This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lagergren, J. Articles by Nyrén, O. Search for Related Content PubMed PubMed Citation Articles by Lagergren, J. Articles by Nyrén, O.

Heredity and Risk of Cancer of the Esophagus and Gastric Cardia¹

Division of Surgery, Karolinska Institutet, Danderyd Hospital, SE-182 88 Danderyd, Sweden [J. L.]; Department of Epidemiology, Karolinska Institutet, SE-171 77 Stockholm, Sweden [J. L., W. Y., O. N.]; and Department of Pathology, Falu Hospital, SE-791 82 Falun, Sweden [A. L.]

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
The importance of genetic factors in the etiology of esophageal cancer is uncertain. We addressed the question of heredity in a population-based, nationwide case-control study conducted in Sweden during 1995 through 1997. The study involved 189 patients with esophageal adenocarcinoma, 262 with cardia adenocarcinoma, 167 with esophageal squamous cell carcinoma, and, for comparison, 820 control subjects. Familial occurrence of cancer was explored at face-to-face interviews. Logistic regression, with multivariate adjustment for potential confounders, was used to calculate odds ratios (ORs), which estimated relative risk. Occurrence of esophageal cancer among first-degree relatives did not increase the risk of adenocarcinoma or squamous cell carcinoma of the esophagus. Neither were there any significant associations with familial occurrence of gastric cancer or other gastrointestinal tumors. The risk of cardia adenocarcinoma was moderately increased among persons with first-degree relatives with gastric cancer (OR, 1.6; 95% confidence interval, 1.0–2.6). Familial occurrence of any cancer was not associated with increased risks of any of the three studied tumors. In conclusion, heredity does not seem to contribute importantly to the occurrence of esophageal cancer of any histological type. A weak association between familial gastric cancer and the risk of cardia cancer may represent a genetic link.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
The incidence of esophageal adenocarcinoma is rising dramatically in Western countries (1) . Although genetic factors cannot conceivably explain this increase, such factors may still be of importance, for instance by determining individuals’ susceptibility to environmental risk factors. There is a remarkable paucity of data about heredity in cancers of the esophagus and gastroesophageal junction. Published studies are generally small and often lump esophageal squamous cell carcinoma, esophageal adenocarcinoma, and cardia adenocarcinoma together, and most investigations have been conducted in Asian high-incidence areas, where esophageal cancer may be a disease entity that is different from that in Western populations (2) .

Our aim was to gather evidence for or against genetic factors in each of the three main types of cancer of the esophagus and gastroesophageal junction: esophageal squamous cell carcinoma, esophageal adenocarcinoma, and cardia adenocarcinoma. We studied familial aggregation by the family history method (3) in a large, population-based case-control study in Sweden.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
Design.
A detailed description of the study has been published elsewhere (4) . In brief, during 1995 through 1997, all patients with newly diagnosed adenocarcinoma of the esophagus or gastric cardia and half of the patients with esophageal squamous cell carcinoma (born on even dates) in the entire Swedish population <80 years of age were eligible as cases. A comprehensive organization with collaboration with all relevant hospital departments and all regional tumor registries in Sweden ensured that every case throughout the country was identified shortly after diagnosis. Cases were uniformly classified histologically and anatomically, and the histological slides were reviewed by the study pathologist. At endoscopy, serial biopsies were obtained to identify the tumor site and the occurrence of intestinal metaplasia of the stomach or the esophagus (Barrett’s esophagus). Surgeons and pathologists gave standardized, detailed descriptions of the location of resected tumors. Adenocarcinomas were classified as cardia cancers if the tumor center was within 2 cm proximal or 3 cm distal to the gastroesophageal junction. Control subjects were randomly selected from the Swedish population register and frequency-matched to resemble the age and sex distribution among the cases.

Data Collection.
All subjects underwent computer-aided face-to-face interviews by professional interviewers from Statistics Sweden. Questions were asked about the occurrence and type of cancer among biological parents, siblings, and children. We did not ask for the relatives National Registration Numbers, a 10-digit unique personal identifier assigned to all Swedish residents, because it was unlikely for subjects to recall this number. Information was collected about potential confounders. In multivariate analyses, we adjusted for age (in 5-year classes), sex, number of biological siblings (continuous), reflux symptoms (occurring at least once per week), body mass index (in quartiles), tobacco smoking (assessed 2 years before the interview and classified into never smoker, previous smoker, and current smoker of any tobacco), alcohol use (total amount of alcohol consumed categorized in four classes), socioeconomic status (years of formal education categorized in three classes), energy intake (categorized in three classes), intake of fruits and vegetables (categorized in three classes), and physical activity (categorized in four classes).

