Lessons from Hereditary Colorectal Cancer

Whether and how human tumours are genetically unstable has been debated for decades. There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels. In a small subset of tumours, the instability is observed at the nucleotide level and results in base substitutions or deletions or insertions of a few nucleotides. In most other cancers, the instability is observed at the chromosome level, resulting in losses and gains of whole chromosomes or large portions thereof. Recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.

Genetic instabilities in human cancers

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

The p53 tumor suppressor gene has come to the forefront of cancer research because it is commonly mutated in human cancer and the spectrum of p53 mutations in these cancers is providing clues to the etiology and molecular pathogenesis of neoplasia (1â€”3). Detection of p53 abnormalities may have diagnostic, prognostic, and therapeutic implications (4). The 15-year history of p53 investigations is a paradigm in cancer research, illustrating the convergence of previously parallel lines of basic, clinical, and epidemiological investigation and the rapid trans fer of research findings from the laboratory to the clinic. p53 is clearly a component in biochemical pathways central to human carcinogen esis; p53 protein alterations due to missense mutations and loss of p53 protein by nonsense or frameshift mutations provide a selective ad vantage for clonal expansion of preneoplastic and neoplastic cells (5). The potential for a missense mutation to cause loss of tumor suppres sor function and gain of oncogenic activity, i.e., to transform cells by two mechanisms, is one explanation for the commonality of p53 mutations in human cancer. Recent studies investigating the mecha nisms underlying the biological activity of p53 indicate that the protein is involved in gene transcription, DNA synthesis and repair, genomic plasticity, and programmed cell death (1â€”6).These complex biochemical processes are performed by multicomponent protein ma chines; therefore, it is not surprising that the p53 protein forms complexes with other cellular proteins (Fig. 1) and that some viral oncoproteins alter the functions of these machines by binding to p53 and perturbing its interaction with other cellular protein components. In this Perspective, we will focus on the origin of p.53 mutations, the mutational spectrum of p.53 in human cancers, and the hypotheses generated by the analysis of p53 mutations in premalignant and malignant cells. The interpretation ofp53 mutations in human cancers is based on observations of the patterns of DNA damage induced by chemical and physical mutagens in model systems. In this Introduc tion, we will review these data, which provide the background for many of the inferences drawn from p53 mutational analysis.

https://cancerres.aacrjournals.org/content/canres/54/18/4855.full.pdf

Mutations in the p53 Tumor Suppressor Gene: Clues to Cancer Etiology and Molecular Pathogenesis

Medical genetics was revolutionized during the 1980s by the application of genetic mapping to locate the genes responsible for simple Mendelian diseases. Most diseases and traits, however, do not follow simple inheritance patterns. Genetics have thus begun taking up the even greater challenge of the genetic dissection of complex traits. Four major approaches have been developed: linkage analysis, allele-sharing methods, association studies, and polygenic analysis of experimental crosses. This article synthesizes the current state of the genetic dissection of complex traits--describing the methods, limitations, and recent applications to biological problems.

https://focus.psychiatryonline.org/doi/pdf/10.1176/foc.4.3.442

Genetic dissection of complex traits

https://www.cell.com/cell/pdf/0092-8674(93)90546-3.pdf

The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer.

Alteration of the human mismatch repair gene hMSH2 has been linked to the microsatellite DNA instability found in hereditary nonpolyposis colon cancer and several sporadic cancers. This microsatellite DNA instability is thought to arise from defective repair of DNA replication errors that create insertion-deletion loop-type (IDL) mismatched nucleotides. Here, it is shown that purified hMSH2 protein efficiently and specifically binds DNA containing IDL mismatches of up to 14 nucleotides. These results support a direct role for hMSH2 in mutation avoidance and microsatellite stability in human cells.

https://science.sciencemag.org/content/sci/266/5189/1403.full.pdf

Binding of mismatched microsatellite DNA sequences by the human MSH2 protein

The human hMSH2 protein is a member of a highly conserved family of postreplication mismatch repair components found from bacteria to humans. Alterations of the gene coding for this protein cosegregate with, and are the likely cause of, chromosome 2-linked hereditary nonpolyposis colon cancer. Postreplication mismatch repair has been found to faithfully replace misincorporated nucleotides, thereby increasing the overall fidelity of DNA replication. Loss of postreplication mismatch repair function leads to a mutator phenotype, which is proposed to account for the multiple mutations required for multistep carcinogenesis. Although the functions of hMSH2 can be anticipated based on its similarity to well-characterized bacterial and yeast proteins, proof of its functions has not been established. Here we demonstrate that purified hMSH2 binds specifically to mismatched nucleotides, providing a target for the excision repair processes characteristic of postreplication mismatch repair.

https://cancerres.aacrjournals.org/content/canres/54/21/5539.full.pdf

Purified Human MSH2 Protein Binds to DNA Containing Mismatched Nucleotides

Hereditary non-polyposis colon cancer (HNPCC) may affect up to 1 in 200 people in industrialized nations (Bishop and Thomas 1990; Lynch et al. 1991, 1993; Peltomaki et al. 1993b). Four genes have been identified in which inherited mutations appear to cause HNPCC. hMSH2 on chromosome 2p21-22 appears to account for up to 60% of HNPCC (Fishel et al. 1993; Leach et al. 1993; Sandkuijl and Bishop 1993; Nystrom-Lahti et al. 1994), hMLH1 on chromosome 3p21 appears to account for up to 30% of HNPCC (Bronner et al. 1994; Nystrom-Lahti et al. 1994; Papadopoulos et al. 1994), and hPMS1 on chromosome 2q31-33 and hPMS2 on chromosome 7p21 may account for 5% of HNPCC (Nicolaides et al. 1994).

Mary Kay Lescoe

Papers

The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer.

Binding of mismatched microsatellite DNA sequences by the human MSH2 protein

Purified Human MSH2 Protein Binds to DNA Containing Mismatched Nucleotides

Human mismatch repair genes and their association with hereditary non-polyposis colon cancer.