International Journal ofPancreatology, 6 (1990) 081-088 $02.00 Copyright 9 1990 by The Humana Press Inc. All rights of any nature whatsoever reserved.
ABO Blood Groups and Cancer of the Pancreas V. Annese, ,,1 M. Minervini, 2 A . Gabbrielli, 3 G. Gambassi, j a n d R. M a n n a ~ Departments o f tGastroenterology and :Hematology "'C. S. S. "" Hospital, 71013 San Giovanni Rotondo (FG), Italy; and 3Department o f Internal Medicine, Catholic University, Largo A. Gemelti 8, 00168 Rome, Raly Received May 16, 1989; Revised September 10, 1989; Accepted September 25, 1989
Summary Few investigations discussing an association between ABO blood groups and pancreatic cancer exist. We have selected a series of 224 patients with histologically-confirmed pancreatic cancer, and their ABO blood groups distribution was compared with two control groups: 7086 patients with various diseases (Group 1) and 7320 voluntary blood donors (Group 2). There was an increased number of pancreatic cancer among the patients with blood group B (relative risk 1.5 vs Group 1 p=0.021; 1.7 vs Group 2 p = 0.0025) and a decreased number in patients with blood group O, when compared with the two control groups.
Key Words: Pancreatic cancer; blood groups; incidence; B blood group. INTRODUCTION A relationship between A B O blood groups and malignant diseases has been suggested by many investigators; however, the significance o f this relationship remains debatable. Cancer of the pancreas assumes a position of growing importance because of its rising incidence and poor prognosis (1). Few reports are available concerning the relationship between A B O blood groups and this neoplasm. The reported data suggest an association between blood group A and the disease (2-4). We have compared the frequency o f A B O b l o o d groups in three different populations: patients with the cancer o f the pancreas; patients with diseases other than pancreatic cancer; and voluntary b l o o d donors.
*Author to whom all correspondence and reprint requests should be addressed.
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Table 1 Anatomical Sites of the Pancreatic Cancers and ABO Blood Group Distribution Site
N
Head Head-Body Body Body-Tail Tail
138 39 26 16 5
Pancreatic Cancer % 61.6 17.4 11.6 %2 2.2
(224 cases) A
B
AB
O
52 17 13 7 3
26 8 4 3 0
8 2 1 1 0
52 12 8 5 2
Table 2 Histological Classification and ABO Blood Group Distribution a Blood groups
Pancreatic cancer (224 cases) Histologic type
N
%
A
B
AB
O
Ductat adenocarcinoma Undifferentiated carcinoma Acinar cell carcinoma Mucinous carcinoma Mixed aden0carcinoma "Nephrogenic" adenocarcinoma Adenosquamous carcinoma Microadenocarcinoma Cystadenocarcinoma Scirrhous carcinoma
183 17 10 5 3 2 1 1 1 1
81.7 7.6 4.5 2.3 1.4 0.9 0.4 0.4 0.4 0.4
71 9 4 3 1 1 1 I 1
34 3 3 1 -
10 1 1 -
68 4 2 2 2 7 1 -
aAccording to Cubilla-Fitzgerald(5).
MATERIALS A N D METHODS During the past 10 years, 274 patients with a diagnosis o f pancreatic cancer were seen in the " A . Gemelli" Hospital-Catholic University o f Rome. O f these, 224 patients (134 males and 90 females) were included in this study, because their ABO group type was available and their cancer was verified histologically. The anatomical sites o f the neoplasia and their histological type, according to the Cubilla-Fitzgerald classification (5) are listed in Tables 1 and 2, respectively. For the first control group, we r a n d o m l y selected 7086 cases (Group I) from 21,000 patients admitted to the same hospital, between J a n u a r y 1st and December 31 st 1988, suffering from various nonmalignant diseases. The second group of controls (Group 2), 7320 cases, were randomly sampled from a pool o f voluntary blood donors coming to the "Transfusional C e n t r e " o f the hospital during the same period. All results were evaluated with the chi square or Fisher's exact tests when appropriate and then the relative risk (RR), etiological fraction (EF) and preventive fraction (PF) were calculated (6) with the following formulas (Table 3)
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Table 3 Formulas for Relative Risk, Etiological Fraction, and Preventive Fraction with an Example of Calculation a,o Example: blood group A pancreatic cancer vs control Group 1 RR = A / A + C x B + D / B 9 2 / 9 2 0.032 • 33.59 = 1.07
+2783 x t32 + 4303 / 132 =
X2 = (Log RR) 2 / Variance = (Log 1.07) 2 / 1/92 + 1/132 + 1/2783 + 1/4303 = 0.0045 / 0.0188 -- 0.24 EF = RR - 1 / R R • A / A
+ B = 1.07 - 1 / 1.07 x 9 2 / 9 2 + 132 = 0.026
PF = (1 - RR) • A / A + B / R R not applicable for RR > 1
x (1 - A / A
+ B) + A / A
+ B
~According to Green (6). hA=exposed individuals with disease; B =nonexposed individuals with disease; C = exposed individuals without disease; D = nonexposed individuals wiithout disease.
