Endometrial cancer was studied in the Swedish Family-Cancer Database, updated in 1999 to cover individuals born after 1934 with their biological parents, totaling 9.6 million persons. Cancer data were obtained from the Swedish Cancer Registry from 1958 to 1996 and included over 20,000 cases of endometrial cancer. Seventy-six families were identified in which both the mother and the daughter had endometrial cancer, giving a familial standardized incidence ratio (SIR) of 3.19 for daughters and 2.78 for mothers. The risk depended inversely on the age at diagnosis, and the risk was almost 10 in daughters who were diagnosed before age 50 when their mothers were also diagnosed before that age. The discordant cancer site that associated with endometrial cancer between the two generations was colon, with a SIR of 1.44–1.68. However, when the maternal endometrial cancer was diagnosed before age 50, increased SIRs were observed in daughters or sons for rectal, pancreatic, nervous system, breast, and ovarian cancers. Second cancers were followed in females diagnosed with endometrial cancer, and the highest overall risks were observed for ovarian and connective tissue cancers; colorectal cancers were also clearly in excess. Among the other family members of the 76 families in which both mother and daughter were affected with endometrial cancer, there were 11 cases of colorectal cancer. When a sister was affected in such families, the SIR of endometrial cancer was 31.40, and the median diagnostic age was several years lower than in endometrial cancer families in which no colorectal cancers were found. Many of these families may have hereditary nonpolyposis colorectal carcinoma syndrome. However, the risk of endometrial cancer was increased even in families presenting no colorectal cancers.

Cancer of the endometrium (uterine corpus, code 172 in ICD-7)3 is the third most common cancer in women in Sweden (1). Two distinct types of epithelial tumors can be recognized: estrogen-related endometrioid carcinomas, with a mean age of onset of 59 years, and a rarer serous carcinoma, with mean age of onset of 68 years (2). Some established risk factors for endometrial cancer are conditions in which chronic estrogen stimulation takes place, including estrogen replacement therapy, early menarche, late menopause, and nulliparity (3). Tamoxifen has also been associated with a risk of endometrial cancer (4). Illnesses and other conditions that are related to a risk of endometrial cancer are obesity, gallbladder disease, diabetes, hypertension, infertility, and lack of physical activity (5, 6, 7, 8). Among dietary constituents, saturated fats have been suggested to increase and vegetables to decrease the risk of endometrial cancer (9). Endometrial cancer is a common second cancer when breast, ovarian, or colon cancer is the first cancer (3).

Endometrial cancer is a part of the Lynch syndrome, together with colorectal, stomach, hepatobiliary, skin, pancreas, and brain cancers (10). The molecular basis of the syndrome has been elucidated in relation to the HNPCC families and is a defect in one of the DNA mismatch repair genes (2, 10, 11). The penetrance of endometrial cancer in HNPCC families is thought to be 20–40% by age 70, whereas that of colorectal cancer is 70% (12, 13). According to a recent study, the risk of colorectal and endometrial cancer is about 70 times higher in the HNPCC families than in the controls (14). The risk of both cancers is also high in relatives of probands who have primary cancers of both colorectum and endometrium (15). Microsatellite instability is found in 20–30% of endometrial cancer patients (2), yet only a fraction of these have a mutation in the known high penetrance mismatch repair genes (2, 11). Another mutation, common to endometrial cancer and glioblastoma is in the PTEN/MMAC1 gene (16), but the role of this in familial endometrial cancer remains unknown. According to epidemiological studies on women under 54 years of age, some 5% of endometrial cancers can be attributable to a family history, and 2% to a family history of colorectal cancer (17). According to another study some 13.5% of endometrial cancer cases had a family history of colorectal cancers (18).

We use here the 1999 update of the nationwide Swedish Family-Cancer Database, which now covers 9.6 million individuals, dead or alive, in a country with a present population of 8.8 million. It offers unique possibilities for reliable estimation of familial risks, because the data on family relationships and cancers were obtained from registered sources of complete coverage (19, 20). An earlier version of the database has previously been used to study familial relationships in endometrial cancers among some 20 other cancer sites (20, 21) or between different sites (22). The risk to daughters of affected mothers was between 3.8 and 4.1 (20, 23). Here we investigate familial relationships of endometrial and other cancers in detail by calculating FRRs and SIRs for daughters and mothers with endometrial cancer when their relatives have similar or different cancers.

