Japanese Journal of Clinical Oncology Advance Access originally published online on February 14, 2006
Japanese Journal of Clinical Oncology 2006 36(3):166-171; doi:10.1093/jjco/hyi233
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© 2006 Foundation for Promotion of Cancer Research
Possible Involvement of Hyperlipidemia in Increasing Risk of Colorectal Tumor Development in Human Familial Adenomatous Polyposis
1 Cancer Prevention Basic Research Project, National Cancer Center Research Institute, Tokyo, 2 Department of Surgery, National Cancer Center Hospital, Tokyo and 3 Genetics Division, National Cancer Center Research Institute, Tokyo, Japan
For reprints and all correspondence: Michihiro Mutoh, Cancer Prevention Basic Research Project, National Cancer Center Research Institute, 1-1 Tsukiji 5-Chome, Chuo-ku, Tokyo 104-0045, Japan. E-mail: mimutoh{at}gan2.ncc.go.jp
Received September 7, 2005; accepted December 19, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: Familial adenomatous polyposis (FAP) results from germline adenomatous polyposis coli (APC) gene mutations and many affected patients die from colorectal cancers which arise from colorectal polyps. We previously reported that two strains of Apc gene-deficient mice developing multiple intestinal polyps exhibit a hyperlipidemic state. The triglyceride (TG) levels were
10-fold higher than the levels observed in wild-type mice. Methods: To examine whether a positive relationship might exist between hyperlipidemia and colorectal tumor development in FAP patients, as with Apc gene-deficient mice, a pilot experiment was performed using readily available clinical data such as ages, serum lipid levels, number of colorectal polyps and cancer development in 28 FAP patients from the National Cancer Center Hospital, Japan.
Results: The overall prevalence of hyperlipidemia in FAP cases was 58%. Average TG levels in the 40–60 year age groups of FAP patients were 
150 mg/dl (the defined threshold level of hyperlipidemia). Moreover, there was a tendency for higher serum TG levels in patients who developed colorectal cancer, as compared with those without colorectal cancer.
Conclusions: These results show that a hyperlipidemic state occurs in FAP patients. Although it is weaker than that in Apc gene-deficient mice, it may be linked to colon tumor development. These data warrant further studies for wider poplulations of FAP patients.
Key Words: APC gene • colorectal cancer • familial adenomatous polyposis • hyperlipidemia
Abbreviations: BMI, body mass index • ChE, cholinesterase • COX, cyclooxygenase • FAP, familial adenomatous polyposis • LPL, lipoprotein lipase • NSAIDs, non-steroidal anti-inflammatory drugs • PPAR, peroxisome proliferator-activated receptor • TC, total cholesterol • TG, triglyceride
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Familial adenomatous polyposis (FAP) is characterized by the appearance of hundreds or thousands of adenomatous polyps in the colon and rectum. The polyps are caused by germline mutations of the adenomatous polyposis coli (APC) gene located on chromosome 5q21. Patients face increased mortality due to inevitable colorectal cancer developing from intestinal polyps. Thus, prophylactic colectomy is performed usually before 25 years of age (1). In such individuals at extremely elevated risk of colorectal cancer, it is mandatory that any promoting factors be elucidated and appropriate preventive measures be devised.
There are several mouse models for FAP with different germline Apc mutation sites such as codons 716, 850, 1309 and 1638 (2–4). We previously reported that two strains of Apc gene-deficient mice, Min (Apc gene mutation at codon 850) and Apc1309 (mutated at codon 1309) mice, show particularly large numbers of intestinal polyps and a hyperlipidemic state (5,6). In these mice, serum triglyceride (TG) levels increase with age, to 500–800 mg/dl when 12–15 weeks old, associated with low mRNA expression levels of lipoprotein lipase (LPL) in the liver and small intestine. These TG levels are 10-fold higher than the 70 mg/dl typically observed in wild-type mice. Serum total cholesterol (TC) levels are slightly elevated. Moreover, we have reported that a peroxisome proliferator-activated receptor (PPAR) 
agonist, bezafibrate, and a PPAR
agonist, pioglitazone, concomitantly suppress hyperlipidemia and intestinal polyp formation in the mice, with induction of LPL mRNA. Indeed, an LPL inducer, NO-1886, also suppresses hyperlipidemia and intestinal polyp formation in the mice (7).
In the present study, we performed a pilot study to examine whether hyperlipidemia might also be a complication in FAP patients, similar to FAP model mice, and possible associations with colon tumor development are discussed.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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FAP PATIENTS
Twenty-eight Japanese FAP patients, presenting at the National Cancer Center Hospital from 1999 to 2004 for follow-up of their health conditions, were reviewed. FAP was diagnosed by observing >100 intestinal polyps and all 28 patients underwent prophylactic colectomy. In addition, pathological studies were performed on these polyps. Germline mutations of the APC gene were investigated in 24 of the 28 cases, but the other 4 patients did not give written informed consent. The following data were collected: age; sex; body mass index (BMI = kg/m2); history of previous surgery; serum levels of albumin, total protein, cholinesterase (ChE), TC and TG; and presence or absence of colon and gastric tumors. Patients who did not give written informed consent for collecting samples and clinical information were excluded. The use of each individual's material was approved by the ethics review committee of the National Cancer Center.