RR = A / A EF = A / A P F = (1 - RR) x A / A
+ C x B + D/B + B • RR -
+ B/RR(1
1 /RR
- A/A+
B) + A / A
+ B
the p o p u lat i on is divided in exposecl individuals, o f w hom A developed the disease and C did not, and n o n e x p o s e d individuals, o f w h o m B developed the disease and D did not, prior to the sampling. Relative Risk gives the relation between risks of the exposed and nonexposed individuals. Etiological Fraction o f the exposed individuals is defined as the p r o p o r t i o n of cases developed in the exposed part o f the population, which is attributable to the exposure. Preventive Fraction o f exposed individuals is defined as the p r o p o r t i o n o f cases prevented by the exposure o f the total, a hypothetical n u m b e r of cases that would have developed in the population o f exposed individuals. T he statistical significance o f relative risk was investigated with the formulas (log RR) 2 / Variance = X: Variance = 1 / A
+ 1/B
+ 1/C
+ 1/D
RESULTS Pancreatic cancer was diagnosed in males at an earlier age than females (60.2 + 11.4 vs 66.2 + 10.7 y) (mean +_SD) ( p < 0.01). A positive family history o f cancer was evident in 21 ~ o f patients, o f which 55~ had gastrointestinal cancer, including two cases with pancreatic cancer (Table 4). A second neoplasia was present in 13 (6070) o f patients. The histologic types o f pancreatic cancer and the blood group type o f the patients are summarized in Table 2. T he A BO blood group distribution was significantly different in the pancreatic cancer patients, c o m p a r e d to G r o u p 1 ( p = 0 . 0 1 5 ) and G r o u p 2 ( p = 0 o 0 0 0 2 5 ) controls (Table 5).
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Annese et al. Table 4 Cancers Distribution in the Relatives of and Second Neoplasia in Pancreatic Cancer Patients Cancers in relatives Stomach 9 Colon-rectum 7 Liver 6 Lung 5 Breast 5 Uterus 3 Pancreas 2 Esophagus 2 Larynx 2 Bladder 2 Prostate 2 Thyroid 1 No. of cases
Second neoplasia Colon 4 Stomach 2 Breast 2 Uterus 2 Larynx 1 Bladder t Skin 1 No. of patients
13
46
A significant difference was found also between Group 1 and 2 blood group distribution with respect to A and O blood group types (p ---0.000028)~ Blood group B was more frequently present in our series of pancreatic cancer, compared to controls. The calculated RR was 1.5 (vs Group 1) and 1.7 (vs Group 2) (Table 6). In contrast, blood group 0 was significantly less frequently presented among the patients than the controls having the RR of < 1, and a protective fraction of 13.1% (vs Group 1) or 19.6% (vs Group 2). These differences existed regardless of whether the total number or the predominant histologic type, such as ductal type adenocarcinoma, were considered (Table 5). There was no significant difference between the ABO blood group distribution and the anatomical locations or the histologic types of pancreatic cancer, nor was there any difference between patients with a positive or absent family history of cancer.
