There is a general expectation that polyps become more numerous with age, both in sporadic and FAP associated colons. The failure of this study to detect age related change deserves comment. Sporadic adenomas become more prevalent with age (Johannsen et al. 1989, Williams et al. 1982). On first principles, one expects the developing FAP colon to be polyp free early on in life and then to gradually develop a population of adenomas. There are no data available in the literature as to how this process occurs in humans. It is possible to envisage a number of models - linear, growth curve, exponential - that could generate a population of FAP adenomas. Practically, distinguishing between alternatives in human subjects is very difficult, not least because of the limitations of endoscopy to assess disease severity in a
quantifiable manner (Wallace et al. 1999).
Interpretation of these data was limited by a number of factors. The standard deviation of age at operation was 10.4 years. Given that the process of adenoma development is a slow one there may have been insufficient variation in age to detect minor age
related changes. Age was non-normal in its distribution and this can influence the strength and validity of regression analyses. 91% of the patients in this study had had their colectomy by the age of 41.4 and 75% by 30.5 years. In the non-MCR groups this
was important because few of these patients had cancer at operation. Inspection of Graph 4a shows that as the FAP population aged the population variance (as a whole) declines but that mean severity remains, roughly, in the middle of the range for the distribution. It suggests that older patients with milder disease (through delayed diagnosis) may influence the results. A patient cannot have severe polypsis at young age and expect to survive until old age.
To try and separate the various influences I segregated FAP patients into mutation groups (e.g. Pre-arm, etc.) and then reanalysed age effects by linear regression analysis. The problems of non-normality generating outlying data with influential residuals and/or leverage did not go away using such an approach. Furthermore, the problems were compounded by loss of statistical power. Subdivision can generate problems assigning appropriate statistical thresholds (hence requiring correction, e.g. Bonferoni). The main grouping I used {ARC domains) only demonstrated a statistically significant association with age (i.e. P < 0.05) in two groups Pre-arm and Pre-MCR (see Table 1). Neither of these reached statistical significance when Bonferoni correction was applied (i.e. P < 0.0071 i.e. 0.05/7: Ppre-Arm = 0.011, Ppre-MCR = 0.31). Detailed analysis of the Pre-Arm demonstrated a complex statistical picture. A few data points had undue influence on the derived correlations. These mostly came from
patients over the age of 40 years. I have therefore been cautious in my intrepretation of the data. Generally, there was no evidence for an age effect in colonic polyp number about the time of colectomy.
Even when I was able to identify an age-severity relationship the utility of the regression line was limited. This is because extrapolation to young ages produced biologically implausible results, e.g. for the Pre-arm group a baby would have about 500 polyps. The validity of the regression analysis is restricted to adults around the time of colectomy and is statistically small. For practical purposes the age-severity
relationship was, and can be, ignored. This was the main finding for the purpose of my further analyses
It is intriguing to speculate what the true nature of the age-severity relationship is. Animal models have indicated that the colon has differential susceptibility to
carcinogens and disease modifying drugs. The intestine is more vulnerable to polyp induction in the neonatal period (in mice) than at later points in life (Shoemaker et al. 1995, Reitmair et al. 1996, Sansom et al. 2001). This ‘window’ coincides with the time of crypt genesis when the crypt fission index is highest (Park et al. 1995, Brunsgaard 1997, Wasan et al. 1998). Therefore, perhaps in humans polyp number is specified early in life and is relatively fixed from then on. Whether, the neonatal mouse and neonatal human are directly comparable is a moot point. The role of developmental context has other implications for modifiers. For example, environmental modifiers are usually considered by dose-response relationships. Different vulnerabilities at specific time points may confound that relationship and its analysis. The genetic modifier scenarios are also made more complex. Neonatal mammals are usually breast-fed. Therefore, the mother’s genotype and environmental exposure could in theory influence the child’s later disease severity.
In contrast with this study, analysis of sporadic adenomas shows an age relationship. Prospective necroscopy series have demonstrated a relationship between age and frequency of adenomas (Williams et al. 1982, Johannsen et al. 1989). Adenomas become more prevalent with age. How the true incidence of sporadic adenomas varies with age and large bowel site is difficult to assess. Williams et al. (1982) found no overall relationship between colon site and adenoma frequency but did find a relationship between colon site and adenoma size. Adenomas in the proximal and distal large bowel were more likely to be greater than 1cm diameter than elsewhere. Endoscopic studies are often biased by their inclusion criteria, e.g. per anal bleeding may bias towards larger left sided adenomas. Endoscopic technology is also limited by
video image resolution constraints, colonie preparation and operator technique.
Therefore, small adenomas are more likely to be missed than other lesions (Wallace et al. 1999).
Not all FAP manifestations change with time. Polkinghorne et al. (1990) demonstrated that CHRPE does not progress with age. Neuroepithelial cells are terminally
differentiated. The retinal epithelial cell-fate-pattern abnormality that constitutes CHRPE is therefore determined very early in life, in utero. Could something similar be happening in the colon? Could polyp number determination represent deranged cell fate specification? This could explain the failure to observe a substantial rate of change in colonic severity in adult years. It would also have implications for drug strategies that seek to delay the development of polyposis.
4.2. Sex
A number of epidemiological studies have implicated gender as a risk factor for colonic neoplasia. Women have an excess incidence of right-sided colon cancer at young age (< 55 years). They also appear to have a higher cancer incidence than men under the age of 55, although the absolute risk in this cohort is small (< 7% of CRC occurs below age 55) and further decreases with younger age. The magnitude of the relative risk of gender (50% in most studies) needs to be evaluated in the context of other risks (e.g. family risk, migratory risk) that are much greater. In older population subgroups, men show a higher incidence of left-sided colon and rectal cancer (DeCosse et al. 1993, Alley and McNee 1986). The relationship between sex and colorectal cancer incidence has been reported as varying with year of birth and has been reported as falling (dos
Santos Silva and Swerdlow 1996). The relative excess of colorectal cancer in women at young ages appears to be falling. The decline could be due to change in population hormone exposure (i.e. the oral contraceptive pill, decreasing parity). However, I think the more likely explanation is the identification of hereditary colon cancer syndromes (FAP, HNPCC) and the better uptake of screening by women than men. Given the low
incidence of colorectal cancer under the age of 55 (5 per 100 000: DeCosse et al. 1993), even a few cases prevented by screening could have a dramatic impact on the statistics in the age group 50 years and below.
The above citations support the hypothesis that hormonal exposure influences colorectal cancer incidence. Oestrogen can interact with molecular pathways
implemented in colon cancer. For example, oestrogen can increase gene transcription via API enhancer elements, as well as its classical response element (Paech et al. 1997). Furthermore, the API interaction is interesting because neoplastic
transformation can be accompanied by increase in API activity (Vallone et al. 1997). The CyclinDI promoter also contains an API site (Tetsu and McCormick 1999). Together, these observations suggest a pathway where by oestrogens can directly interact with cell cycle machinery that is a component of the WNT signaling pathway.
My data did not identify any relationship between adenoma number and gender. I have examined adenoma number, whereas most epidemiological studies have evaluated colorectal cancer. Therefore, initiation may be less influenced than progression by hormones (gender as proxy).