DETECTION OF HYPERLIPIDEMIA IN FAP PATIENTS
The criteria for hyperlipidemia (hypertriglyceridemia and/or hypercholesterolemia) were based on the Japan Atherosclerosis Society Guideline (8): a fasting serum TG level 150 mg/dl and a fasting serum TC level 220 mg/dl. Decisions were made using data from more than two blood samples collected independently, with at least a month's interval. Values obtained within a month of receiving abdominal surgery were disregarded. The data for TG levels at different ages were those from 2002.
DETECTION OF RECTAL POLYPS IN FAP PATIENTS
Rectal polyps were examined by front-viewing endoscopy and recorded as digital photographs. The numbers were counted and the rectal polyps were classified into two types as follows: confluent (jammed together) and scattered (isolated from each other). The extent of rectal polyp development was further classified into five groups: no polyps/field of view (–), 1–5 polyps/field of view (±), 6–10 polyps/field of view (+), 11–20 polyps/field of view (++) and >20 polyps/field of view (+++).
IDENTIFICATION OF GERMLINE MUTATIONS IN THE APC GENE
Germline APC gene mutations were analysed in colon cancer samples or genomic DNA and cDNA samples prepared from the peripheral lymphocytes. Mutations were first screened by a protein truncation test (9) followed by confirmation by direct sequencing of the PCR-amplified genomic sequences.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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THE OVERALL PREVALENCE OF HYPERLIPIDEMIA IN FAP PATIENTS
Data for history of colorectal cancer development and numbers of rectal polyps in the 28 FAP patients presenting at the National Cancer Center Hospital from 1999 to 2004 are summarized in Table 1. Serum lipid levels for the patients are given in Table 2. Twenty-seven FAP patients had undergone prophylactic colectomy and none received medical treatment and/or nutritional management for hyperlipidemia. Serum lipid data for Patients 7 and 8 were not informative enough and were excluded from the analysis.
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Table 1 provides general data for ages and genders, the positions of APC germline mutation, existing rectal polyps in 2004 and past history of colorectal cancer. In Table 2, the data for minimum, maximum and average TG levels, and also the maximum levels of TC are shown. Patients in a hyperlipidemic state with serum TG levels
150 mg/dl and/or TC levels 220 mg/dl, determined at least two times independently, are underlined. In addition, frequencies of blood examination and number of occasions on which TG was 150 mg/dl are shown. The overall prevalence of hyperlipidemia in the patients was 57.7% (15/26): the prevalence of hypertriglyceridemia (150–429 mg/dl) was 73.3% (11/15) and the prevalence of hypercholesterolemia (220–296 mg/dl) was 53.3% (8/15). Differences in other clinical data such as BMI, serum albumin levels, serum total protein levels and serum ChE levels were not observed between patients with and without hyperlipidemia (data not shown).
CHANGE OF SERUM TG AND TC LEVELS DURING AGING
Regarding the changes in average serum TG levels during aging, age-dependent increases of TG levels were observed in patients in their thirties and maximum levels were observed in those in their sixties (Fig. 1A). Reported average serum TG levels in each 10 year cohort of the Japanese are highest in those in their forties [129 mg/dl, total number = 12,839, ref. (10)]. Meanwhile, the average serum TC levels in FAP patients were <220 mg/dl except for two FAP patients in their seventies (253 mg/dl, Fig. 1B). Reported average serum TC levels in each 10 year cohort of the Japanese are highest in those in their sixties [211 mg/dl, ref. (10)]. Sex difference is apparent in the serum lipid levels: males tend to have high TG levels (150 mg/dl for men in their forties) and females to have TC levels (218 mg/dl for women in their fifties and sixties). In the present study, the number of male patients was twice the number of female patients, but the average TG levels exceeded 150 mg/dl between the ages of 40 and 60 years.