DISCUSSION Immunohistochemical examinatin of the human pancreas has shown A B H antigens in vascular, ductal, and acinar cells (7). It also has been shown that membrane glycoproteins of human pancreatic cancer cells contain N-acetylglucosamine residues (8). H u m a n pancreatic cancer has been found to either express A or B antigens, corresponding to the individual blood group (9), or lose the blood group antigen expression in 80~ of the cases (10). Pour et al. (11) recently found a different reactivity of polyclonal or monoclonal antibodies against blood group antigens in normal and malignant pancreatic tissue and have shown that blood group antigens, including the B isoantigen, are specific markers for induced pancreatic duct tumors in hamsters. Dele-
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Table 5 ABO Blood Group Distribution Blood groups A B AB O
Pancreatic cancer (224 cases) 92 (41.1%) 41 (18.3%) 12 (5.3~ 79 (35.307o)
Control group 1 (7086 cases) 2783 903 276 3124
(39.3%) (12.7%) (3.9~ (4407o)
Xz
p
0.22 5.48 0.87 6.5
0.63 0.019 0.35 0.010
0,002 4.9 0.78 3.2
0.95 0,026 0.37 0.07
X2 = 10.4 p =0.015 Ductal Adenoca 183 cases) A B AB O
Control group 1
71 (38.8070) 34 (18.6%) 10 (5.5%) 68 (37.1 ~
2783 903 276 3124
(39.3%) (12.7%) (3.9%) (44%)
X2 = 7.8 p = 0.05 Pancreatic cancer (224 cases) A B AB O
92 (41.1 ~ 41 (18.3%) 12 (5.3~ 79 (35.3070)
Control group 2 (7320 cases) 2699 835 267 3519
(36.9%) (11.4%) (3.6~ (4807o)
X2
p
1.46 9.41 1.33 13.77
0.22 0.0021 0.24 0.0002
0.2 8.28 1.18 8.09
0.64 0.(X)4 0.27 0.004
x 2= 19.1 p = 0.00025
A B AB O
Ductal Adenoca (183 cases) 71 (38.8~ 34 (18.6%) 10 (5.5%) 68 (37.1o7o)
Control group 2 2699 (36.9%) 835 (11.4~ 267 (3.607o) 3519 (4807o) x 2 = 14.1 p =0.0027
Control group 1 (7086 cases) A B AB O
2783 903 276 3124
(39.3%) (12.7%) (53.9%) (44%)
Control group 2 (7320 cases) 2699 835 267 3519
(36.9%) (11.4%) (3.6%) (48%)
X2
p
8.71 5.93 0.54 22.8
0.0031 0.014 0.46 0.00002
Xz = 23.78 p = 0.000028
tion of an expected A, B, H, or Le" antigen, or incompatible expression o f A or B antigen in h u m a n pancreatic cancer cells, also have been shown ( 1 2 , 1 3 ) . Koprowski et al. ( 1 4 ) suggested that individuals with Leab-blood type may have a different susceptibility to pancreatic cancer. Nearly all patients with this neoplasm express gastrointestinal cancer antigen (GICA), the sugar sequence o f which includes Le a and Le b antigens.
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A nnese et al. Table 6 RR, EF, and P F Values
Blood groups
Relative Risk (RR)
Etiologic Fraction (EF)
Protective Fraction (PF)
x 2 of RR
p
0.24 5.3 1.03
0.62 0.021 0.31
Pancreatic cancer (224 cases) vs control group 1 A:not A B:not B AB:not AB O:not 0
1.07 1.5 1.36 0.7
2.6~ 6.1070 1.4% -
13.1~
-
-
Ductal adenocaracinoma (183 cases) vs control group 1 A:not A B:not B AB:not AB O:not O
0.98 1.54 1.41 0.75
6.5~ 1.5070 -
0.7070 11070
4.99 1.07 -
0.025 0.30 -
1.03 9.11 1.61 -
0.31 0.0025 0.20 -
Pancreatic cancer (224 cases) vs control group 2 A:not A B:not B AB:not AB O:not O
1.15 1.7 1.47 0.59
5.3o70 7.5~ 1.707o -
19.6~
Ductal adenocaracinoma (183 cases) vs control group 2 A:not A B:not B AB:not AB O:not O
1.08 1.74 1.5 0.64
2.8~ 7.9~ 1.8% -
22.3~
0.26 8.21 1.49 -
0.61 0.004 0.22 -
S o m e familial p a n c r e a t i c c a n c e r p a t t e r n s suggest that heredity plays a role in the d e v e l o p m e n t o f this c a n c e r (15). O n l y a few studies are available concerning the relationship between A B O b l o o d g r o u p s and cancer o f the p a n creas. A slight increase in the incidence o f p a n c r e a t i c cancer in b l o o d g r o u p A individuals has been r e p o r t e d (2-4,16). H o w e v e r , in these studies, the cases were few (4), t u m o r s were n o t verified histologically, and b l o o d d o n o r s were used as c o n t r o l g r o u p s (2-4,16). M a n u i l a et al. (17) s h o w e d the possible sources o f e r r o r a n d the p r o b l e m s i n h e r e n t in s t u d y i n g A B O b l o o d g r o u p s d i s t r i b u t i o n , including d i f f e r e n c e s in ethnic a n d racial c o m p o s i t i o n b e t w e e n cases a n d c o n t r o l g r o u p s , statistical sampling errors, a n d errors in b l o o d grouping procedures. In the p r e s e n t study, we e x a m i n e d the A B O b l o o d groups d i s t r i b u t i o n in m a n y patients with a histologically c o n f i r m e d diagnosis o f p a n c r e a t i c cancer. T h e two c o n t r o l g r o u p s were s a m p l e d r a n d o m l y f r o m either p a t i e n t s with various n o n m a l i g n a n t diseases ( G r o u p 1) o r f r o m v o l u n t a r y b l o o d d o n o r s ( G r o u p 2) a d m i t t e d to the C a t h o l i c U n i v e r s i t y H o s p i t a l f r o m the s a m e regions (central a n d s o u t h e r n Italy). We f o u n d m o r e pancreatic cancer patients having b l o o d g r o u p B t h a n in c o n t r o l g r o u p s (18.3~ vs 1 2 . 7 % , G r o u p 1, p = 0.019;
