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H Blaszyk

Publications and source records attributed to H Blaszyk.

31 records · Page 2Linked to original sources
PubMed1996

Database of mutations in the p53 and APC tumor suppressor genes designed to facilitate molecular epidemiological analyses.

Germline and somatic mutations in the p53 and APC genes contribute to neoplasia. The patterns of these and other acquired mutations in cancers reflect environmental mutagens and endogenous factors that contribute to carcinogenesis. Herein, we describe a database of almost 2,300 mutations in the p53 and APC genes published until September 1, 1993. In addition to cataloging the mutations, multiple fields of information have been added to facilitate future molecular epidemiological analyses of human cancer. The accuracy of the database has been checked by the present authors and, by soliciting feedback from the original corresponding authors. The strengths and limitations of the primary literature are discussed.

Computer Communication Networks↗
PubMed1996

A polymorphism but no mutations in the GADD45 gene in breast cancers.

The p53 gene product is part of a pathway regulating growth arrest at the G1 checkpoint of the cell cycle. Mutation of other components of this pathway, including the products of the ataxia telangiectasia (AT), GADD45, mdm2, and p21WAF1/CIP1 genes may have effects comparable to mutations in the p53 gene. The GADD45 gene is induced by ionizing radiation and several DNA-damaging xenobiotics. Induction requires the binding of wild-type p53 to an evoulutionarily highly conserved putative intronic p53 binding site in intron 3 of GADD45. We recently analyzed the entire coding region of the p53 gene in primary breast cancers of Midwestern white women and found 21 mutations among 53 tumors (39.6%). We now have shown by direct sequencing that there are no mutations in the intronic p53 binding site of the GADD45 gene in any of the 53 primary breast cancers and no mutations in the entire coding region of the GADD45 gene in a subset of 26 consecutive tumors (12 with p53 mutation and 14 without p53 mutation). The only sequence variation detected was a common polymorphism in intron 3. The absence of mutations in the GADD45 gene, including the putative p53-binding intronic site, suggests that this gene is not a frequent target of mutations in breast cancer. Although mutations of the p53 gene have been studied in a wide spectrum of human cancers, GADD45 has not been examined in any tumor or cell line to the best of our knowledge. Our results raise the possibility that mutation of the GADD45 gene alone is not functionally equivalent to loss of wild-type p53 activity.

Base Sequence↗
PubMed1996

High frequency of p53 gene mutations in primary breast cancers in Japanese women, a low-incidence population.

The pattern of acquired mutations in the p53 tumour-suppressor gene is potentially useful for determining factors contributing to carcinogenesis in diverse populations differing in incidence and/or mortality from the disease. We previously reported differences in mutational patterns of the p53 gene in primary breast cancers from Midwest US Caucasian, African-American and Austrian women. Herein, we report 16 mutations in 27 primary breast cancers from Japanese women from Hirosaki, a population with a low incidence of breast cancer. The frequency of 59.3% of p53 mutations is the highest reported in breast cancers from a particular ethnic group thus far. A relatively high number of mutations (7/16) were heterozygous in at least some tumour cell clusters. Intergroup comparisons of the mutational pattern between this population and several other US, European and Japanese populations do not show any statistically significant differences. There were recurrent mutations at two sites, codon 273 (R --> H; three mutations), a common hotspot of mutations in breast and other cancers, and codon 183 (S --> Stop; two mutations), a very rare location for p53 mutations. These mutations were shown to be independent and presumably not in the germ line. The highest frequency of p53 mutations raises the possibility that p53 mutagenesis is a predominant factor for breast cancer development in this low-risk Japanese group, whereas in other cohorts different mechanisms are likely to account for the higher proportion of breast cancer. Further studies are needed to confirm the present observations.

Adult↗
PubMed1995

p53 gene mutations inside and outside of exons 5-8: the patterns differ in breast and other cancers.

