A Registry Program for Familial Gastric Cancer Patients Referred to Cancer Institute of Iran

Gastric cancer is the second most common cause of cancer death in the world, after lung cancer (Caldas et al., 1999). Based on the data from Iran National Cancer Registry in 2005, gastric cancer is the second prevalent cancer in men and fourth cancer in women (The Ministry of Health Treatment and Edjucation, 2005). Family history of gastric cancer in first degree relatives, low socioeconomic status (because of more exposure to food contaminated with bacteria), infection with Helicobacter pylori, smoking, salt-rich food, decreased acidity of stomach, history of gastric surgery, pernicious anemia, atrophic gastritis and long-term use of H2 antagonists have been considered as the possible risk factors (The Ministry of Health Treatment and Edjucation, 2005). Gastric cancer has poor prognosis because of its nature of ambiguous symptoms and delay in diagnosis. The overall 5-year survival of gastric cancer from 18 SEER geographical areas during 2002-2008 was 26.9% (Howlader et al., 1975-2009 (Vintage 2009 Populations)). Many factors such as anatomic appearance of the cancer (lower stomach better cured compared to higher stomach


Introduction
Gastric cancer is the second most common cause of cancer death in the world, after lung cancer (Caldas et al., 1999). Based on the data from Iran National Cancer Registry in 2005, gastric cancer is the second prevalent cancer in men and fourth cancer in women (The Ministry of Health Treatment and Edjucation, 2005). Family history of gastric cancer in first degree relatives, low socioeconomic status (because of more exposure to food contaminated with bacteria), infection with Helicobacter pylori, smoking, salt-rich food, decreased acidity of stomach, history of gastric surgery, pernicious anemia, atrophic gastritis and long-term use of H2 antagonists have been considered as the possible risk factors (The Ministry of Health Treatment and Edjucation, 2005).
Gastric cancer has poor prognosis because of its nature of ambiguous symptoms and delay in diagnosis. The overall 5-year survival of gastric cancer from 18 SEER geographical areas during 2002-2008 was 26.9% (Howlader et al., 1975(Vintage 2009). Many factors such as anatomic appearance of the cancer (lower stomach better cured compared to higher stomach means gastric cardia), lymph node involvement and distant metastasis can affect the prognosis (Rustgi, 2012).
Seeking different methods, such as the finding risk factors or the susceptible person, is very critical for finding a way to prevent cancer incidence (Giordano and Cito, 2012;Kato and Asaka, 2012). Screening cases of hereditary cancers by interview and genetic consulting is one of such methods to discover the members of families at risk (Scheuner et al., 2010).
Familial cancer is defined as the presence of the same or related (such as breast and ovary) cancer in a family, sometimes with unusual presentations (such as younger age of incidence or uncommon types of cancer like breast cancer in males), pair organ primary cancer (bilateral breast cancer) or multiple primary cancers. It is usually inherited as an autosomal dominant pattern with different types of gene penetration (Brose et al., 2003;Petrucelli et al., 2011).
Familial cancer comprises of approximately 10% of all gastric cancers in the world (Richards et al., 1999). Mutations of somatic cells in CDH1 gene, which is encoding epithelial adherence junction molecule E-cadherin, have been involved in the carcinogenesis of a considerable quantity of diffused types of gastric and invasive lobular breast carcinomas (Keller et al., 1999;Jiang et al., 2004). It is well established that prophylactic procedures such as prophylactic gastrectomy in patients at risk who have somatic mutations especially in CDH1 gene will increase the risk of cancer among members of a family with a hereditary cancer syndrome.
In this study a cancer registry system was devised to find out the prevalence of familial gastric cancer (FGC) among patients referred to the Cancer Institute of Iran and also a practical method to find out the population at risk in order to prevent gastric cancer.

Materials and Methods
A criteria list was prepared according to standardized criteria of different countries. 30 patients who had referred to our cancer institute were interviewed as the pilot study. The aim of this pilot study was to evaluate the practical usage of the questionnaire and to estimate FGC prevalence.
After necessary modifications in the questionnaire, the final study was performed on 197 patients who had referred to our cancer institute from January 2010 to June 2012. All demographic information, clinical and pathology data, and family history were recorded. The patients were informed about the aim of the study prior to their enrollment and written consent was taken from them. Data elicitation was recorded in MS Excel 2010. After the primary analysis, the rest of the work was conducted with SPSS 16.0 (SPSS Inc).