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18.3% vs 11.4% Group 2, p =0.0021). Fewer patients had blood group O (35.3% vs 44% Group 1 , p = 0 . 0 1 0 ; 35.3% vs 48%, Group 2 , p =0.0002)~ No significant difference was found between the A and AB blood group types and the ABO blood group type or the incidence of various histologic types of pancreatic cancer. A significant difference was found in the blood group distribution between the two control groups with respect to the A and O types (Table 5). This difference could be attributed to the possible presence of "professional" blood donors, n o n r a n d o m selection of blood donors with specific blood groups~ Therefore, it appears that a randomized group of general hospital patients provides a more reliable control group and excludes a bias (18). In contrast, blood donors are not a truly randomized group, because some blood groups, such as group O, are requested more frequently because of increased hospital need. An association between a given factor (exposure) and a given disease or condition can be considered when the occurrence of the disease differs between exposed and nonexposed individuals. If the association is positive, the incidence of the disease is higher among the exposed than the nonexposed population. The magnitude of the association may simply be measured as the ratio (or difference) between the disease frequency among the exposed and nonexposed. Unlike the environmental factors, genetic factors, such as the blood groups, are present and unchanged from conception throughout the entire lifespan of an individual and represent extremely simplified and stable situations from the epidemiologist's point of view. By using appropriate formulas, we found a RR of 1.5 in pancreatic cancer patients with the B blood group (p =0.021) vs the others and an EF of 6.1~ (Table 6). On the other hand, subjects with the O blood groups had a RR significantly < 1 and a PF of 13.1%o The concept of exposure or risk should be interpreted very widely. The exposure does not necessarily need to be an etiological factor, but may present a cofactor. Our results show significant differences between the ABO blood group distribution on the incidence of pancreatic cancer. Another factor could be the presence of the familial history for neoplasias in the patients of our series. This suggest that genetic factors play a role in the multifactorial etiology of pancreatic cancer (19). The reasons for the association between blood group B type and pancreatic cancer remains unclear, as does incompatible expression of B antigen in pancreatic cancer cells found in a recent study (13). However, as in another study (20), there was no correlation between expression of blood groups antigens, the anatomical localization, and the histologic types of pancreatic tumors.
ACKNOWLEDGMENT This paper was presented, in part, as an abstract at the "International Symposium on Pancreatic Cancer: biochemical and clinical aspects," Padua, Italy, October 24-25, 1986.
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A n n e s e et aL
REFERENCES t 2 3 4 5 6 7 8 9 I0 11 12 13
14 15 16 17 18 19 20
Williamson RCN. Pancreatic cancer: the greater oncological challenge. Br. Med. J. 1988; 296: 445-446. Aird J, Lee DR, Roberts JA. ABO blood groups and cancer of oesophagus, cancer of pancreas and pituitary adenoma. Br. Med. J. 1960; 1: 1t63-1166. Mourant AE, Kopec' AC, Sobczak KD. Blood groups and diseases. Oxford University Press, Oxford, 1978. Newell GR, Gordon JE, Monlezum AP, Horwitz JS. ABO blood groups and cancer. J. Natl. Cancer Inst. 1974; 52: 1425-1430. Cubilla A, Fitzgerald PJ. Pancreas cancer. I. Duct adenocarcinoma. A clinico-pathologic study of 308 patients. Path. Ann. 1978; 13: 241-289. Green A. The epidemiological approach to studies of association between HLA and disease. II. Estimation of absolute risks~ etiological and preventive fraction. Tissue Antigens t982; 19: 259-268. Rouger PH, Goossens D, Gane P, Salmon CH. Distribution of blood groups antigens in adult human pancreas. Tissue Antigen 1981; 18: 51-55. Kim YS, Tsao D, Hicks J. McIntyre LJ. Surface membrane glycoproteins of cultured human pancreatic cancer cells. Cancer 1981; 47: 1590-1596. Ernst C, Atkinson B, Wysocka M, Blaszczyk M, Herlyn M, Sears HF, Steplewski Z, Koprowski H. Monoclonal antibody localization of Lewis antigens in fixed tissue. Lab. Invest. 