Most studies of mutations in the p53 tumor suppressor gene in tumors have examined only exons 5-8. Our laboratory previously found 64 mutations in exons 5-8 of the p53 gene in 194 primary breast cancers. Herein, we report 18 additional mutations found outside of exons 5-8. Mutations are present in exons 4, 9 and 10, and flanking splice junctions, but not in the promotor region or in exons 1, 2, 3 and 11. No missense mutations are found outside of exons 5-8. Instead, there is a predominance of frameshift mutations with lesser numbers of nonsense and splice site mutations. In contrast, the majority of mutations in exons 5-8 in this sample are missense changes and all of these are at amino acids that are identical in the 11 known p53 sequences that represent about 1.6 billion years of evolutionary divergence. The difference in mutational pattern between these two regions of the p53 gene is due to a lack of missense mutations and inframe microdeletions outside of exons 5-8. A review of our database of p53 mutations (De Vries et al., in preparation) shows that the patterns of mutation inside and outside of exons 5-8 differ in other types of cancers as well. The paucity of missense mutations in exons 2-4 and 9-11 in breast and other cancers (even at amino acids identical throughout p53 gene evolution) suggest that at least some missense mutations result in a phenotype other than malignant transformation. These data also illustrate the importance of examining identical exons when comparing the pattern of p53 gene mutations in different populations.

Adult↗
PubMed1995

Novel pattern of P53 mutation in breast cancers from Austrian women.

Since mutagens produce an extraordinary diversity of mutational patterns, differential mutational exposures among populations are expected to produce different patterns of mutation. Classical epidemiological methods have been successful in implicating specific mutagens in cancers such as those of lung and skin in which one mutagen predominates. In breast cancer, however, no mutagens have been implicated in an unequivocal manner. In an attempt to facilitate epidemiological studies, we have been studying the pattern of p53 gene mutations in breast cancers from multiple populations with high and low breast cancer incidences. We previously reported that breast cancers from Midwest United States, predominantly rural Caucasian women, have a different pattern of p53 gene mutation from populations of Western European women. Herein, we analyze patterns of p53 mutations from Graz, Austria, another population with a high incidence of breast cancer. Among the 60 Austrian breast cancers analyzed, 14 (23%) have a p53 gene mutation in exons 5-9 or in adjacent splice junctions. Analysis of the patterns of mutation shows differences between the "Western European" profile and the Austrian and Midwest United States groups (P = 0.027 and 0.024, respectively). The Austrian pattern is characterized by a high frequency of A:T-->T:A transversions (P = 0.006). The presence of distinct patterns of mutation among the limited number of analyzed populations of Western European origin supports the idea that differential mutagenic exposure and/or genetic differences contribute to breast cancer mutagenesis among geographically distinct Caucasians of Western European origin.

Aged↗
PubMed1995

Rapid and efficient screening for p53 gene mutations by dideoxy fingerprinting.

Dideoxy fingerprinting (ddF) is an efficient method for detecting single base and other sequence changes in PCR-amplified DNA segments. This screening method is a hybrid between single-strand conformation polymorphism analysis (SSCP) and Sanger dideoxy sequencing. It involves a Sanger sequencing reaction with one dideoxynucleotide followed by non-denaturing gel electrophoresis. We are using ddF to screen for mutations in the p53 tumor suppressor gene in primary breast cancers. ddF detected more than 100 mutations in different regions of the gene, including all types of single-base mutations and microdeletions/microinsertions of various sizes. Furthermore, ddF reliably detected heterozygous mutations, if the region of interest was screened in both directions. In a blinded, prospective study, ddF detected all 25 mutations within exons 4-10 and adjacent flanking intronic regions previously found by direct sequencing. ddF was also useful in scoring two common polymorphisms within the p53 gene. Guidelines for preventing false-positive and false-negative results are summarized.

Breast Neoplasms↗
PubMed1994

Novel pattern of p53 gene mutations in an American black cohort with high mortality from breast cancer.

The pattern of acquired mutations in the p53 gene can be used to study differences in factors contributing to carcinogenesis. We investigated mutations in exons 5-9 and adjacent intronic regions in 47 breast cancers of black women from Michigan, a population with the highest breast-cancer mortality in the US. The 16 mutations detected differed from those of other populations. In particular, the black women had an excess of A:T-->G:C transitions compared with rural white US midwest women. While the causes of the different pattern of acquired mutation remain to be determined, this molecular epidemiological approach detects the consequences of mutagenic processes in specific populations. Mutation patterns will constrain hypotheses to mechanisms consistent with the observed biochemical alterations.

