book. However, the BRCA1 and BRCA2 genes account for less than half of all familial breast cancer.4.
The highly polymorphic HRAS1 variable number of tandem repeats (VNTR) has been described as an inherited predisposing factor in various human cancers. The aim of the present study was to evaluate the association between the presence of rare HRAS1 VNTR alleles and colorectal adenoma and cancer. A total of 165 Japanese patients underwent total colonoscopy with informed consent, and were divided into 2 groups: colorectal neoplastic and non-neoplastic patients. Two hundred and sixteen HRAS1 VNTR alleles from 108 colorectal neoplastic patients (67 adenomas and 41 cancers) and 114 alleles from 57 non-neoplastic patients were genotyped using PCR-based long-agarose gel elec- trophoresis assay of peripheral blood leukocyte DNA. Rare alleles were differentiated from 4 types of common allele (a1, a2, a3 and a4) by shifts in electrophoretic mobility. The prevalence of rare HRAS1 VNTR alleles was higher in colorectal neoplastic patients than in non-neoplastic patients (25.4% and 34.1% versus 8.8%). The adjusted odds ra- tio with at least one rare allele was 8.65 (95% confidence interval = 2.93-25.53, P < 0.0001) in colorectal neoplastic patients. The presence of rare HRAS1 VNTR alleles could be a genetic predisposing factor for risk of colorectal neoplasm in Japanese people.
PCR-based typing of Hras1minisatellite alleles was carried out in 226 non-small cell lung cancer (NSCLC) patients and 207 unaffected controls. Application of this method permitted detection of four common (a1toa4) and 25 other alleles, differing from any common allele by one or more repeat units. Depending on their frequency in control group, these alleles were defined as intermediate or rare (the frequency over 0.5% or less than 0.5%, respectively). It was established that the frequency of rare alleles in the group of NSCLC patients (7.1%) was statistically significantly higher than in healthy individuals (2.2%, P= 0.002), while the difference in the distribution of common and intermediate alleles between the compared groups was not statistically significant. In addition, rareHras1alleles were more frequent (P= 0.02) among nonsmoking patients (P= 0.02) compared to the patients subjected to of tobacco carcinogens. The presence of heavy (a3–a4) alleles was associated with an increased risk of low-differentiated and/or actively metastasizing tumors and also with the risk of lung cancer in the patients under 50 years of age (P< 0.05).="" these="" data="" indicate="" that="" an="" approach="" including="" application="" of="" modern="" highly="" sensitive="" techniques="">Hras1allele typing in combination with preliminary examination of healthy control population can be employed for identifying carcinogenic risk groups as well as for prognosis of the NSCLC clinical course.