1984; 50: 394-400. Davidsohn IN, Ni LY, Stejskal R. Tissue isoantigens A, B and H in carcinoma of the pancreas. Cancer Res. 1971; 31 : 1244-1250. Pour PM, Uchida E, Burnett DA, Steplewski Z. Blood group antigen expression during pancreatic cancer induction in hamsters. Int. J. Pancreat. 1986; t: 327-340. Itzkowitz SH, Yuan M, Ferrell LD, Ratcliffe M, Chang YS, Satake K, Umeyama K, Jones RT, Kim YS. Cancer-associated alterations of blood group antigen expression in the human pancreas. J. Natl. Cancer Inst. 1987; 79: 425-434. Pour PM, Tempero MM, Takasaki H, Uchida E, Takiyama Y~ Burnett DA. Expression of blood-group related antigens ABH, Lewis A, Lewis B, Lewis X, Lewis Y, and CA 19-9 in pancreatic cancer cells in comparison with the patient's blood group type. Canc. Res. 1988; 48: 5422-5426. Koprowski H, Brockhaus M, Blaszczyk M, Magnani J, Steplewski Z, Ginsburg V. Lewis blood-type may affect the incidence of gastrointestinal cancer. Lancet 1982; 1: 1332-1333. Ghadirian P, Simard A, Baillargeon J. Cancer of the pancreas in two brothers and one sister. Int. J. Pancreat. 1987; 2: 383-391. Vogel F. ABO blood groups and disease. Am. J. Hum. Genet. 1970; 22: 464-475. Manuila A. Blood group and disease-hard facts and delusions. JAMA 1958; 167: 2047-2053. Wiener AS. Blood groups and disease. Am. J. Hum. Genet. 1970; 22: 476-483. Lin RS, Kessler I. A multifactorial model for pancreatic cancer in man. Epidemiologic evidence. JAMA 1981; 245: 147-152. Uchida E, Tempero MA, Burnett DA, Steplewski Z, Pour PM. Correlative studies on antigenicity of pancreatic cancer and blood group types. Cancer Detec. Prevent. 1987; Suppl. 1: 145-148.
International Journal of Pancreatology
Volume 6, 1990
ABO Blood Groups and Cancer of the Pancreas V. Annese, ,,1 M. Minervini, 2 A . Gabbrielli, 3 G. Gambassi, j a n d R. M a n n a ~ Departments o f tGastroenterology and :Hematology "'C. S. S. "" Hospital, 71013 San Giovanni Rotondo (FG), Italy; and 3Department o f Internal Medicine, Catholic University, Largo A. Gemelti 8, 00168 Rome, Raly Received May 16, 1989; Revised September 10, 1989; Accepted September 25, 1989
Summary Few investigations discussing an association between ABO blood groups and pancreatic cancer exist. We have selected a series of 224 patients with histologically-confirmed pancreatic cancer, and their ABO blood groups distribution was compared with two control groups: 7086 patients with various diseases (Group 1) and 7320 voluntary blood donors (Group 2). There was an increased number of pancreatic cancer among the patients with blood group B (relative risk 1.5 vs Group 1 p=0.021; 1.7 vs Group 2 p = 0.0025) and a decreased number in patients with blood group O, when compared with the two control groups.
Key Words: Pancreatic cancer; blood groups; incidence; B blood group. INTRODUCTION A relationship between A B O blood groups and malignant diseases has been suggested by many investigators; however, the significance o f this relationship remains debatable. Cancer of the pancreas assumes a position of growing importance because of its rising incidence and poor prognosis (1). Few reports are available concerning the relationship between A B O blood groups and this neoplasm. The reported data suggest an association between blood group A and the disease (2-4). We have compared the frequency o f A B O b l o o d groups in three different populations: patients with the cancer o f the pancreas; patients with diseases other than pancreatic cancer; and voluntary b l o o d donors.
*Author to whom all correspondence and reprint requests should be addressed.
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Table 1 Anatomical Sites of the Pancreatic Cancers and ABO Blood Group Distribution Site
N
Head Head-Body Body Body-Tail Tail
138 39 26 16 5
Pancreatic Cancer % 61.6 17.4 11.6 %2 2.2
(224 cases) A
B
AB
O
52 17 13 7 3
26 8 4 3 0
8 2 1 1 0
52 12 8 5 2
Table 2 Histological Classification and ABO Blood Group Distribution a Blood groups
Pancreatic cancer (224 cases) Histologic type
N
%
A
B
AB
O
Ductat adenocarcinoma Undifferentiated carcinoma Acinar cell carcinoma Mucinous carcinoma Mixed aden0carcinoma "Nephrogenic" adenocarcinoma Adenosquamous carcinoma Microadenocarcinoma Cystadenocarcinoma Scirrhous carcinoma
183 17 10 5 3 2 1 1 1 1
81.7 7.6 4.5 2.3 1.4 0.9 0.4 0.4 0.4 0.4
71 9 4 3 1 1 1 I 1
34 3 3 1 -
10 1 1 -
68 4 2 2 2 7 1 -
aAccording to Cubilla-Fitzgerald(5).
