The HER-2/neu oncogene is a member of the erbB-like oncogene family, and is related to, but distinct from, the epidermal growth factor receptor. This gene has been shown to be amplified in human breast cancer cell lines. In the current study, alterations of the gene in 189 primary human breast cancers were investigated. HER-2/neu was found to be amplified from 2- to greater than 20-fold in 30% of the tumors. Correlation of gene amplification with several disease parameters was evaluated. Amplification of the HER-2/neu gene was a significant predictor of both overall survival and time to relapse in patients with breast cancer. It retained its significance even when adjustments were made for other known prognostic factors. Moreover, HER-2/neu amplification had greater prognostic value than most currently used prognostic factors, including hormonal-receptor status, in lymph node-positive disease. These data indicate that this gene may play a role in the biologic behavior and/or pathogenesis of human breast cancer.

https://science.sciencemag.org/content/sci/235/4785/177.full.pdf

Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene

Many human melanoma tumors express antigens that are recognized in vitro by cytolytic T lymphocytes (CTLs) derived from the tumor-bearing patient. A gene was identified that directed the expression of antigen MZ2-E on a human melanoma cell line. This gene shows no similarity to known sequences and belongs to a family of at least three genes. It is expressed by the original melanoma cells, other melanoma cell lines, and by some tumor cells of other histological types. No expression was observed in a panel of normal tissues. Antigen MZ2-E appears to be presented by HLA-A1; anti-MZ2-E CTLs of the original patient recognized two melanoma cell lines of other HLA-A1 patients that expressed the gene. Thus, precisely targeted immunotherapy directed against antigen MZ2-E could be provided to individuals identified by HLA typing and analysis of the RNA of a small tumor sample.

https://science.sciencemag.org/content/sci/254/5038/1643.full.pdf

A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma

The genomes of various tumour cells contain mutant oncogenes that act dominantly, in that their effects can be observed when they are introduced into non-malignant cells. There is evidence for another class of oncogenes, in which tumour-predisposing mutations are recessive to wild-type alleles. Retinoblastoma is a prototype biological model for the study of such recessive oncogenes. This malignant tumour, which arises in the eyes of children, can be explained as the result of two distinct genetic changes, each causing loss of function of one of the two homologous copies at a single genetic locus, Rb, assigned to the q14 band of human chromosome 13. Mutations affecting this locus may be inherited from a parent, may arise during gametogenesis or may occur somatically. Those who inherit a mutant allele at this locus have a high incidence of non-ocular, second tumours, almost half of which are osteosarcomas believed to be caused by the same mutation. Here we describe the isolation of a complementary DNA segment that detects a chromosomal segment having the properties of the gene at this locus. The gene is expressed in many tumour types, but no RNA transcript has been found in retinoblastomas and osteosarcomas. The cDNA fragment detects a locus spanning at least 70 kilobases (kb) in human chromosome band 13q14, all or part of which is frequently deleted in retinoblastomas and osteosarcomas.

/pdf/a-human-dna-segment-with-properties-of-the-gene-that-kc0q4f65ya.pdf

A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma

Multiple genetic changes occur during the evolution of normal cells into cancer cells. This evolution is facilitated in cancer cells by loss of fidelity in the processes that replicate, repair, and segregate the genome. Recent advances in our understanding of the cell cycle reveal how fidelity is normally achieved by the coordinated activity of cyclin-dependent kinases, checkpoint controls, and repair pathways and how this fidelity can be abrogated by specific genetic changes. These insights suggest molecular mechanisms for cellular transformation and may help to identify potential targets for improved cancer therapies.

https://science.sciencemag.org/content/sci/266/5192/1821.full.pdf

Cell cycle control and cancer

Cells prepare for S phase during the G1 phase of the cell cycle. Cell biological methods have provided knowledge of cycle kinetics and of substages of G1 that are determined by extracellular signals. Through the use of biochemical and molecular biological techniques to study effects of growth factors, oncogenes, and inhibitors, intracellular events during G1 that lead to DNA synthesis are rapidly being discovered. Many cells in vivo are in a quiescent state (G0), with unduplicated DNA. Cells can be activated to reenter the cycle during G1. Similarly, cells in culture can be shifted between G0 and G1. These switches in and out of G1 are the main determinants of post-embryonic cell proliferation rate and are defectively controlled in cancer cells.

https://science.sciencemag.org/content/sci/246/4930/603.full.pdf

G1 events and regulation of cell proliferation.

