A H Wyllie

p53 Deficiency in liver reduces local control of survival and proliferation, but does not affect apoptosis after DNA damage.

Despite good evidence for p53 dysfunction in human hepatocellular carcinomas, little is known of the significance of p53 to normal hepatocytes and whether p53 dysfunction is relevant to early hepatocarcinogenesis. We have therefore examined the consequences of targeted p53 deficiency in hepatocytes for regulation of apoptosis, proliferation, and ploidy. p53 deficiency was silent in normal liver and did not affect progression from diploidy to polyploidy in the aging liver. However, in primary culture the absence of p53 resulted in increased hepatocyte proliferation indices and decreased sensitivity to proliferation inhibition by TGFβ. Moreover, p53‐deficient cells continued to survive and proliferate under conditions of minimal trophic support that led to growth arrest and apoptosis of wild‐type cells. In vivo, p53‐deficient mice had enhanced proliferative responses to both xenobiotic hepatomitogen and CCl4‐induced liver necrosis, although lack of persistent proliferation showed that other control mechanisms are important. There was no simple relationship between p53 and apoptosis after DNA damage because UV irradiation led to p53‐independent apoptosis, even though p53 was stabilized. However, p53 did couple DNA damage to growth arrest, and abnormal mitoses after γ‐irradiation of regenerating p53 null livers demonstrated circumstances where loss of G1 and G2 checkpoints may generate abnormal ploidy. Thus p53 becomes important when hepatocytes are released from G0 and stressed, sensitizing them to mitogen and cytokine regulators of cell cycle progression and apoptosis. Hence p53 deficiency is likely to be significant in an environment of persistent regenerative stimuli and unfavorable trophic support or in the presence of other enabling genetic lesions. This model is relevant to human hepatocarcinogenesis, which almost always occurs against a background of chronic hepatocellular destruction in hepatitis and cirrhosis. In that context, by reducing the need for cytokine support and disabling DNA damage‐induced growth arrest, p53 deficiency should facilitate the expansion of preneoplastic clones in chronic liver disease.—Bellamy, C. O. C., Clarke, A. R., Wyllie, A. H., Harrison, D.J. p53 deficiency in liver reduces local control of survival and proliferation, but does not affect apoptosis after DNA damage. FASEB J. 11, 591–599 (1997)

A polymorphism in the CYP17 gene is associated with male breast cancer

SummaryThe CYP17 gene codes for the cytochrome P450c17α enzyme that is involved in the synthesis of oestrogens. This case-control study from the South East of Scotland shows that a polymorphism of the CYP17 gene is associated with an increased risk of male breast cancer.

Apoptosis. Clues in the p53 murder mystery.

p53 protein is a central player in the process that results in the repair or in the death by apoptosis of potentially cancerous cells. New work unveils several genes that are controlled by p53. It gives a tantalizing view of the way in which cell death may be mediated by p53-induced, death-specifying transcripts, which generate a burst of reactive oxygen species (ROS) on the mitochondrial membrane. In turn, ROS activate the final killing mechanism of apoptosis. Further research will show whether this seductive scheme is a true reflection of what happens in p53-determined cell death.

LOSS OF HETEROZYGOSITY AT 5q21 IN NON‐SMALL CELL LUNG CANCER: A FREQUENT EVENT BUT WITHOUT EVIDENCE OF APC MUTATION

Four genetic polymorphisms in the APC and MCC genes at chromosome 5q21 were analysed for loss of heterozygosity (LOH) in 97 primary squamous carcinomas and adenocarcinomas of the lung. LOH was identified in at least two polymorphic loci in 41 percent of informative cases. There was no significant difference in the frequency of LOH between squamous carcinomas and adenocarcinomas. Within the adenocarcinoma group, however, LOH appeared to be more common in tumours having a bronchial origin (5/9; 56 per cent) than in parenchymal adenocarcinoma (6/21; 29 per cent). All 32 tumours showing LOH at one or more polymorphic sites were examined for mutations in the mutation cluster region (MCR) of APC by single‐strand conformational polymorphism (SSCP) analysis. Mutations were not detected in any of these cases. We therefore propose that it is likely that a tumour suppressor gene on 5q other than APC is involved in the pathogenesis of lung cancer.