MATERIALS A N D METHODS During the past 10 years, 274 patients with a diagnosis o f pancreatic cancer were seen in the " A . Gemelli" Hospital-Catholic University o f Rome. O f these, 224 patients (134 males and 90 females) were included in this study, because their ABO group type was available and their cancer was verified histologically. The anatomical sites o f the neoplasia and their histological type, according to the Cubilla-Fitzgerald classification (5) are listed in Tables 1 and 2, respectively. For the first control group, we r a n d o m l y selected 7086 cases (Group I) from 21,000 patients admitted to the same hospital, between J a n u a r y 1st and December 31 st 1988, suffering from various nonmalignant diseases. The second group of controls (Group 2), 7320 cases, were randomly sampled from a pool o f voluntary blood donors coming to the "Transfusional C e n t r e " o f the hospital during the same period. All results were evaluated with the chi square or Fisher's exact tests when appropriate and then the relative risk (RR), etiological fraction (EF) and preventive fraction (PF) were calculated (6) with the following formulas (Table 3)
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Table 3 Formulas for Relative Risk, Etiological Fraction, and Preventive Fraction with an Example of Calculation a,o Example: blood group A pancreatic cancer vs control Group 1 RR = A / A + C x B + D / B 9 2 / 9 2 0.032 • 33.59 = 1.07
+2783 x t32 + 4303 / 132 =
X2 = (Log RR) 2 / Variance = (Log 1.07) 2 / 1/92 + 1/132 + 1/2783 + 1/4303 = 0.0045 / 0.0188 -- 0.24 EF = RR - 1 / R R • A / A
+ B = 1.07 - 1 / 1.07 x 9 2 / 9 2 + 132 = 0.026
PF = (1 - RR) • A / A + B / R R not applicable for RR > 1
x (1 - A / A
+ B) + A / A
+ B
~According to Green (6). hA=exposed individuals with disease; B =nonexposed individuals with disease; C = exposed individuals without disease; D = nonexposed individuals wiithout disease.
RR = A / A EF = A / A P F = (1 - RR) x A / A
+ C x B + D/B + B • RR -
+ B/RR(1
1 /RR
- A/A+
B) + A / A
+ B
the p o p u lat i on is divided in exposecl individuals, o f w hom A developed the disease and C did not, and n o n e x p o s e d individuals, o f w h o m B developed the disease and D did not, prior to the sampling. Relative Risk gives the relation between risks of the exposed and nonexposed individuals. Etiological Fraction o f the exposed individuals is defined as the p r o p o r t i o n of cases developed in the exposed part o f the population, which is attributable to the exposure. Preventive Fraction o f exposed individuals is defined as the p r o p o r t i o n o f cases prevented by the exposure o f the total, a hypothetical n u m b e r of cases that would have developed in the population o f exposed individuals. T he statistical significance o f relative risk was investigated with the formulas (log RR) 2 / Variance = X: Variance = 1 / A
+ 1/B
+ 1/C
+ 1/D
RESULTS Pancreatic cancer was diagnosed in males at an earlier age than females (60.2 + 11.4 vs 66.2 + 10.7 y) (mean +_SD) ( p < 0.01). A positive family history o f cancer was evident in 21 ~ o f patients, o f which 55~ had gastrointestinal cancer, including two cases with pancreatic cancer (Table 4). A second neoplasia was present in 13 (6070) o f patients. The histologic types o f pancreatic cancer and the blood group type o f the patients are summarized in Table 2. T he A BO blood group distribution was significantly different in the pancreatic cancer patients, c o m p a r e d to G r o u p 1 ( p = 0 . 0 1 5 ) and G r o u p 2 ( p = 0 o 0 0 0 2 5 ) controls (Table 5).
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Annese et al. Table 4 Cancers Distribution in the Relatives of and Second Neoplasia in Pancreatic Cancer Patients Cancers in relatives Stomach 9 Colon-rectum 7 Liver 6 Lung 5 Breast 5 Uterus 3 Pancreas 2 Esophagus 2 Larynx 2 Bladder 2 Prostate 2 Thyroid 1 No. of cases
Second neoplasia Colon 4 Stomach 2 Breast 2 Uterus 2 Larynx 1 Bladder t Skin 1 No. of patients
13
46
A significant difference was found also between Group 1 and 2 blood group distribution with respect to A and O blood group types (p ---0.000028)~ Blood group B was more frequently present in our series of pancreatic cancer, compared to controls. The calculated RR was 1.5 (vs Group 1) and 1.7 (vs Group 2) (Table 6). In contrast, blood group 0 was significantly less frequently presented among the patients than the controls having the RR of < 1, and a protective fraction of 13.1% (vs Group 1) or 19.6% (vs Group 2). These differences existed regardless of whether the total number or the predominant histologic type, such as ductal type adenocarcinoma, were considered (Table 5). There was no significant difference between the ABO blood group distribution and the anatomical locations or the histologic types of pancreatic cancer, nor was there any difference between patients with a positive or absent family history of cancer.
