Heterogeneity of colorectal cancer risk by tumour characteristics: Large prospective study of UK women

Methods

Results

Overall 1,310,390 women without prior cancer, with a mean age at recruitment of 56.1 (SD 4.6) years, were included in the analyses. Women were followed for incident colorectal cancer over 18.1 million person‐years, with a mean duration of follow‐up of 13.8 (SD 3.4) years per woman. During this period, 18,518 incident primary invasive colorectal cancers were registered, with a mean age at diagnosis of 66.9 years (SD 6.2). By site, 12,761 cancers were in the colon (6,278 specified in the right colon and 5,269 in the left colon), and 5,757 in the rectum. The remaining 1,214 tumours were of overlapping or unknown site. By morphology, 15,543 cancers (83.9%) were reported as adenocarcinoma, 1,270 (6.8%) as mucinous tumours, 107 (0.6%) as signet ring cell tumours, and 234 (1.3%) as neuroendocrine tumours (predominantly carcinoid); the remaining 1,364 cancers were of other or unspecified histological type.

Table 1 shows characteristics of women in the analysis. Women diagnosed with colorectal cancer were somewhat less likely to smoke, undertake strenuous physical activity, or ever to have taken HT, and more likely to drink 15 or more units of alcohol a week. Characteristics did not vary much by cancer site, but there were some differences between women by tumour type (Supporting Information Appendix Table 2). Those diagnosed with signet ring or neuroendocrine tumours were more likely to be current smokers than those diagnosed with other tumour types; they tended also to be younger at recruitment and at cancer diagnosis.

Table 2 shows the distribution of colorectal cancers cross‐classified by site and type. While adenocarcinomas are approximately evenly distributed between right colon, left colon and rectum, mucinous, signet ring and (in particular) neuroendocrine tumours are predominantly found in the right colon.

Table 3 shows adjusted relative risks for incident colorectal cancer for the 14 exposures examined. Taking multiple testing into account, cancer risk was significantly increased (p < 0.05) in relation to taller height, greater BMI, smoking, higher alcohol intake, and in parous versus nulliparous women; and risk was significantly decreased in relation to higher levels of physical activity, and to ever use of hormone replacement therapy. No significant associations were seen for socioeconomic status or for the remaining reproductive factors examined (including number of children in parous women).

Figures 1 and 2 show, respectively, results by site and by tumour morphology for six factors most strongly associated with risk of colorectal cancer. Details of the analyses for all exposures by site and by morphology are shown in the Supporting Information Appendix Tables 3 and 4. Results for parity versus nulliparity are not included in the figures (but are given in the Supporting Information Appendix) as the inconsistency with associations by number of births among parous women suggests that this finding may well be due to chance.

There was no significant heterogeneity by tumour location for any of the 14 factors examined (Fig. 1 and Supporting Information Appendix Table 3). Associations for smoking varied substantially, however, by tumour morphology (Fig. 2). For two rare subtypes of colorectal cancer, signet ring cell and neuroendocrine tumours, risks were doubled in current versus never smokers (RRs = 2.31, 95% CI 1.41–3.79 and 2.08, 1.49–2.91 respectively); but for the most common subtype, adenocarcinoma, any association with smoking was weak (1.11, 1.07–1.17). In the more detailed analyses, risks for both signet ring cell and neuroendocrine tumours were substantially higher for current smokers of 15+ cigarettes per day (RRs around 3) than for current smokers of <15 cigarettes per day (RRs around 1.6), with p < 0.001 for heterogeneity by tumour morphology (Supporting Information Appendix Table 4). Obesity (BMI 30+ vs. <25 kg/m²) was more strongly associated with signet ring cell (RR 2.06, 1.24–3.41), mucinous (1.32, 1.13–1.55) and neuroendocrine tumours (1.30, 0.89–1.89) than with adenocarcinoma (1.07, 1.02–1.12); these differences were of borderline statistical significance (corrected p = 0.055). There was no significant heterogeneity by tumour morphology for height, alcohol intake, use of HT, physical activity or parity (Fig. 2, Supporting Information Appendix Table 4); nor for the other seven risk factors examined (Supporting Information Appendix Table 4).

Results from the three sensitivity analyses (restricting to women with no missing information on covariates; censoring at first invitation to bowel cancer screening; with additional adjustment for dietary factors and for parental history of colorectal cancer) did not differ substantially from those reported above (Supporting Information Appendix Table 5).