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OVERALL PREVALENCE OF COLORECTAL POLYPS AND CANCER IN FAP PATIENTS
Among FAP patients who had >20 polyps in an endoscopic field or had polyps of the confluent type, hyperlipidemia was observed in eight patients and normal serum lipid levels in five patients (Table 1). Fifteen patients had colorectal cancer, all diagnosed as adenocarcinomas, five had gastric cancers (Patients 8, 12, 13, 16 and 21) and two had both. The percentage of hyperlipidemic patients with colorectal cancer was 53.8% (7/13) and with hypertriglyceridemia was 46.2% (6/13). Interestingly, when counting levels of serum TG
150 mg/dl and/or serum TC 220 mg/dl occurring even once as hyperlipidemic, 93.3% of the patients who had colorectal cancer demonstrated hyperlipidemic states. There were four patients who had gastric cancer with hyperlipidemia. Statistically significant differences were not observed in serum lipid levels between the patients with colorectal cancer and those without colorectal cancer. However, the average maximum serum TG and TC values in FAP cases with colorectal cancer tended to be higher than in those without colorectal cancer, 222.7 versus 158.9 and 232.6 versus 192.5 mg/dl, respectively (Table 2 and Fig. 2).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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In the present pilot study, we found hyperlipidemia to be a relatively frequent complication in FAP patients, suggesting its possible link to colorectal cancer development. There is standard serum lipid level data for the Japanese (n = 12 839, aged 4 through 99 years) collected in 36 institutes from various districts around Japan in 2000 (10). The mean serum TG and TC levels in each 10 year group were <150 and <220 mg/dl, respectively (mean TG levels for Japanese in their thirties, forties, fifties and sixties were 118, 129, 129 and 123 mg/dl; TC levels for Japanese in their thirties, forties, fifties and sixties were 195, 201, 211 and 209 mg/dl, respectively). Although males tend to have higher TG levels than females, the population ratio of hyperlipidemia did not show any difference. Thus, our pilot study suggested the need for a larger number study to confirm high TG levels in female FAP patients. Extracolonic and serious complications in FAP include adenocarcinomas in the duodenum and pancreas, and desmoid tumors developing from operation scars. Reported benign lesions are osteomas, odontomas, epidermoid cysts, stomach and thyroid adenocarcinomas, congenital hypertrophy of the retinal pigment epithelium and fundic gland polyposis (11–14), but a hyperlipidemic state has hitherto not received attention as a potentially important aspect. Three points can be raised as explanations for the lack of any focus on blood lipids: (i) myocardial infarction and stroke are not major causes of death in FAP [1.9 and 1.5% in Japanese FAP patients, respectively, ref. (15)]; (ii) hyperlipidemia may not develop at an early age [the mean ages at death of FAP patients were 44.1 years for males and 40.5 years for females before 1990, ref. (15)]; and (iii) no correlation between the APC gene and hyperlipidemia has hiterto been reported. Since we found only a tendency for serum TG levels to be associated with colorectal tumor development, we are now planning to investigate a large number of FAP patients for confirmation.
Prophylactic colectomy may weaken gastrointestinal function with a disorder of liver bile circulation including the lipid absorbing function of the small intestine, and if hyperlipidemia is caused by APC germline mutations, it is assumed that much more severe hyperlipidemia may be observed in FAP patients before prophylactic colectomy. The position of the APC germline mutation may affect the severity of FAP (16). The weak dominant negative effects on the wild-type APC protein by formation of unstable heterodimers result in small numbers of polyps (17). Since codons 1014–1210 and 1263–2013 are suggested to be the binding sites of ß-catenin, their mutation could play an important role in formation of intestinal polyps and hyperlipidemic states (16). An FAP patient with mutations at codon 1309 (Patient 19) showed a similar hyperlipidemic state to Apc1309 mice. Clearly, serum lipid levels may be more readily affected by environmental factors or aging than the mutated position of the APC gene, and other genetic factors such as LPL and angiopoietin-like protein 3 may also influence the extent of hyperlipidemia (18). Therefore, our pilot study suggests the need for further studies comparing the patient before and after colectomy and also for studies to elucidate possible mechanisms linking functional genetic alteration, hyperlipidemia and colorectal cancer development.
It is of interest to point out that an agent reducing polyp formation without affecting serum lipid levels in Apc-deficient mice may clarify the relationship between polyps and hyperlipidemia. We are in favor of the hypothesis that hyperlipidemia is not causative at least for the onset of adenoma, but may promote intestinal polyp development. If so, an antihyperlipidemic agent is justified to be a candidate for chemoprevention. Early prophylactic colectomy is considered to be the most effective way to prevent colorectal cancer development in FAP patients, although chemopreventive agents such as selective cyclooxygenase-1 (COX-1) and -2 inhibitors, prostaglandin receptor EP1 and EP4 selective antagonists, PPAR agonist and PPAR agonist can reduce intestinal polyps in Apc-deficient mice (5,6,19–22). Several clinical studies have already been performed with non-steroidal anti-inflammatory drugs (NSAIDs) for prophylactic purposes in FAP patients (23,24). From our present results, not only NSAIDs and/or COX-2 inhibitors but also PPAR/ agonists might warrant further attention and clinical trials.
In conclusion, our data lead us to hypothesize that both hyperlipidemia and polyp formation may be caused by APC mutation, where a hyperlipidemic state may contribute to the development of polyps. This encourages us to investigate a large number of FAP patients with matched controls. Hyperlipidemia may be observed even after prophylactic colectomy, and improving a hyperlipidemic state might be of benefit for protection against neoplasia or other adverse outcomes.
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Acknowledgments |
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This work was supported by grants-in-aid for Cancer Research for the Third-Term Comprehensive 10-Year Strategy for Cancer Control and for Research on Advanced Medical Technology from the Ministry of Health, Labor and Welfare of Japan, as well as a grant from the Public Trust Nishi Cancer Research Fund. We also thank Ms Masami Komiya for her skillful assistance.
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References |
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