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At least 685 records · Page 38Linked to original sources
PubMed1995

High K-ras mutation rates in goblet-cell-type adenocarcinomas of the lungs.

Adenocarcinomas of the lungs show a variable histology. We have subclassified such lesions into five cell types: hobnail, columnar, polygonal, mixed and goblet cell types, and investigated their relationships with K-ras mutations. Codons 12, 13 and 61 of the K-ras gene in 120 surgically resected pulmonary adenocarcinomas were examined by the mutation-allele-specific amplification method. Point mutations were observed in 10% of the adenocarcinomas limited to K-ras codon 12 and the commonest base substitution (nine cases) was a G to T transversion. Of the five types, goblet cell lesions demonstrated the highest mutation index, which at 100% (6/6) was significantly different from that of all other cell types. No relationship between K-ras mutation and cigarette smoking was observed. From these findings, it appears that development of goblet-cell-type adenocarcinomas of the lung may involve different carcinogenic mechanisms from adenocarcinomas of other subtypes.

Adenocarcinoma↗
PubMed1989

Development of molecular approaches to estimating germinal mutation rates. I. Detection of insertion/deletion/rearrangement variants in the human genome.

DNA from 130 individuals was studied with up to 18 (primarily cDNA) probes for the frequency of variants in this initial experiment to determine the feasibility of this approach to screening for germinal gene mutations. This approach, a modification of the usual restriction enzyme mapping strategy, focuses on the detection of insertion/deletion/rearrangement (I/D/R) variants, because the DNA is digested with only two restriction enzymes before transfer to membranes and hybridization with an extensive series of unrelated probes. Some 4000 noncontiguous, independent DNA fragments ("loci"), functional loci, pseudogenes or anonymous fragments, (a total of approximately 77,400 kb) were screened. 19 different classes and 31 copies of presumably I/D/R variants were detected while 4 different classes and 24 individuals exhibiting base substitution variants were observed. 18 of the 19 I/D/R classes were rare variants, that is, each were observed at a frequency, within this population, of less than 0.01; 3 of the base substitution classes existed at polymorphic frequencies and only 1 was a rare variant. 10 of the I/D/R classes, occurring in a total of 18 individuals, were detected with probes which are not known to be associated with repetitive elements. This is a variant frequency for I/D/R variants without known repetitive elements of 0.15 classes and 0.23 copies for each 1000 kb screened; this would extrapolate to 1600 such variant sites in the genome of each individual. Within the context of a mutation screening program, the rare variants, either with or without repetitive elements, would have a higher probability of being de novo mutations than would polymorphic variants; this former group would be the focus of family studies to test for the heritability of the allele (fragment pattern). Sufficient DNA probes are available to screen a significant portion of the human genome for genetic variation and de novo mutations of this type.

Blotting, Southern↗
PubMed2002

Disruption of Brca2 increases the spontaneous mutation rate in vivo: synergism with ionizing radiation.

The breast cancer predisposition gene BRCA2 encodes a protein involved in the repair of DNA double-strand breaks, which arise spontaneously and following exposure to ionizing radiation (IR). To develop a mouse model that examines the effect of BRCA2 mutation and IR exposure on in vivo somatic mutation acquisition, we crossed mice with targeted disruption of Brca2 with a LacZ transgenic mutation reporter strain. Loss of both wild-type Brca2 alleles caused a 2.3-fold increase, equivalent to an extra 100 mutations per cell, in the in vivo acquisition of spontaneous somatic mutation by 2 weeks gestation. IR (4 Gy) had a disproportionate effect on animals homozygous for Brca2 disruption, inducing 3.4-fold more mutations compared with wild-type animals. These data provide the first evidence that loss of Brca2 increases in vivo somatic mutation acquisition and synergizes with IR exposure, with potential attendant implications for mammographic screening and therapeutic IR in mutation carriers.

Animals↗