ß-catenin mutations in hepatoblastoma: bad connections between bad cells

An increased risk of hepatoblastoma (HB), an embryonal liver tumor that occurs in the first few years of life, has been observed in familial adenomatous polyposis (FAP) patients who carry germline mutations in the adenomatous polyposis coli (APC) gene. However, HB cases with germline mutations in APC only account for a small percentage of cases. The gene product of APC is part of a multiprotein complex that regulates the cytoplasmic level of ß-catenin, a protein important for developmental signaling as well as cell-to-cell adhesion. Activating (i.e., mutations which increase activity) somatic mutations in ß-catenin as well as deactivating somatic mutations in APC have been observed in approximately 20% of colorectal cancers. Koch et al [Cancer Res 59: 269-73, 1999] investigated sporadic (i.e., non-FAP associated) HBs to determine the prevalence of somatic ß-catenin or APC mutations. A total of 52 HB biopsies and three HB cell lines were evaluated for mutations in either of these two genes. No mutations were observed in the mutation cluster region of APC; however, using single-stranded conformational polymorphism (SSCP) and direct sequencing analysis, nearly half (48%) of the sporadic HBs demonstrated mutations in the ß-catenin gene. The mutations specifically occurred in an area of the gene that normally targets the ß-catenin protein for degradation. Thus, mutations in this region resulted in an excess accumulation of the protein, as evidenced by Western blot analysis. The authors specula may be implicated in the development of c-ALL and HD, a definitive conclusion can only be reached when that agent is identified. Andrine R. Swensen

COMMENT: This is a interesting study given that nearly half of all sporadic HBs demonstrated ß-catenin mutations, which is clearly more than what has been observed in any solid tumor investigated thus far. Mutations in cell-cell signaling pathways have been extensively investigated in colon cancer. Given that HB occurs so early in life, it would be important to investigate mutations in specific developmental signaling pathways (including the wingless/WNT pathway) as they may provide further information regarding carcinogenesis at this site. Julie A. Ross

Blinded by the light? The relationship between sunlight and retinoblastoma

An ecological study examining the potential relationship between exposure to sunlight and incidence of retinoblastoma was recently conducted by Hooper[Br J Cancer 1999, 79:1273-6]. Retino-blastoma incidence rates were obtained from published sources. The annual ambient dose of ultraviolet B radiation was calculated for each location based on its average latitude and longitude. A statistically significant relationship was found between UVB dose and retinoblastoma incidence (slope=0.004,p<0.01). To further explore this relationship, analyses were stratified based on laterality of the tumor for the small number of registries that collected this information. A relationship was found between UVB dose and retinoblastoma for unilateral tumors (thought be sporadic), but not for bilateral tumors (thought to be familial in origin). These findings supported the investigatorís hypothesis if the two-hit theory of carcinogenesis is considered. Using data from Murphree and Munier [in Retina (ed. Ryan SJ, 2^nd ed, pp. 571-86, Mosby:St. Louis, 1994], the author argues that the first hit lesions involve specific mutations that include some C to T transitions (which are consistent with- but not the most typical of- the action of UV radiation), and the second hit lesions are usually uninformative and involve gross chromosomal changes. Thus, Hooper suggests that as the initial mutation for bilateral cases is often present in the germline, only the incidence of sporadic cases should be affected by increased exposure to UVB radiation. The author concluded that sunlight exposure might be related to retinoblastoma incidence, but that further research is needed.

COMMENT: Ecological studies are often an efficient way to explore and generate new hypotheses. However, one of the major limitations of these studies is that individual exposure data are not collected. Therefore, any conclusions regarding causality are tenuous at best. The findings from this study must be interpreted cautiously. While sunlight exposure may make a small contribution to the etiology of retinoblastoma, clearly other factors influencing risk are important. Retinoblastoma essentially does not occur after the age of 5 years, while sunlight exposure is cumulative over oneís lifetime. Andrine R. Swensen 

Neuroblastoma and viruses

A Scandinavian study [Flaegstad et al, Cancer Res 59:1160-3, 1999] has reported the identification of BK virus DNA in neuroblastoma, and suggests that this may play a role in etiology. The authors studied 18 human neuroblastoma samples and 5 normal human adrenal glands taken from children, including 2 with normal adrenal tissue from children with neuroblastoma. They detected BK virus DNA in all the neuroblastomas and in none of the 5 normal adrenal glands using PCR. Using in situ hybridization, they found polyoma viral DNA in the tumor cells of 17 of 18 of the neuroblastomas, but none of the 5 normal adrenals. Using immunochemistry they showed that the BK virus T antigen and P53 was co-localized in the cytoplasm of tumor cells.