Statistical Analyses.
Logistic regression was used in univariate and multivariate modeling. Model parameters were estimated by the maximum likelihood method. From these estimates, ORs³ with 95% CIs were calculated. In multivariate modeling, adjustments were made for the 11 potential confounding variables mentioned above. The possibility of interaction between a family history of cancer and all of the variables listed above was tested in a multiplicative model with cross-product terms representing the interaction. Among 33 tests of interactions between heredity and the variables listed, the only significant effect was found between cancer heredity and reflux symptoms among esophageal squamous cell carcinoma cases. Because reflux symptoms are not associated with squamous cell carcinoma and our multiple testing increases the likelihood of chance findings, this effect was deemed to be an effect of chance. From here on in the text, we do not take interaction into further consideration.

Ethics.
The study was approved by all regional ethics committees in Sweden. Individual informed consent to participate was obtained.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Subjects.
We interviewed 189 cases with esophageal adenocarcinoma, 262 with cardia adenocarcinoma, and 167 with esophageal squamous cell carcinoma. These constituted 87, 83, and 73%, respectively, of all eligible cases in the study base. Physical or mental disorders or early death prevented participation in 12–22% of the case groups and unwillingness in 1–5%. The 820 population-based control subjects constituted 73% of all who had been selected; 19% declined to participate, 6% had physical or mental disorders, and 2% could not be traced. The proportions of men among the cases of esophageal adenocarcinoma, cardia adenocarcinoma, and esophageal squamous cell carcinoma were 87, 85, and 72%, respectively, and among the control subjects, 83%. The median ages in these groups were 69, 66, 67, and 68 years, respectively.

Adenocarcinoma of the Esophagus.
There was no statistically significant association between a positive history of esophageal cancer among first-degree relatives and the risk of esophageal adenocarcinoma among our study subjects. Neither did we identify any association between familial occurrence of cancer of the gastrointestinal tract at any site or at all sites combined (Table 1) . No individual tumor site among relatives was significantly associated with the risk of esophageal adenocarcinoma. There was no association found among subjects who reported more than one first-degree relative with cancer (data not shown). No cases and only one control subject reported more than one first-degree with esophageal cancer. The age- and sex-adjusted estimates (data not shown) remained virtually unchanged after adjustment for all 11 covariates presented in "Materials and Methods," indicating absence of substantial confounding by these factors.

Squamous Cell Carcinoma of the Esophagus.
There was no increased risk of esophageal squamous cell carcinoma among persons with relatives with esophageal cancer or other cancers of the gastrointestinal tract (Table 1) . The only statistically significant association was found among persons who reported a first-degree relative with a history of lung cancer (OR, 2.3; 95% CI, 1.1–4.7). About 2% (4 of 167) of the cases with squamous cell carcinoma reported more than one first-degree relative with gastric cancer. None had multiple occurrences of esophageal cancer in their families. We did not identify any increased risk when all types of cancer among relatives were combined. Multivariate adjustment did not substantially change the age- and sex-adjusted risk estimates (data not shown).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
We found no important association between a family history of esophageal cancer and risk of this cancer, regardless of histological type. In contrast, patients with gastric cardia cancer reported a family history of gastric cancer more often than controls.

In contrast to our findings, several epidemiological studies in endemic areas in China have demonstrated excess risk of esophageal cancer (mainly squamous cell carcinoma) among members of families with a history of such cancers (5, 6, 7, 8, 9) . Case-control studies have yielded ORs of 1.6–6.0 among persons with esophageal cancer in the family (5 , 6 , 8) . Confounding by family-specific environmental or lifestyle factors may, however, explain these associations. A case-control study of unspecified esophageal cancer from a Western high-incidence population (North Carolina) did not identify any familial link (10) , and in a study conducted in a low-incidence population (New York; Ref. 11 ), none of 139 male patients with esophageal squamous cell carcinoma had a family history. It is possible that many esophageal cancers in Asian high-risk populations represent an etiologically distinct disease entity, an assumption supported by the absence of associations with Western risk factors such as male sex, smoking, and alcohol use (2) . At least for the "Western type" of esophageal squamous cell carcinoma, it appears that genetic factors play a minor role.

