A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods. Probable predisposing mutations have been detected in five of eight kindreds presumed to segregate BRCA1 susceptibility alleles. The mutations include an 11-base pair deletion, a 1-base pair insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary, and encodes a predicted protein of 1863 amino acids. This protein contains a zinc finger domain in its amino-terminal region, but is otherwise unrelated to previously described proteins. Identification of BRCA1 should facilitate early diagnosis of breast and ovarian cancer susceptibility in some individuals as well as a better understanding of breast cancer biology.

https://courses.washington.edu/gs466/readings/miki.pdf

A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1

NOTE The report of the Committee without its annexes appears as Official Records of the General Assembly, Sixty-third Session, Supplement No. 46. The designations employed and the presentation of material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the United Nations concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries. The country names used in this document are, in most cases, those that were in use at the time the data were collected or the text prepared. In other cases, however, the names have been updated, where this was possible and appropriate, to reflect political changes. Scientific Annexes Annex A. Medical radiation exposures Annex B. Exposures of the public and workers from various sources of radiation INTROdUCTION 1. In the course of the research and development for and the application of atomic energy and nuclear technologies, a number of radiation accidents have occurred. Some of these accidents have resulted in significant health effects and occasionally in fatal outcomes. The application of technologies that make use of radiation is increasingly widespread around the world. Millions of people have occupations related to the use of radiation, and hundreds of millions of individuals benefit from these uses. Facilities using intense radiation sources for energy production and for purposes such as radiotherapy, sterilization of products, preservation of foodstuffs and gamma radiography require special care in the design and operation of equipment to avoid radiation injury to workers or to the public. Experience has shown that such technology is generally used safely, but on occasion controls have been circumvented and serious radiation accidents have ensued. 2. Reviews of radiation exposures from accidents have been presented in previous UNSCEAR reports. The last report containing an exclusive chapter on exposures from accidents was the UNSCEAR 1993 Report [U6]. 3. This annex is aimed at providing a sound basis for conclusions regarding the number of significant radiation accidents that have occurred, the corresponding levels of radiation exposures and numbers of deaths and injuries, and the general trends for various practices. Its conclusions are to be seen in the context of the Committee's overall evaluations of the levels and effects of exposure to ionizing radiation. 4. The Committee's evaluations of public, occupational and medical diagnostic exposures are mostly concerned with chronic exposures of …

sources and effects of ionizing radiation

Inactivation of the adenomatous polyposis coli (APC) tumor suppressor gene initiates colorectal neoplasia. One of the biochemical activities associated with the APC protein is down-regulation of transcriptional activation mediated by beta-catenin and T cell transcription factor 4 (Tcf-4). The protein products of mutant APC genes present in colorectal tumors were found to be defective in this activity. Furthermore, colorectal tumors with intact APC genes were found to contain activating mutations of beta-catenin that altered functionally significant phosphorylation sites. These results indicate that regulation of beta-catenin is critical to APC's tumor suppressive effect and that this regulation can be circumvented by mutations in either APC or beta-catenin.

/pdf/activation-of-b-catenin-tcf-signaling-in-colon-cancer-by-36zmclwahi.pdf

Activation of β-Catenin-Tcf Signaling in Colon Cancer by Mutations in β-Catenin or APC

https://pure.knaw.nl/ws/files/7023847/S0092_8674_00_00122_7_1_.pdf

Linking Colorectal Cancer to Wnt Signaling

Caught up in a Wnt storm: Wnt signaling in cancer.

Germline mutations of the APC gene are responsible for familial adenomatous polyposis, an autosomal dominant inherited predisposition to colorectal tumors. Mutation of the APC gene is also an early, if not initiating, event for sporadic colorectal tumorigenesis. In both cases, almost all of the currently identified mutations of APC result in the truncation of the protein. In this study, we demonstrate that truncated APC proteins can associate with the wild type APC in vivo. Using in vitro expression and immunoprecipitation, we show that the first 171 residues of APC are sufficient for APC oligomerization and that the first 45 amino acids of APC is necessary for this interaction. These results indicate that most mutant APC proteins should be able to bind to wild type APC protein and perhaps inactivate it in a dominant negative manner.

/pdf/association-between-wild-type-and-mutant-apc-gene-products-304eq4bs33.pdf

Association between Wild Type and Mutant APC Gene Products

Germ-line mutations of the APC gene are responsible for familial adenomatous polyposis (FAP), an autosomal dominantly inherited disease in humans. Patients with FAP develop multiple benign colorectal tumors. Recently, a mouse lineage that exhibits an autosomal dominantly inherited predisposition to multiple intestinal neoplasia (Min) was described. Linkage analysis showed that the murine homolog of the APC gene (mApc) was tightly linked to the Min locus. Sequence comparison of mApc between normal and Min-affected mice identified a nonsense mutation, which cosegregated with the Min phenotype. This mutation is analogous to those found in FAP kindreds and in sporadic colorectal cancers.

Li-Kuo Su

Papers

Association between Wild Type and Mutant APC Gene Products

Corrections and Clarifications: Multiple Intestinal Neoplasia Caused By a Mutation in the Murine Homolog of the APC Gene