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Indian Journal of Cancer, Vol. 47, No. 1, January-March, 2010, pp. 3-5 Guest Editorial Family history and colorectal cancer: Is it worth the risk? Lohar P Consultant Medical Oncologist and Hematologist, M.N. Budhrani Cancer Institute, Inlaks and Budhrani Hospital, Pune, India Code Number: cn10002 PMID: 20071781 DOI: 10.4103/0019-509X.58850 Colorectal cancer (CRC) remains an important cause of death from cancer in the Western countries, accounting for 9% of all cancer mortality in the United States. [1] Although no accurate estimates are available, this number is lower in most Asian countries. The burden of CRC is expected to increase four-fold by 2030 in a westernized Asian country like the Kingdom of Saudi Arabia, where CRC currently accounts for 9% of all newly diagnosed cases. [2] Colon cancer rates have, historically, been among the lowest in India and North Africa. [3] Survival rates in India have been dismal. In one study, the overall 5-year survival rate from all CRCs was only about 40% from a population in Mumbai, which might reflect a delay in diagnosis and treatment of such tumors as well as a lack of effective treatment options available at that time. [4] The etiology of CRC is complex and involves an interesting interaction between environmental and genetic factors. Family history confers an increased lifetime risk of CRC, but that elevated risk depends on the type of family history. Whereas genetic syndromes (FAP, HNPCC and Peutz-Jeghers syndrome/juvenile polyposis) are more "fascinating," they account for only up to 5% of all CRC incidences in the West. These syndromes do not appear to account for at least a two-fold increased risk in first-degree relatives (FDRs) of sporadic CRC patients. The increased susceptibility in those with a positive family history could be due to a combination of low penetrance, but high frequency variations in the same genes that are involved in the inherited syndromes, genes involved in methylation or metabolic pathways, oncogenes, tumor suppressor genes, those with an effect on colon microenvironment and those involved in immune response. [5] The current issue of The Indian Journal of Cancer includes an original report of a case-control study by Safaee et al. from Iran, in which an effort has been made to determine the risk of CRC in subjects with a family history of cancer. Case-control studies can be an effective means for gathering family history in index cancer patients. In one study of self-reported and database-linked family history of cancer data, there was no significant difference between cases and controls in the self-reported accuracy. [6] In another large case-control study, sensitivity of self-reported positive family history was around 87% among cases and 82% among controls, and specificity was around 97% in both groups. [7] However, one potential problem with self-reported data is the danger of underreporting. Glanz et al. demonstrated that more than a quarter of those known to have a sibling or a parent with CRC reported having no FDRs with CRC. [8] In India, this problem is further compounded by the potential stigma of the disease, hence avoiding reference to cancer in the family. [9] Although not performed in the reported study from Iran, it may also be helpful to verify positive and negative family history through review of medical records and linkage to cancer registries. The ideal primary objective of the study would have been to assess the risk of CRC in family members of a known case of CRC. Nevertheless, there has been adequate demonstration of familial clustering of CRC in this study, with chances of CRC being present increasing by 4.5-times in those with a family history of CRC. One has to be careful in interpreting the data because odds ratio is not the same as relative risk, although it points to the same outcome. One meta-analysis showed that those with one FDR had a two-fold higher risk of CRC while those with two FDRs had an almost four-fold increased risk, which was independent of age at diagnosis. [1],[10] Although difficult to prove, the effect of environmental factors on family history needs to be studied further. Family studies are informative, but unfortunately do not take into account shared lifestyle and genes. Hemminki et al. used the Swedish Family-Cancer database to show that a shared lifestyle explains only a small proportion of increased cancer susceptibility. [11] Their conclusion was that familial cancer risks between parents and their offspring are more likely to be due to inherited causes, than an environmental effect, because lifestyles are more likely to be different between parents and offspring than between spouses. Could dietary supplements influence the family history? In a large prospective study, Fuchs et al. showed that very high values of folate intake substantially decreased the excess risk of CRC among women with a positive family history. [12] An explanation forwarded for the above is - inherited polymorphisms of genes responsible for methyl group metabolism are associated with increased risk of CRC and the effect of these genes can be modified by the consumption of folate. There is no doubt that more epidemiological studies, such as the one reported by Safaee et al., will be required to identify the heightened risk of developing CRC in family members of those with the disease, especially in developing countries, if we are to achieve reasonable prevention of the disease and decrease mortality from the same. In that regard, a nationwide Cancer Registry and Family-Cancer database needs to be established. The Swedish Family-Cancer database has been quite a revelation in this regard. It includes more or less the entire population in families starting from the year 1932 and lists all cancers in the family members. The database has been updated several times and familial cancer risks have been published, including those for CRC. [13],[14],[15] Unfortunately, no population-based or case-control studies have been reported from India regarding family history and CRC. Neither have there been any Indian studies published on CRC prevention. One study, recently published online, is the first hospital-based case-control study on CRC from India, which has looked at diet and the risk of CRC. [16] In keeping with the diet and lifestyle, rural incidence rates in India for large bowel cancers are roughly half of that of the urban rates, but reliable trends for India are available mainly from the Bombay registry. [17] Although the National Cancer Registry Program of India (NCRP) has initiated the ICMR Cancer Atlas project ( http://www.canceratlasindia.org/ ), recognition of large bowel cancer as a disease is surprisingly lacking, despite the fact that almost 35,000 new cases of CRC will be diagnosed in India in 2009. One would pose the question, What is all the fuss about family history? In most families, no hereditary syndrome is identified. Hence, no genetic tests can be offered to relatives with an increased risk of colon cancer. FDRs (parent, sibling or child) of patients with CRC are advised to have screening colonoscopy. In one study, the percentage of siblings who underwent this procedure was significantly higher (27%) among the siblings whose index patients were aware of the increased risk for the FDRs as compared to the siblings of the patients who were not aware of this risk (20%). [18] This serves to highlight the fact that better awareness of the risk of CRC to family members among patients could result in an increase in screening colonoscopy, which, in turn, might lead to a reduction in CRC occurrence in such families. Obviously, one of the barriers to targeted colonoscopic screening of FDRs of CRC patients is the lack of information available to primary care physicians as well as the time and support staff needed to communicate this information to the FDRs and to inform and persuade index patients to transfer information about screening to their FDRs. There is a need for education of patients (and FDRs), as well as physicians, to increase participation in screening. It makes more sense to assess FDRs of CRC patients in the general population to identify more people who are at moderately increased CRC risk than to identify families with relatively rare, but high, CRC risk. This would be of particular importance in medium-resource countries like Iran and India. Finally, it will serve as a reminder that, despite all the information available to us regarding family history and CRC, the vast majority of patients who are diagnosed with CRC do not have any FDRs at all. The large international variation in the incidence of CRC as well as studies in migrant populations suggest that the causes of CRC are mainly environmental. References
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