Epstein–Barr Virus in Burkitt's Lymphoma and Nasopharyngeal Carcinoma: EBV DNA in Biopsies of Burkitt Tumours and Anaplastic Carcinomas of the Nasopharynx

EBV DNA in biopsies of Burkitt tumours and anaplastic carcinomas of the nasopharynx.

Summary Host resistance against methylcholanthrene (MC)-induced sarcomas, demonstrated by previous authors after transplantation to isologous recipients, could also be shown to occur in the primary autochthonous host, whose tumor had been operatively removed The autochthonous mice, together with groups of isologous animals, were pretreated with irradiated sarcoma cells and subsequently challenged with increasing doses of viable cells, also inoculated into untreated isologous controls An increased resistance could be demonstrated with twelve out of sixteen tumors in the autochthonous and nineteen out of 22 tumors in the isologous host Resistance was relative rather than absolute and broke down when the dose of viable cells was progressively increased It was usually stronger in isologous than in autochthonous mice, but this was not a general rule Isologous mice pretreated with irradiated normal tissues and subsequently challenged with viable sarcoma cells showed either no increase in resistance or a slight increase that exceeded the control level but did not reach the level found in isologous hosts pretreated with irradiated cells of the same sarcoma Isologous, untreated mice that had received total-body irradiation before being challenged with viable sarcoma cells supported the growth of small viable inocula better than did unirradiated isologous hosts In the cases tested, resistance against a given sarcoma did not lead to cross-resistance against a different sarcoma, induced in the same genotype by MC Serial treatment with homologous, MC-induced sarcoma tissue did not reduce the yield of primary sarcomas obtained after application of MC Lymph node cells, but not serum, of isologous mice pretreated with heavily irradiated sarcoma cells, could neutralize the sarcoma cells wholly or partially upon incubation in vitro Lymph node cells of untreated animals and preimmunized lymph node cells killed by freezing and thawing had no effect

/pdf/demonstration-of-resistance-against-methylcholanthrene-3f7uh5vw1f.pdf

Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host.

It is generally accepted that tumours arise through the accumulation of several changes affecting the control of cell growth. Recent advances in molecular biology have made it possible to define some of these changes in molecular terms and to trace the steps by which certain tumours evolve.

Evolution of tumours and the impact of molecular oncology.

Genes that can inhibit the expression of the tumorigenic phenotype have been detected by the fusion of normal and malignant cells, the phenotypic reversion of in vitro transformants, the induction of terminal differentiation of malignant cell lineages, the loss of "recessive cancer genes," the discovery of regulatory sequences in the immediate vicinity of certain oncogenes, and the inhibition of tumor growth by normal cell products Such tumor suppressor genes will probably turn out to be as, if not more, diversified as the oncogenes Consideration of both kinds of genes may reveal common or interrelated functional properties

The Approaching Era of the Tumor Suppressor Genes

Summary Fifty-two polyoma-induced primary mouse tumors were tested for transplantability in isologous recipients. Thirty-five tumors grew progressively in the subcutaneous tissue, and several lines have been established in serial transplantation. The remaining tumors did not grow out at all upon transfer. Eleven among the transplantable tumors have been tested by inoculating known numbers of cells to the following three groups of adult isologous recipients: ( a ) untreated mice, maintained at a separate, polyoma-free colony, ( b ) mice preimmunized as adults against polyoma virus containing supernatant fluids from infected mouse embryo tissue cultures, and ( c ) mice pretreated with heavily irradiated cells of the same tumor. There was a clear and consistent difference between groups a and b for ten of eleven tumors, indicating a state of resistance against transplantation of the established polyoma tumors in the virus-immunized group. With the exception of two out of nine experiments, there was no evidence of resistance in group c , pretreated with irradiated tumor cells. Serum of virus-immunized mice had a certain inhibiting effect on viable polyoma tumor cells upon incubation in vitro with one of four tumors. The possible implications of these findings have been discussed.

/pdf/transplantation-of-polyoma-virus-induced-tumors-in-mice-2we05aswui.pdf

George Klein

Papers

EBV DNA in biopsies of Burkitt tumours and anaplastic carcinomas of the nasopharynx.

Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host.

Evolution of tumours and the impact of molecular oncology.

The Approaching Era of the Tumor Suppressor Genes

Transplantation of Polyoma Virus-induced Tumors in Mice