Non Avoidable Risk Factors

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Certain differences in sex incidence emerge when carcinomas are assessed separately for the large bewed. Right colon lesions have been observed to be more common in women while men seem to be at higher risk for rectal cancer. The prevalence of colon cancer has a ratio of females/males equal to 1.2:1, and rectal cancer a ratio of males/females equal to 1.4:1. Right colon cancers have been shown to account for a greater percentage of colorectal neoplasms in older patients while left colon and rectum neoplasms seem to appear in relatively younger patients [56].

CRC is slightly more common in females before the age of 60, but thereafter it predominates in males [57, 58].

The risk of CRC increases as people get older. Age is the most important risk factor for both colon and rectal cancer. There is a peak of incidence in subjects aged 60-69 years. Only 3% of all cancers develop in persons under 40 years [59]. There is a sharp rise in the incidence of CRC between 40 and 50 years, and the number of people affected is even higher over the age of 50 years. Everyone above 50 can be considered at medium risk for the disease.

Genetic factors appear to influence the age of onset of CRC. Early onset of cancer is seen in hereditary conditions like FAP and HNPCC. The mean age of diagnosis is in the early 30s for FAP [60] and in the 40s for HNPCC [61]. First degree relatives of patients are estimated to have an average onset of cancer 10 years earlier than people with sporadic cancer. Knowledge of age is important to address screening strategies for average- and high-risk groups.

The populations of Western nations tend to have a higher incidence of CRC than developing countries, or Asian and African populations. However, it appears that ethnic and racial discrepancies are not very relevant. Migrant studies suggest that when ethnic and racial discrepancies exist, environmental factors play a major role. In the United States, today, the risk seems to be stronger for African Americans [62]. African Americans have a higher rate of proximal cancer compared to Caucasians, who have higher rates of distal and rectal cancer [63].

Among other factors, tall adult height, which is partly determined by sufficient nutrition in childhood and adolescence, could be associated with increased risk [64].

The hypothesis that the development of CRC (both sporadic and familial inherited forms) is from premalignant lesions, and particularly large adeno-matous polyps, is widely accepted [65,66].

The development of CRC is a multistep process that involves some genetic changes [67]. About 85% of all CRCs are due to events resulting in chromosomal instability and the remaining 15% are due to microsatellite instability [68]. Specific genetic mutations, inherited as autosomal dominant, have been identified as the cause of inherited colon cancer risk in prone families.

The first group of heritable syndromes is represented by familial polyposis syndromes. The most important, and best known [69] is FAP, which involves the early onset of pancolon adenomatous polyps. A less severe form is known as attenuated familial adenomatous polyposis [70]. Polyps in FAP are not present at birth, but have developed by late adolescence. The condition is characterised by hundreds of polyps (500-2500). A minimum of 100 is needed for the diagnosis of FAP. This syndrome affects approximately 1 in every 8000 individuals. Without intervention, virtually all patients develop CRC. A variant of FAP is Gardner syndrome. It is inherited as an autosomal dominant trait, which occurs with half the frequency of FAP [67]. In affected individuals, the entire large and small bowel may present adenomas. This syndrome is accompanied by mesenchymal abnormalities, and tumours may coexist as: lipomas, fibromas, osteomas, sebaceous cysts and desmoid tumours. Other very rare syndromes, probably with the same genetic defect [68], are Oldfield's syndrome and Turcot's syndrome. In Oldfield's syndrome (multiple sebaceous cysts, poly-posis and adenocarcinomas) [71] and Turcot's syndrome (malignant central nervous system tumours and bowel polyposis) [72], polyps arise within 10-20 years and CRCs follow after 10-15 years.

The second group of heritable syndromes includes HNPCC syndromes. A strong family history of CRC is present at an early age for individuals classified as HNPCC [73]. HNPCC syndromes, inherited as an autosomal dominant trait, have been subdivided into the Lynch I and II syndromes [74]. In Lynch I syndrome, where the colon is more frequently involved than the rectum, the development of multiple colon cancers occurs at an earlier stage (and earlier age) than expected in sporadic CRC. A more generalised condition, Lynch II syndrome is always inherited as an autosomal dominant condition and has been described for families with multiple colon and extracolon adenocarcinomas (familial adenocarcinomato-sis). Colorectal malignant neoplasia is associated with cancers of the ovary, pancreas, breast, bile duct, urinary ways, stomach, and frequently, of the endometrium [75]. The diagnosis of HNPCC is based on the Amsterdam criteria: CRC present in three or more family members, two generations affected, a patient who is a first-degree relative of another affected person and a cancer diagnosis before the age of 50 [76].

Other hereditary syndromes like juvenile polyposis and Peutz-Jeghers syndrome have also been linked to an increased risk of CRC [77, 78].

A family history of colon carcinoma is another significant clinical risk factor [79-81]. In this case, it has been demonstrated that there is a threefold increased risk. The relative risk of developing this malignancy when one first-degree family member is affected is 2.3; while with two first-degree family members affected the relative risk increases to 4.3. If the first-degree family member is younger than 45 years at the time of diagnosis, the relative risk rises to 3.9 [82].

Patients with a personal history of colorectal carcinoma are at greater risk of developing a second colorectal malignant neoplasia. A history of colorec-tal polyps can determine a higher risk of cancer. It has been found that the cumulative risk of cancer developing in a 'not removed polyp' is 3% at 5 years, 8% at 10 years and 24% at 20 years after the diagnosis [83]. It should be noted that adenomas may be larger and more numerous in subjects without HNPCC or FAP but with a strong family history of CRC [84]. There are other individual clinical condi tions that can increase susceptibility to CRC. An increased risk for CRC has been confirmed in patients with inflammatory bowel disease of significant duration (8-10 years). Ulcerative colitis is more strongly associated with cancer than Crohn's disease. The incidence of malignancy seems to augment with the extent of bowel involvement and with the severity and duration of the disease [85, 86]. The risk of carcinoma is increased with the duration of colitis; it has been estimated to be more than 30% in the third decade of the disease [87]. Other clinical risk factors are a history of pelvic irradiation and non-cancer surgery. Pelvic radiotherapy, which involves mostly women treated for gynaecological neoplasms, can be relevant to the risk of rectal cancer [88]. Some evidence suggests that patients who have undergone cholecystectomy [89] and ureterosigmoidostomy [90] may have an increased chance of CRC too. A history of breast, endometrial or ovarian carcinoma [91] and no or low parity have been linked to higher risk of CRC among women [92].

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