The Swedish Family-Cancer Database, updated in 1999, includes people (“offspring”) born in Sweden after 1934 with their biological parents, totaling over 9.6 million individuals; the structure of the Family-Cancer Database is described in detail elsewhere (20, 24). Cancers were retrieved from the nationwide Swedish Cancer Registry from 1958 to 1996 and linked with the unique personal identification number to the family registry. After linkage, the personal identifiers were deleted. The coverage of the family and Cancer Registries is thought to be practically complete (1, 24). In the 1999 update, the number of invasive cancers in the second generation (offspring) increased from 50,000 to 92,000. The records of the Database are organized by mother, listing her children by birth date and their fathers. Thus parent-offspring and sibling-sibling linkages can readily be made. A four-digit diagnostic code according to ICD-7 was used. ICD code 172 was used for endometrial cancers, which were adenocarcinomas. In most analysis, both the first and the second primary endometrial cancer was considered combined. The following ICD-7 codes were pooled: oral cancer codes 161 (larynx) and 140–148 (lip, mouth, and pharynx), except for code 142 (salivary glands), lymphoma codes 200 (non-Hodgkin’s lymphoma), 201 (Hodgkin’s disease), and 202 (reticulosis), and leukemia codes 204–207 (leukemias), 208 (polycytemia vera), and 209 (myelofibrosis). Rectal cancer (ICD-7 code 154) was separated for anus (squamous cell carcinoma, code 154.1) and mucosal rectum (code 154.0). Basal cell carcinoma of the skin is not registered in the Cancer Registry.

FRRs were calculated within each of two age strata (<50 and ≥50 years) for both mothers and daughters. Age-specific incidence rates in daughters and mothers were calculated by the 5-year diagnosis ages from 15 to 61 years. Standardized incidence ratios (SIRs) were calculated as the ratio of the observed to the expected number of cases (25). The expected numbers were calculated using the overall incidence rates from the Family-Cancer Database and the person-years in the actual study group. 95% CIs were calculated assuming a Poisson distribution (25). SIRs were calculated to 2 decimals, but they were rounded down to one decimal in the tables. For second cancers after endometrial cancer, SIRs were calculated in 5-year age- and period-standardized groups. Multiple cancers in a family were considered independent events and included in calculations as separate events. No family contained more than two offspring presenting colorectal or endometrial cancer.

We carried out analyses of endometrial cancer in the offspring (in most analyses, the daughters) of endometrial cancer probands (mothers) and vice versa, in mothers of daughter probands. The daughters had 1,959 and the mothers 18,111 endometrial cancers as a first or second cancer. A main difference in such comparisons was the age distribution, 15–61 years in daughters and any age over 14 in mothers. There were a total of 76 mother-daughter pairs concordant for endometrial cancer in the Database. There were six sister pairs with endometrial cancer, but they all lacked an affected mother. Age-specific FRRs of endometrial cancer in daughters are shown in Table 1. The overall familial risk was 3.33, and it was highest, close to 10, in daughters who were diagnosed before age 50 when their mothers had also been diagnosed before age 50. The familial and overall incidence rates of endometrial cancer are shown in Fig. 1 by 5-year age groups. The incidence of endometrial cancer increased steeply after age 40, but the FRR decreased with age. The highest FRR was observed in those who were diagnosed between ages 25 and 29 years, but it was based on only two cases. FRRs were also calculated for mothers by daughters’ endometrial cancer, and the results were quite similar to those observed for daughters (data not shown).

Table 2 lists the numbers and SIRs of endometrial cancers in daughters by any cancer in mother and the numbers and SIRs of endometrial cancers in mothers by any cancer in daughters. SIR of endometrial cancer was 3.19 for daughters whose mothers had endometrial cancer, and it was smaller for any discordant cancer in mothers (Table 2). The only discordant site showing an increased risk was maternal colon (SIR, 1.44). The results for mothers agreed (Table 2).

A similar type of analysis was carried out by calculating the numbers and SIRs for diverse cancers in offspring of mothers diagnosed for endometrial cancer before or after age 50 (Table 3). Because one mother could have several affected daughters, the numbers of cancers are not equal in Tables 2 and 3. SIRs were generally higher when mothers were diagnosed before age 50. In this group of daughters, significant increases were observed for endometrium (SIR, 6.86), colon (3.56), ovary (2.98), nervous system (2.65), and breast (1.69). For sons of mothers diagnosed before age 50, the SIR of pancreas cancer was 11.23, and the SIRs of colon and rectal cancer were 5.55 and 6.10, respectively.