DISCUSSION Immunohistochemical examinatin of the human pancreas has shown A B H antigens in vascular, ductal, and acinar cells (7). It also has been shown that membrane glycoproteins of human pancreatic cancer cells contain N-acetylglucosamine residues (8). H u m a n pancreatic cancer has been found to either express A or B antigens, corresponding to the individual blood group (9), or lose the blood group antigen expression in 80~ of the cases (10). Pour et al. (11) recently found a different reactivity of polyclonal or monoclonal antibodies against blood group antigens in normal and malignant pancreatic tissue and have shown that blood group antigens, including the B isoantigen, are specific markers for induced pancreatic duct tumors in hamsters. Dele-
International Journal of Pancreatology
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Table 5 ABO Blood Group Distribution Blood groups A B AB O
Pancreatic cancer (224 cases) 92 (41.1%) 41 (18.3%) 12 (5.3~ 79 (35.307o)
Control group 1 (7086 cases) 2783 903 276 3124
(39.3%) (12.7%) (3.9~ (4407o)
Xz
p
0.22 5.48 0.87 6.5
0.63 0.019 0.35 0.010
0,002 4.9 0.78 3.2
0.95 0,026 0.37 0.07
X2 = 10.4 p =0.015 Ductal Adenoca 183 cases) A B AB O
Control group 1
71 (38.8070) 34 (18.6%) 10 (5.5%) 68 (37.1 ~
2783 903 276 3124
(39.3%) (12.7%) (3.9%) (44%)
X2 = 7.8 p = 0.05 Pancreatic cancer (224 cases) A B AB O
92 (41.1 ~ 41 (18.3%) 12 (5.3~ 79 (35.3070)
Control group 2 (7320 cases) 2699 835 267 3519
(36.9%) (11.4%) (3.6~ (4807o)
X2
p
1.46 9.41 1.33 13.77
0.22 0.0021 0.24 0.0002
0.2 8.28 1.18 8.09
0.64 0.(X)4 0.27 0.004
x 2= 19.1 p = 0.00025
A B AB O
Ductal Adenoca (183 cases) 71 (38.8~ 34 (18.6%) 10 (5.5%) 68 (37.1o7o)
Control group 2 2699 (36.9%) 835 (11.4~ 267 (3.607o) 3519 (4807o) x 2 = 14.1 p =0.0027
Control group 1 (7086 cases) A B AB O
2783 903 276 3124
(39.3%) (12.7%) (53.9%) (44%)
Control group 2 (7320 cases) 2699 835 267 3519
(36.9%) (11.4%) (3.6%) (48%)
X2
p
8.71 5.93 0.54 22.8
0.0031 0.014 0.46 0.00002
Xz = 23.78 p = 0.000028
tion of an expected A, B, H, or Le" antigen, or incompatible expression o f A or B antigen in h u m a n pancreatic cancer cells, also have been shown ( 1 2 , 1 3 ) . Koprowski et al. ( 1 4 ) suggested that individuals with Leab-blood type may have a different susceptibility to pancreatic cancer. Nearly all patients with this neoplasm express gastrointestinal cancer antigen (GICA), the sugar sequence o f which includes Le a and Le b antigens.