A small American case-control study found no association between a history of any cancer in first-degree relatives and risk of esophageal and gastric cardia adenocarcinoma combined (12) , which is in agreement with our results. An Italian case-control study with 68 cases of cardia cancer found essentially no increase in risk among cases with one first-degree relative with gastric cancer (OR, 1.2), but two or more such relatives introduced an 8-fold increased risk (13) . This observation, like our findings, indicate that a genetic link with gastric cancer may exist.

Strengths of our study include the almost complete, nationwide inclusion of patients during a 3-year period and strict random sampling of control subjects from our well-defined study base, making this a truly population-based investigation. The thorough tumor classification allowed us to isolate histological type-specific associations. All subjects were interviewed personally, and the interviews provided information of potential confounding.

Weaknesses include possible misclassification of cancers in relatives and a limited statistical precision because of the rarity of the studied cancers, weaknesses that our study shares with all previous studies. We could not objectively confirm the reported cancer among relatives because the National Registration Numbers were not available for matching with the Swedish Cancer Register. The accuracy of laymen’s reports of cancer occurrence in first-degree relatives has been shown to be acceptable for some cancers (14, 15, 16) but more questionable for others, including abdominal cancers (15 , 17 , 18) . Because the Swedish word "mage" means both stomach and abdomen, gastric cancer may be confused with other intra-abdominal malignancies. Esophageal cancers are probably less likely to be confused with other cancers, but there are no data to substantiate this assumption. Nondifferential misclassification, i.e., errors that occur independently of case/control status, generally biases the ORs toward the null (19) . Because the error rate varies by the closeness of the relationship (14 , 17 , 18) , we restricted our inquiries to first-degree relatives, and it is unlikely that strong associations were canceled by nondifferential misclassification.

Data about cardia cancer, an entity that is unknown to most people, must be interpreted with skepticism. Among our subjects, the only ones aware of the existence of the specific cardia cancer disease were case patients with a cardia cancer diagnosis, thus producing a possibly spurious association. In the analysis of cardia cancer patients, we therefore combined cardia cancer with all gastric cancer among relatives.

Different recollections among cases and controls would probably inflate the estimates, because patients with cancer are likely to tax their memories for previous occurrences of cancers in the family more than healthy control subjects. Although such recall bias is generally of minor importance in first-degree relatives (15 , 17) , the excess risk of cardia cancer among subjects with a family history of gastric cancer may partly be explained by such bias.

Because the subjects were generally unaware of the distinction between adenocarcinomas and squamous cell carcinomas, it was impossible for us to evaluate histological type-specific heredity for these tumors. If such heredity would exist, for instance if patients with esophageal adenocarcinoma would have an excess of family histories of adenocarcinomas, these patients would also have some excess of family histories of all esophageal cancer, however.

We found no substantial confounding by any of the studied covariates. Residual confounding by smoking could, however, explain the association found between familial lung cancer and esophageal squamous cell carcinoma. Tobacco smoking is strongly associated with both these tumors, and smoking is more common among persons with first-degree relatives who smoke (20) .

There is no obvious biological mechanism that could explain the unexpected finding of an association between familial breast cancer and the risk of cardia cancer. Chance may explain this finding. A similar tendency toward association was, however, observed by Zhang et al. (12) .

Familial clustering of Barrett’s esophagus and gastroesophageal reflux disease, with or without esophageal adenocarcinoma, has been described (21, 22, 23) , and there are indications of a genetic predisposition as a component in the etiology of reflux disease and its complications (21 , 24) . Because reflux and Barrett’s esophagus are strongly linked with esophageal adenocarcinoma (4) , any hereditary components in reflux disease and Barrett’s esophagus would probably shine through in the pattern of occurrence of esophageal adenocarcinoma. Our null findings with regard to heredity in this cancer type provides indirect evidence that putative hereditary forms of reflux and Barrett’s esophagus do not have substantial impact on the occurrence of esophageal adenocarcinoma in Sweden.

In conclusion, important genetic components are unlikely in the etiologies of esophageal adenocarcinoma or squamous cell carcinoma in Sweden. Nondifferential misclassification may, however, have canceled weak associations between a positive family history and risk in our study. Although recall bias cannot be ruled out as the explanation for the association between a family history of gastric cancer and risk of cardia cancer, this association also has been reported previously and may therefore be real.

	Acknowledgments

 
We express our gratitude to Leila Nyrén for invaluable coordination of the field work and to the 225 doctors for acting as contact persons at the participating departments and/or providing invaluable input during the planning of this study. We apologize for not providing individual names.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Funding provided by National Cancer Institute Grant R01 CA57947-03 and the Swedish Cancer Society (to J. L. and O. N.).