Ki-ras MUTATIONS IN ADENOMAS: A CHARACTERISTIC OF CANCER-BEARING COLORECTAL MUCOSA

Activating mutations in the Ki‐ras2 oncogene are frequently observed in sporadic colorectal adenomas and their incidence is reported to rise in large and tubulovillous adenomas to values close to those in carcinomas. This study shows that this property is a feature of adenomas growing in large bowel that has already demonstrated its propensity to engender malignant tumours: i.e., bowel in which there is a synchronous carcinoma. Adenomas from cancer‐free bowel do not share this high incidence of Ki‐ras mutations. This difference in mutation incidence between adenomas from cancer‐free and cancer‐bearing patients does not appear to derive from sampling bias relative to adenoma size, site, or patient age, nor is it found in another gene (APC) known to be of importance in adenoma formation. Large, dysplastic adenomas from cancer‐bearing bowel, however, are particularly liable to carry Ki‐ras mutations when they arise in patients over 70 years old. The observations suggest that the role of Ki‐ras mutations may be more subtle than merely enhancing adenoma growth. Adenoma cells of cancer‐prone individuals may suffer more mutational events than those in persons selected as cancer‐free.

The CAG repeat within the androgen receptor gene in male breast cancer patients

Editor—Mutations of the BRCA1 and BRCA2 tumour suppressor genes have been identified in some cases of familial and early onset breast cancer.1 2 Mutations of these genes, however, account for a relatively small proportion of the total cases of female breast cancer. Male breast cancer is a very rare disease, accounting for approximately 1% of all cases of breast cancer. Less is known about the genetic influences in its development. Male breast cancer has been linked to mutations of the BRCA2 gene in some cases, with the frequency of mutations varying widely (from 4-40%) in those series studied.3 4 nnIt has been suggested that there may be other genetic factors that confer a lower absolute risk to the person, but potentially could result in a substantial number of cases within a whole population.5 We have already shown that a polymorphism in the CYP17 gene is associated with an increased risk of male breast cancer.6 nnA region within exon 1 of the gene coding for the androgen receptor (located on chromosome Xq11-12) is highly polymorphic and contains a variable number of CAG repeats. The variability of the number of these repeats between different ethnic populations in the USA has been studied.7 In vitro studies have shown that a relatively short CAG repeat sequence increases the level of transactivation of the androgen receptor.8 The androgen receptor itself binds dihydrotestosterone and therefore is one factor in the regulation of the growth of prostate cells. This may account for the finding that short CAG repeat sequences have been associated with a higher risk of developing prostate cancer. …

Specific patterns of chromosomal abnormalities are associated with RER status in sporadic colorectal cancer.

Current opinion of the genetic events driving colorectal tumourigenesis focuses on genomic instability. At least two apparently independent mechanisms are recognized, microsatellite instability and chromosomal instability. The genetic defects underlying each type of instability are only partially understood and controversy remains as to the role of p53 in the generation of chromosomal defects in colorectal cancer. This study sought to clarify the relationships between chromosomal abnormalities and defects of both p53 and mismatch repair. Extensive chromosomal analysis was undertaken, using flow cytometry and comparative genomic hybridization, of a series of sporadic colorectal cancers which had been grown to early passage as subcutaneous xenografts in SCID mice. Overall levels of chromosomal defects were observed to be low in RER+ cancers compared with RER− and distinctive patterns of chromosomal anomalies were found to be associated with both the RER+ and RER− phenotype. No particular level or pattern of chromosomal anomalies appeared to be associated with p53 status, supporting recent observations that abnormal p53 function is not sufficient to cause chromosomal anomalies in colorectal tumours. Copyright

A polymorphic tetranucleotide repeat in the CYP19 gene and male breast cancer

The CYP19 gene codes for the aromatase enzyme that is involved in the synthesis of oestrogens. This case–control study examines the relationship between a tetranucleotide repeat sequence in the CYP19 gene and the development of male breast cancer. No significant differences were found between male breast cancer cases and controls.