Discussion

In this large cohort of UK women, overall risk of incident invasive colorectal cancer was positively associated with height, body mass index, both past and current smoking, and alcohol intake; and inversely associated with physical activity and with use of hormone therapy for the menopause. The relative risk estimates for colorectal cancer were small, generally in the range 0.9 to 1.2. Colorectal cancer risk was lower in parous than in nulliparous women, but there was no trend in risk by number of births among parous women, and no associations were found with other reproductive factors, or with socioeconomic status. For smoking there was substantial heterogeneity across tumour morphological types; strong associations, with relative risks around 2 or greater were seen in current smokers for both signet ring cell and neuroendocrine tumours. Obese women were at similarly increased relative risk for signet ring cell tumours. For adenocarcinoma, the large majority of colorectal cancers in the cohort, the associations with BMI and with smoking were weak, with relative risks around 1.1. No significant differences in risk by tumour location were seen for any of the 14 factors examined.

This large prospective study, with 18,600 incident colorectal cancers, provides an opportunity to study risk factor associations in detail, taking account of potential confounding factors. In particular we were able to compare directly associations both by tumour site and by morphological type. For colorectal cancer overall, our results are consistent with past findings of small increases in risk of incident cancer in relation to taller height, adiposity, both past and current smoking, and moderately high alcohol intake; and of small decreases in risk associated with physical exercise, and with use of hormone therapy for menopause. Reproductive factors were in general not associated with risk of colorectal cancer; the lower risk in parous women is not accompanied by evidence for a trend in risk by number of births, and may be due to chance.

Existing evidence on risk factor associations by site of colorectal cancer is inconsistent.15, 16, 17 It has been suggested that risks may differ between colon and rectal cancers, or between right‐sided and left‐sided colon (or colorectal) cancers,18, 19 but results have been varied and interpretation often hindered by lack of statistical power to test reliably for differences between sites. We found little to suggest differences by tumour site for the 14 risk factors examined.

All the associations between smoking and cancer risk by site were modest. By contrast, the associations we found between smoking and risk of signet ring cell and neuroendocrine tumours are stronger and the results suggest a trend in risk with amount smoked (Supporting Information Appendix Table 3). While there is limited understanding of the relationship between morphological and molecular subtypes of colorectal cancer,20 our results on smoking appear consistent with recent evidence from molecular epidemiological studies, which have suggested a stronger association between smoking and risk of colorectal tumours21, 22, 23, 24, 25 and polyps26, 27 thought to arise from non‐conventional pathways (such as the serrated neoplasia pathway)2 than with adenocarcinomas arising from the conventional pathway typified by chromosomal instability. Less is known of possible differential risks for colorectal cancer by molecular (or morphological) type for other exposures. Our findings suggest that obesity may also be a stronger risk factor for the less common tumour types, in particular signet ring cell tumours, than for adenocarcinoma.

Strengths of this large study include prospectively‐collected information on potential risk and confounding factors, and virtually complete follow‐up through linkage to routinely‐collected, reliable, cancer registration data, giving sufficient power to compare risk associations directly both by site and by morphological type. The majority of colorectal cancers in this study were diagnosed in women who had not had access to bowel cancer screening, and results remained similar when women invited for screening were excluded from the analyses; screening acceptance has been shown in this cohort to be related to individual characteristics, such as smoking and BMI,12 and differential access to diagnosis could potentially bias studies of risk factors in screened populations. A limitation is that there was no independent assessment of the morphological classification of tumours, but misclassification (assumed to be unrelated to exposure status) would be likely to attenuate, rather than create, differences in risk associations by type. Even in this large study, we had limited numbers of tumours of rarer subtypes. The extent to which our findings are generalisable to men, and to other populations is not known.

We have shown in this large prospective study in UK women that associations of colorectal cancer risk with major lifestyle risk factors do not vary greatly by tumour site. There are however some substantial differences by morphological type, smoking in particular being associated with two to threefold increased risk of signet ring call carcinoma and of neuroendocrine tumours, but only weakly associated with risk of adenocarcinoma.

Abbreviations

BMI

body mass index

CI

confidence interval

HT

hormone therapy for menopause

ICD‐10

Tenth revision of the International Classification of Diseases

ICD‐O

International Classification of Diseases for Oncology

NHS

National Health Service

OC

oral contraceptive

RR

relative risk

SD

standard deviation

Supporting information