Second cancers after diagnosis of endometrial cancer were analyzed in all females (Table 4). Among all second cancers SIRs were increased for colon, rectum, breast, ovary, other female genitals, kidney, urinary bladder, skin, and connective tissue. The follow-up time after the first cancer was divided into three periods: <1 year, 1–9 years, and ≥10 years. The last period may show the effects of treatment; e.g., the SIR of 2.33 for bladder cancer may be related to late effects of radiotherapy.

Endometrial cancer can be a part of the Lynch syndrome, the most common feature of which is colorectal cancer. Thus endometrial cancers were analyzed separately in families in which colorectal cancer (cancer of colon, rectum, or small intestine) was diagnosed in a family member. It should be noted that the types of families are not mutually exclusive. Among the 79 pairs in which both the mother and the daughter had endometrial cancer, there were 16 cases of colorectal cancer, including five mothers with both endometrial and colorectal cancer. According to Table 5, the SIR of endometrial cancer in daughters was 31.40 when the mother had endometrial cancer and a sister had colorectal cancer. However, endometrial cancer was also increased in the 68 families in which no colorectal cancers were diagnosed (SIR, 2.98). In the bottom part of Table 5, maternal risks of endometrial cancers are shown, given other cancers in families. SIR was highest, 10.90, when one daughter had endometrial cancer and another daughter had colorectal cancer. The SIR was 2.57 in families presenting no colorectal cancers. As a control for the effects of common environment, it was shown that colorectal cancer in husbands did not associate with a risk of endometrial cancer in wives (SIR, 0.96). Interestingly, three of six pairs of sisters, both of whom had endometrial cancer, came from families with colorectal cancer but a mother lacking endometrial cancer, giving a crude risk of 14.7 (ratio of 3 of 120 to 3 of 1763; data not shown). For daughter without other affected family members, the median age at diagnosis of endometrial cancer was 51; it was 39–47 when there were other endometrial and colorectal cancers in the family (Table 5). The corresponding change in median age for mothers was from 61 to 52 years.

In previous epidemiological studies on endometrial cancer, family histories were obtained in an interview, and the accuracy of the data may be imperfect (17, 26, 27). The relative risks were small in older women, but in 20–54-year-old women the risk was 2.2 for all first-degree relatives. In a previous analysis from this Database covering women below age 55, before the updating of 1999, the risk of endometrial cancer was 4.1 (20). This was among the highest familial risks, below only thyroid and testicular cancer, among the 20 sites covered. Here we assayed a somewhat older (15–61 years) population of female offspring, and the familial risks were reduced to 3.19 for daughters and 2.78 for mothers. We identified a clear dependence of risk on the age of onset. FRR was close to 10 for the daughters when they and their mothers were below age 50 at diagnosis, as compared to an FRR of 3.0 when both were 50 years or older. Contrary to our results, no effect by age of onset was observed in a previous study (17).

Age of onset also modulated the risk of discordant cancers between the two generations. Young diagnostic age of endometrial cancer in mothers was consonant with an increased risk of discordant cancers in the offspring. The cancer sites emerging in such analysis were colon, rectum, pancreas, nervous system, breast, and ovary. These sites also emerged when second cancers after endometrial cancer were recorded, with the exception of pancreas and nervous system cancer. Additionally, some other tumor sites, probably unrelated to treatment, emerged in the follow-up after endometrial cancer, at kidney, skin (squamous cell carcinoma), and connective tissue.

The discordant sites observed with endometrial cancer were heterogeneous, but each one has been described in families with Lynch syndrome or HPNCC (10, 13). The syndrome also includes stomach and hepatobiliary cancer, but these were not found in excess in the endometrial cancer families. The mean age of the epidermoid form of endometrial cancer is given as 59 years (2), matching our findings for mothers, 59–61 years. The median age of endometrial cancer in HNPCC families is given as 46 years (13), somewhat younger than our data for mothers in the colorectal cancer families, 52 years. In these families, the SIR of endometrial cancer was 18.96–31.40 for daughters and 6.47–10.90 in mothers. These risks are lower than those (about 70-fold) found in HNPCC families (14) but they are similar to those for families identified through double primary endometrial and colorectal cancers (15). In our study, SIR of endometrial cancer was 6.04 for the five daughters when their mothers presented two such primary cancers. As an interesting detail, we showed that endometrial and colorectal cancers lacked common environmental risk factors, because the SIR of endometrial cancer was 0.96 in women whose husbands had colorectal cancer. We identified six sister pairs with endometrial cancer, but none had a mother with endometrial cancer; three mothers had colorectal cancer, and three had neither colorectal nor endometrial cancer. The crude risk of observing affected sister pairs in families with colorectal cancer was 15.