COMMENT: BK virus is one of the polyoma viruses (also includes SV40 and JC virus). BK virus is ubiquitous within the population and most children have been infected by the age of 10 years. In animal models, all the polyoma viruses can be tumorigenic, focusing interest on these viruses and cancer in human population (see C3 vol. 8, No 3). A protein produced by the viruses, called large T antigen, complexes with P53 and interferes with its function, which is a possible mechanism of tumorigenesis. In this study the authors show the presence of BK virus within the tumor cells and the presence of T antigen in the cytoplasm of P53. It is important to appreciate the presence of the virus in the tumor cells clearly does not establish a cause and effect relationship. Frequent infection within the population may mean that this finding is coincidental, and a larger cohort of normal control material would strengthen the association. Previous studies implicating the polyoma virus SV40 in cancer have been greeted with great fanfare, particularly because of the use of polio virus contaminated with SV40 between 1955 and 1963. SV40-like sequences have been identified in pleural tumors and in ependymomas. However, epi-demiological data did not support any change in incidence of potentially SV40-related tumors during the period of exposure to contaminated virus [Strickler et al, JAMA 279:292-5, 1998], and clear evidence of causality is still lacking. Although these findings in neuroblastoma are of interest, much more data are required before they can be determined to be important in etiology. Stella M. Davies

Potential risks of parenthood later in life

There are inconsistencies regarding the relationship of advanced parental age and the risk of certain childhood malignancies including leukemia and brain tumors. Hemminki et al [Epidemiology, 10:271-75, 1999] analyzed the effect of parental age on the incidence of leukemia and brain tumors over time during the period 1960-1994 using the Swedish Family-Cancer Database. This database includes all persons born in Sweden after 1940 (with their biological parents) whose cancers were retrieved from the Swedish Cancer Registry from the years 1958-1994. Cancer registration in this database currently approaches 100%. For this analysis, children were included only if age data were available for both parents. Incidence rates of brain tumors and leukemia were calculated for 5-year age groups for the period 1960-1994. Comparisons were made between relative incidence rates for children diagnosed < 15 years of age by calculating rate ratios in parental age groups at birth using Poisson regression. Approximately 1500 cases of brain tumors and 1500 cases of leukemia were included in this analysis. During the period 1960-1994, brain tumor incidence increased primarily among the youngest children (ages 0-4), which was largely attributable to increases in astrocytoma. For leukemia, there was a modest increase for the younger age groups until about 1980, after which there was little change in rates. The effect of parental age on diagnosis was also evaluated for both sites. For brain tumors (adjusted for time trends and birth order), there was little effect of maternal age at diagnosis for brain cancer, irrespective of paternal age. However, paternal age was associated with an increased incidence of brain tumors in offspring, independent of maternal age. There was an approximate 25% increase in the risk of brain tumors in offspring for fathers over 40. For leukemia, maternal age at birth increased the risk by about 50% between the ages of 35 and 39, independent of paternal age. Interestingly, there was relatively little effect on leukemia incidence for motherhood after 40. No independent effect of paternal age was observed for childhood leukemia. The authors suggest that an accumulation of chromosomal mutations in aging germ cells may help explain these findings.

COMMENT: This is the largest study to date that has explored the effects of maternal and paternal age on the occurrence of brain tumors and leukemia in offspring. One of the attractive aspects of this study is the ability to adjust for one parent's age independent of the other, which is difficult to do with smaller numbers associated with case-control studies. It is possible that there are other explanations for these findings. For example, for leukemia, the authors were unable to adjust for potential confounding variables (including Cesarean section and high birth weight), which have been associated with increased maternal age. However, given our increased knowledge concerning the effects of aging on biological indices of cancer risk (such as higher mutation frequencies, decreasing DNA repair, etc), it seems plausible that these age-associated effects could also affect germ cells in both the mother and the father. It will be interesting to see if these age-related associations are found in other population-based cancer registries. Julie A. Ross
 

C3 Quarterly Newsletter
Children's Cancer Research Fund
Epidemiology Research Unit
Division of Pediatric Epidemiology
Clinical Research
University of Minnesota
420 Delaware St. SE, Box 422
Minneapolis, MN 55455
pedsepi@umn.edu

Editors: 
Stella M. Davies, MD, PhD, and Julie A. Ross, PhD