Results
Data was collected from 197 patients with gastric cancer. 23 patients (11.8%) were younger than 45 years old and 172 (88.2%) older than 45 years old. In case of marital status, 187 cases (91.2 percent) were married. Number of 129 cases (65.5%) were male and 68 cases (34.5%) were female ( Table 1). Majority of the patients were living in Tehran province (48 cases, 24.4%), and the rest in the provinces of West Azarbayjan (25 cases, 12.7%) and Lorestan (18 cases, 9.1%). Concerning occupation, 77 cases (39.1%) had jobs with low income and high physical activity while 91 cases (46.2%) were working in jobs without physical activity. 10 cases (5.1%) were working with chemical agents (such as paint, petroleum).     DOI:http://dx.doi.org/10.7314/APJCP.2014.15.5.2141 Familial Cancer Registry Program cases with a history of alcohol consumption (17 cases, 85%) versus 3 cases (15%) in females. Also, the majority of smokers in any blood type (from heavy smokers to social smokers) were male. Consumption of unhealthy foods, i.e. smoked, salty, and nitrite added, also had a male predominance with 6 (85.7%), 19 (86.4%), and 5 cases (83.3%) respectively. Infection with Helicobacter Pylori (H Pylori) was another risk factor. In this sense, 35 cases had a previous history of H.pylori (20 cases in males, 57.1% and 15 cases, 42.9% in females) ( Table 2). Adenocarcinoma was the dominant pathologic feature (172 cases, 87.3%) ( Table 3). 33 cases (16.8%) had one first degree relative with a history of cancer and 14 cases (7.1%) had a history of two first degree relatives. Concerning second degree relatives with a history of cancer, 18 cases (9.1%) had one relative and 4 cases (2%) had two relatives. In addition, 7 cases had a third degree relatives (3.6%) and 2 cases (1 percent) had 2 third degree relatives (Table 4).

Discussion
Cancer is the third cause of death in Iran (Mousavi et al., 2009;Kolahdoozan et al., 2010). Among cancers, gastric cancer has a high mortality rate and is second in cancer death all over the world (Everatt et al., 2012). According to the national cancer report of Iran, gastric cancer prevalence was second in females and fourth in men in 2005 (The Ministry of Health Treatment and Edjucation, 2005). The highest incidence in females was in the provinces of Ardabil, Guilan, Mazandaran, Kordestan, and West Azarbaijan respectively, while in males, it was in Ardabil, Guilan, Mazandaran, West Azarbaijan and Kordestan. Although geographic distribution in patients of this center does not represent an exact disease prevalence of each area, it follows approximately the same dispersal pattern, as northern and west-northern provinces of Iran have the most number patients after Tehran province (The Ministry of Health Treatment and Edjucation, 2005).
Mean of age in comparison to other reports was lower. For example, in a study in china during 2004-2008, the mean age was around 65 years old (ranging from 47 to 90) (Zhang et al., 2012). In China, incidence of gastric cancer is between 50-70 years of age and with 2/1 male to female predominance (Goldman and Schafer, 2012). Still in our study, the age distribution was compatible with other studies.
Gastric cancer usually affects those older than 45 years old. In this study, the population of younger patients was higher than most other studies to our knowledge (11.8%). In this sense, in a study on 33,236 patients with gastric adenocarcinoma in the United States, 8.3% were younger than 45 years old (Al-Refaie et al., 2011).
Studies have shown that blood type A has a higher risk of association with gastric cancer (Edgren et al., 2010). However, in our study many of the cases had no information about their blood type, yet 'A' was the dominant blood type among them.
Modifications in high risk behavior is essential in primary prevention of gastric cancer (Kang et al., 2011 ). Many studies have demonstrated an association between unhealthy food (i.e. smoked, salty, and nitrite added) and incidence of gastric cancer (Brenner et al., 2009;Strnad, 2010;Wang et al., 2009). In this study, however, this was not a significant risk for gastric cancer incidence, although this kind of high risk behavior was more prominent among males (Jacobs et al., 2007).
About 90% of gastric cancers are adenocarcinoma which are categorized into two categories of intestinal and diffused types based on Lauren's classification (Kumar, 2010). Rest of the pathologies include: lymphoma, GIST, and liomyosarcoma (Kumar, 2010). In the diffused type of adenocarcinoma, the lesion does not make a glandular form to surround the gastric wall (leather wall) (Kumar, 2010). In our study, adenocarcinoma was the dominant feature of pathologic appearance.
About 43 cases of this study (21.8%) had the inclusion criteria (Table 5) for FGC which is a higher percentage compared to other reports. The usual population for FGC is 5-10% of the total gastric cancer population which in our study a higher incidence of familial type was seen (Barber et al., 2006). This could suggest a presumption of higher incidence of gastric cancer among Iranian population or just reveal the referral characteristics of our cancer institute which its younger patients have a family history of cancer referring to specialized centers. On the other hand, it might be a warning for increased number of familial cases in Iran which requires a national survey for approval. In many cases of FGC, E-cadherin (CDH1) gene mutation is responsible for hereditary enhancement of cancer susceptibility. Families with this mutation have 80% lifetime risk of developing gastric cancer (Kaurah & Huntsman, 2011).
Screening for FGC is a critical procedure and since it has a higher risk of incidence, prophylactic gastrectomy is recommended to the members who have inherited the mutant gene (Chen et al., 2011). The importance of screening for prevention is that it will decrease cancer incidence and mortality by lowering the annual burden of society for cancer treatment and control (Winawer, 2005). Finding the familial syndromes, susceptible members and genotypes requires precise interview with pedigree.
In conclusion, what we have shown in this study is a higher percentage of familial gastric cancer which may suggest a necessity to perform a national survey for incidence of FGC. Screening the families at risk is another ongoing program by our team to seek out members of such families.