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A nnese et al. Table 6 RR, EF, and P F Values
Blood groups
Relative Risk (RR)
Etiologic Fraction (EF)
Protective Fraction (PF)
x 2 of RR
p
0.24 5.3 1.03
0.62 0.021 0.31
Pancreatic cancer (224 cases) vs control group 1 A:not A B:not B AB:not AB O:not 0
1.07 1.5 1.36 0.7
2.6~ 6.1070 1.4% -
13.1~
-
-
Ductal adenocaracinoma (183 cases) vs control group 1 A:not A B:not B AB:not AB O:not O
0.98 1.54 1.41 0.75
6.5~ 1.5070 -
0.7070 11070
4.99 1.07 -
0.025 0.30 -
1.03 9.11 1.61 -
0.31 0.0025 0.20 -
Pancreatic cancer (224 cases) vs control group 2 A:not A B:not B AB:not AB O:not O
1.15 1.7 1.47 0.59
5.3o70 7.5~ 1.707o -
19.6~
Ductal adenocaracinoma (183 cases) vs control group 2 A:not A B:not B AB:not AB O:not O
1.08 1.74 1.5 0.64
2.8~ 7.9~ 1.8% -
22.3~
0.26 8.21 1.49 -
0.61 0.004 0.22 -
S o m e familial p a n c r e a t i c c a n c e r p a t t e r n s suggest that heredity plays a role in the d e v e l o p m e n t o f this c a n c e r (15). O n l y a few studies are available concerning the relationship between A B O b l o o d g r o u p s and cancer o f the p a n creas. A slight increase in the incidence o f p a n c r e a t i c cancer in b l o o d g r o u p A individuals has been r e p o r t e d (2-4,16). H o w e v e r , in these studies, the cases were few (4), t u m o r s were n o t verified histologically, and b l o o d d o n o r s were used as c o n t r o l g r o u p s (2-4,16). M a n u i l a et al. (17) s h o w e d the possible sources o f e r r o r a n d the p r o b l e m s i n h e r e n t in s t u d y i n g A B O b l o o d g r o u p s d i s t r i b u t i o n , including d i f f e r e n c e s in ethnic a n d racial c o m p o s i t i o n b e t w e e n cases a n d c o n t r o l g r o u p s , statistical sampling errors, a n d errors in b l o o d grouping procedures. In the p r e s e n t study, we e x a m i n e d the A B O b l o o d groups d i s t r i b u t i o n in m a n y patients with a histologically c o n f i r m e d diagnosis o f p a n c r e a t i c cancer. T h e two c o n t r o l g r o u p s were s a m p l e d r a n d o m l y f r o m either p a t i e n t s with various n o n m a l i g n a n t diseases ( G r o u p 1) o r f r o m v o l u n t a r y b l o o d d o n o r s ( G r o u p 2) a d m i t t e d to the C a t h o l i c U n i v e r s i t y H o s p i t a l f r o m the s a m e regions (central a n d s o u t h e r n Italy). We f o u n d m o r e pancreatic cancer patients having b l o o d g r o u p B t h a n in c o n t r o l g r o u p s (18.3~ vs 1 2 . 7 % , G r o u p 1, p = 0.019;
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18.3% vs 11.4% Group 2, p =0.0021). Fewer patients had blood group O (35.3% vs 44% Group 1 , p = 0 . 0 1 0 ; 35.3% vs 48%, Group 2 , p =0.0002)~ No significant difference was found between the A and AB blood group types and the ABO blood group type or the incidence of various histologic types of pancreatic cancer. A significant difference was found in the blood group distribution between the two control groups with respect to the A and O types (Table 5). This difference could be attributed to the possible presence of "professional" blood donors, n o n r a n d o m selection of blood donors with specific blood groups~ Therefore, it appears that a randomized group of general hospital patients provides a more reliable control group and excludes a bias (18). In contrast, blood donors are not a truly randomized group, because some blood groups, such as group O, are requested more frequently because of increased hospital need. An association between a given factor (exposure) and a given disease or condition can be considered when the occurrence of the disease differs between exposed and nonexposed individuals. If the association is positive, the incidence of the disease is higher among the exposed than the nonexposed population. The magnitude of the association may simply be measured as the ratio (or difference) between the disease frequency among the exposed and nonexposed. Unlike the environmental factors, genetic factors, such as the blood groups, are present and unchanged from conception throughout the entire lifespan of an individual and represent extremely simplified and stable situations from the epidemiologist's point of view. By using appropriate formulas, we found a RR of 1.5 in pancreatic cancer patients with the B blood group (p =0.021) vs the others and an EF of 6.1~ (Table 6). On the other hand, subjects with the O blood groups had a RR significantly < 1 and a PF of 13.1%o The concept of exposure or risk should be interpreted very widely. The exposure does not necessarily need to be an etiological factor, but may present a cofactor. Our results show significant differences between the ABO blood group distribution on the incidence of pancreatic cancer. Another factor could be the presence of the familial history for neoplasias in the patients of our series. This suggest that genetic factors play a role in the multifactorial etiology of pancreatic cancer (19). The reasons for the association between blood group B type and pancreatic cancer remains unclear, as does incompatible expression of B antigen in pancreatic cancer cells found in a recent study (13). However, as in another study (20), there was no correlation between expression of blood groups antigens, the anatomical localization, and the histologic types of pancreatic tumors.
ACKNOWLEDGMENT This paper was presented, in part, as an abstract at the "International Symposium on Pancreatic Cancer: biochemical and clinical aspects," Padua, Italy, October 24-25, 1986.
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A n n e s e et aL
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