² To whom requests for reprints should be addressed, at Division of Surgery, Danderyd Hospital, S-182 88 Danderyd, Sweden. Fax: 46-8-31-49-75; E-mail: Jesper.Lagergren{at}mep.ki.se

³ The abbreviations used are: OR, odds ratio; CI, confidence interval.

Received 11/11/99; revised 3/ 8/00; accepted 4/24/00.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Blot W. J., Devesa S. S., Kneller R. W., Fraumeni J. F. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. J. Am. Med. Assoc., 265: 1287-1289, 1991.[Abstract/Free Full Text]
2. Munoz N., Day N. E. Esophagus Schottenfield D. Fraumeni J. F. eds. . Cancer Epidemiology and Prevention, 681-706, Oxford University Press New York 1996.
3. Khoury M. J., Beaty T. H., Cohen B. H. . Fundamentals of Genetic Epidemiology, Oxford University Press New York-Oxford 1993.
4. Lagergren J., Bergström R., Lindgren A., Nyrén O. Symptomatic gastroesophageal reflux is a strong risk factor for esophageal adenocarcinoma. N. Engl. J. Med., 340: 825-831, 1999.[Abstract/Free Full Text]
5. Li J. Y., Ershow A. G., Chen Z. J., Wacholder S., Li G. Y., Guo W., Li B., Blot W. J. A case-control study of cancer of the esophagus and gastric cardia in Linxian. Int. J. Cancer, 43: 755-761, 1989.[Medline]
6. Chang-Claude J. C., Wahrendorf J., Liang Q. S., Rei Y. G., Munoz N., Crespi M., Raedsch R., Thurnham D. I., Correa P. An epidemiological study of precursor lesions of esophageal cancer among young persons in a high-risk population in Huixian, China. Cancer Res., 50: 2268-2274, 1990.[Abstract/Free Full Text]
7. Hu N., Dawsey S. M., Wu M., Bonney G. E., He L. J., Han X. Y., Fu M., Taylor P. R. Familial aggregation of oesophageal cancer in Yangcheng County, Shanxi Province, China. Int. J. Epidemiol., 21: 877-882, 1992.[Abstract/Free Full Text]
8. Wang Y. P., Han X. Y., Su W., Wang Y. L., Zhu Y. W., Sasaba T., Nakachi K., Hoshiyama Y., Tagashira Y. Esophageal cancer in Shanxi Province, People’s Republic of China: a case-control study in high and moderate risk areas. Cancer Causes Control, 3: 107-113, 1992.[Medline]
9. Chang-Claude J., Becher H., Blettner M., Songliang Q., Guanrei Y., Wahrendorf J. Familial aggregation of oesophageal cancer in a high incidence area in China. Int. J. Epidemiol., 26: 1159-1165, 1997.[Abstract/Free Full Text]
10. Morris Brown L., Blot W. J., Schuman S. H., Smith V. M., Ershow A. G., Marks R. D., Fraumeni J. F., Jr. Environmental factors and high risk of esophageal cancer among men in coastal South Carolina. J. Natl. Cancer Inst., 80: 1620-1625, 1988.[Abstract/Free Full Text]
11. Wynder E. L., Bross I. J. A study of etiological factors in cancer of the esophagus. Cancer (Phila.), 14: 389-413, 1961.
12. Zhang Z. F., Kurtz R. C., Sun M., Karpeh M., Jr., Yu G. P., Gargon N., Fein J. S., Georgopoulos S. K., Harlap S. Adenocarcinomas of the esophagus and gastric cardia: medical conditions, tobacco, alcohol, and socioeconomic factors.. Cancer Epidemiol. Biomark. Prev., 5: 761-768, 1996.[Abstract]
13. Palli D., Bianchi S., Decarli A., Cipriani F., Avellini C., Cocco P., Falcini F., Puntoni R., Russo A., Vindigni C., Fraumeni J. F., Blot W. J., Buiatti E. A case-control study of cancers of the gastric cardia in Italy. Br. J. Cancer, 65: 263-266, 1992.[Medline]
14. Theis B., Boyd N., Lockwood G., Tritchler D. Accuracy of family cancer history in breast cancer patients. Eur. J. Cancer Prev., 3: 321-327, 1994.[Medline]
15. Kerber R. A., Slattery M. L. Comparison of self-reported and database-linked family history of cancer data in a case-control study. Am. J. Epidemiol., 146: 244-248, 1997.[Abstract/Free Full Text]
16. Mussio P., Weber W., Brunetti D., Stemmermann G. N., Torhorst J. Taking a family history in cancer patients with a simple questionnaire. Anticancer Res., 18: 2811-2814, 1998.[Medline]
17. Koch M., Hill G. B. Problems in establishing accurate family history in patients with ovarian cancer of epithelial origin. Cancer Detect. Prev., 10: 279-283, 1987.[Medline]
18. Douglas F. S., O’Dair L. C., Robinson M., Evans D. G., Lynch S. A. The accuracy of diagnoses as reported in families with cancer: a retrospective study. J. Med. Genet., 36: 309-312, 1999.[Abstract/Free Full Text]
19. Rothman K. J., Greenland S. Precision and validity in epidemiologic studies. Modern Epidemiology, Ed. 2 127-132, Lippincott Philadelphia 1998.
20. Bierut L. J., Dinwiddie S. H., Begleiter H., Crowe R. R., Hesselbrock V., Nurnberger J. I.,, Jr., Porjesz B., Schuckit M. A., Reich T. Familial transmission of substance dependence: alcohol, marijuana, cocaine, and habitual smoking: a report from the Collaborative Study on the Genetics of Alcoholism. Arch. Gen. Psychiatry, 55: 982-988, 1998.[Abstract/Free Full Text]
21. Crabb D. W., Berk M. A., Hall T. R., Conneally P. M., Biegel A. A., Lehman G. A. Familial gastroesophageal reflux and development of Barrett’s esophagus. Ann. Intern. Med., 103: 52-54, 1985.
22. Jochem V. J., Fuerst P. A., Fromkes J. J. Familial Barrett’s esophagus associated with adenocarcinoma. Gastroenterology, 102: 1400-1402, 1992.[Medline]
23. Eng C., Spechler S. J., Ruben R., Li F. P. Familial Barrett’s esophagus and adenocarcinoma of the gastroesophageal junction. Cancer Epidemiol. Biomark. Prev., 2: 397-399, 1993.[Abstract]
24. Romero Y., Cameron A. J., Locke G. R., III, Schaid D. J., Slezak J. M., Branch C. D., Melton L. J., III Familial aggregation of gastroesophageal reflux in patients with Barrett’s esophagus and esophageal adenocarcinoma. Gastroenterology, 113: 1449-1456, 1997.[Medline]