Base Sequence↗
PubMed1994

p53 gene mutations in breast cancers in midwestern US women: null as well as missense-type mutations are associated with poor prognosis.

We determined the pattern of mutations in exons 2-11 and adjacent intronic regions in breast cancers from Midwestern US white women. Twenty-one mutations were detected in 53 tumors (39.6%). Comparisons of the pattern of mutations within exons 5-9 showed that the frequency of missense mutations (44%) was lower in breast cancers of US Midwestern women than in most tumor types including breast cancers in other populations. Compared to breast cancers reported in a Scottish population, US women had a high frequency of G:C-->T:A transversions (P = 0.046). These findings suggest that environmental or endogenous factors contribute to p53 mutagenesis in mammary tissue to different extents among different populations. With a median follow-up of 19 months, the presence of a mutation was associated with shorter time to disease recurrence (P = 0.05) and shorter survival (P = 0.003). Putative dominant negative missense-type mutations (missense and in-frame microdeletions; P = 0.001) and null mutations (hemizygous nonsense and frameshift mutations; P = 0.007) were equally ominous. Thus, tumors with missense p53 mutations resulting in over-expression of a dysfunctional but otherwise intact protein have a clinical outcome similar to tumors with null mutations resulting in a truncated or garbled protein.

Adult↗
PubMed1993

Persistent proliferation of normal hepatocytes and promotion of preneoplastic development by N-nitrosodibenzylamine in rats.

In a traditional long-term study N-nitrosodibenzylamine (NDBzA) was proven to be noncarcinogenic, but recently the substance was found to produce genotoxic lesions in hepatocytes. Our own experiments have shown that relatively low single doses of NDBzA cause liver hypertrophy and additive proliferation of hepatocytes in rats. Both effects are known from well-documented promoters and non-genotoxic carcinogens, respectively, in rodents. Investigation of NDBzA in an initiation-promotion assay (IP assay) showed it to cause an increase in the number and size of preneoplastic liver cell foci. This occurred only after initiation with diethylnitrosamine, but not when 2-acetylaminofluorene was used. Another property of NDBzA is its sustained mitotic stimulation of extrafocal hepatocytes. This is inconsistent with their adaptive loss of susceptibility to mitogens in IP assays using other promoters of hepatocarcinogenesis. The following conclusions can be drawn. First, "differential inhibition" of the proliferation of extrafocal hepatocytes, in contrast to the selective mitostimulation of preneoplastic cells, is obviously no prerequisite for cancer development. Second, primary mitogenicity of a compound in short-term studies can be a useful indicator for tumorigenic potential. In the case of NDBzA the data available at present are still insufficient to classify it unequivocally in terms of genotoxic or nongenotoxic carcinogenicity.

Animals↗
PubMedDate not supplied

Acute aortic regurgitation due to spontaneous rupture of a fenestrated cusp: report in a 65-year-old man and review of seven additional cases.

A 65-year-old man with chronic hypertension developed dyspnea, a cough, and a new diastolic murmur. Two-dimensional echocardiography showed severe aortic regurgitation. No valvular vegetations were identified and blood cultures were negative. Surgical intervention was recommended, but the patient died of an acute intracranial hemorrhage two weeks later. At autopsy, the posterior aortic cusp was flail, due to rupture of the residual cord above two large fenestrations. There was no acute or healed endocarditis. To our knowledge, this is the eighth reported case of aortic valve incompetence due to spontaneous rupture of a fenestrated cusp. Patients ranged in age from 31-67 years (mean, 54), and 4 (50%) were older than 60 years. Seven (88%) of the 8 were men, and 4 (57%) of 7 had chronic hypertension. Analogously, in another four reported cases, aortic insufficiency developed following spontaneous rupture of the fenestrated raphe of an atypical congenitally bicuspid aortic valve. Noninfective and nontraumatic rupture of cord-like aortic valve structures may result in severe acute aortic regurgitation, particularly in men with chronic hypertension.

Acute Disease↗