This article has been cited by other articles:

				S. R. DeMeester Adenocarcinoma of the Esophagus and Cardia: A Review of the Disease and Its Treatment Ann. Surg. Oncol., January 1, 2006; 13(1): 12 - 30. [Abstract] [Full Text] [PDF]

				W. Garavello, E. Negri, R. Talamini, F. Levi, P. Zambon, L. Dal Maso, C. Bosetti, S. Franceschi, and C. La Vecchia Family History of Cancer, Its Combination with Smoking and Drinking, and Risk of Squamous Cell Carcinoma of the Esophagus Cancer Epidemiol. Biomarkers Prev., June 1, 2005; 14(6): 1390 - 1393. [Abstract] [Full Text] [PDF]

				J Lagergren Adenocarcinoma of oesophagus: what exactly is the size of the problem and who is at risk? Gut, March 1, 2005; 54(suppl_1): i1 - i5. [Abstract] [Full Text] [PDF]

				M Aoki, K Yamamoto, H Noshiro, K Sakai, J Yokota, T Kohno, T Tokino, S Ishida, S Ohyama, I Ninomiya, et al. A full genome scan for gastric cancer J. Med. Genet., January 1, 2005; 42(1): 83 - 87. [Full Text] [PDF]

				P. C. Enzinger and R. J. Mayer Esophageal Cancer N. Engl. J. Med., December 4, 2003; 349(23): 2241 - 2252. [Full Text] [PDF]

				A Chak, T Lee, M F Kinnard, W Brock, A Faulx, J Willis, G S Cooper, M V Sivak Jr, and K A B Goddard Familial aggregation of Barrett's oesophagus, oesophageal adenocarcinoma, and oesophagogastric junctional adenocarcinoma in Caucasian adults Gut, September 1, 2002; 51(3): 323 - 328. [Abstract] [Full Text]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lagergren, J. Articles by Nyrén, O. Search for Related Content PubMed PubMed Citation Articles by Lagergren, J. Articles by Nyrén, O.