The interest in second cancer following endometrial cancer in the present context was to test whether second cancer signals hereditary susceptibility. In breast cancer, multiple primary cancers in the same individual associate with familial risks (28). Of course, second cancers may arise by chance alone and because of treatment, such as radiotherapy for endometrial cancer. Treatment-related effects would be expected to emerge with a latency time, which may be of the order of 10 years for solid tumors after radiotherapy (29). In an earlier study from Sweden, increased risk in follow-up after endometrial cancer was observed for colon and ovarian cancers and for some other treatment-related sites (29). We also observed an increased risk in colon, rectum, and ovary, and also in breast, kidney, and connective tissue. Increased risks were also noted in bladder, female genitals, and skin, but all these emerged toward the end of the follow-up and may be related to treatment.

It is likely that many, if not most, of the present families with colorectal cancers have HNPCC. Unfortunately, because the Family-Cancer Database only contains two generations, we cannot directly apply the Amsterdam criteria of HNPCC on its first point: “At least 3 relatives must have histologically verified colorectal cancer, and at least one must be a first degree relative of the other two” (30). It is also likely that some HNPCC families are missed because of the age-truncated population of daughters and because of incomplete penetrance. A related question is whether there is familial endometrial cancer, in addition to HNPCC. Our data allow no firm conclusions on this point, but based on the high SIRs in the 66 families lacking colorectal cancer (SIR, 2.98 in daughters and 2.57 in mothers) and the later median age of onset, the results suggest that most familial cases of endometrial cancer are unrelated to HPNCC. It is also possible that conditions such as chronic estrogen stimulation may act in concert with HNPCC. For any non-HNPCC endometrial cancer, there would be a number of underlying mechanisms. Many of the medical and physiological conditions, given as risk factors of endometrial cancer in the Introduction, have both genetic and environmental bases, and thus could explain a familial aggregation. In a previous study, the familial aggregation of endometrial cancer was only found in women not using exogenous estrogens, whereas diabetes and hypertension had no effect (17). Although the proportion of HNPCC in familial endometrial cancer can be defined with a reasonable accuracy, the remaining factors are likely to be a complex interplay of environmental and genetic influence.

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

Supported by The Swedish Council for Planning and Co-ordination of Research, The Cancer Fund, and The King Gustaf V’s Jubileefund.

                
3

The abbreviations used are: ICD-7, 7th revision of the International Classification of Diseases; FRR, familial relative risk; SIR, standardized incidence ratio; HNPCC, hereditary nonpolyposis colorectal carcinoma.

Fig. 1.

Age-specific incidence rates of endometrial cancer shown in all daughters and in familial cases, in which the mother also has endometrial cancer. FRRs are given on the right Y-axis. The number of cases for the familial cancers were as follows: 2 (95% CI, 1.3–39.6) for ages 25–29, 2 (0.6–18.7) for ages 30–34, 7 (2.1–10.8) for ages 35–39, 9 (1.4–4.4) for ages 40–44, 16 (1.6–4.4) for ages 45–49, 26 (2.1–4.7) for ages 50–54, and 14 (1.4–4.3) for ages 55–61.

Fig. 1.

Age-specific incidence rates of endometrial cancer shown in all daughters and in familial cases, in which the mother also has endometrial cancer. FRRs are given on the right Y-axis. The number of cases for the familial cancers were as follows: 2 (95% CI, 1.3–39.6) for ages 25–29, 2 (0.6–18.7) for ages 30–34, 7 (2.1–10.8) for ages 35–39, 9 (1.4–4.4) for ages 40–44, 16 (1.6–4.4) for ages 45–49, 26 (2.1–4.7) for ages 50–54, and 14 (1.4–4.3) for ages 55–61.

Close modal
Table 1

Age-specific FRR for endometrial cancer in daughters

Maternal age at diagnosis (yr)Daughter’s ageat diagnosis (yr)Totala
<50≥50
No.FRR95% CINo.FRR95% CINo.FRR95% CI
<50 9.6 4.13–17.55 2.7 0.26–7.92 10 5.7 1.91 –12.02 
≥50 28 3.2 2.16–4.58 38 2.9 2.10–3.99 66 3.0 2.13–4.24 
Total 36 3.8 2.34–5.72 40 2.9 2.00–4.20 76 3.3 2.14–4.85 
Maternal age at diagnosis (yr)Daughter’s ageat diagnosis (yr)Totala
<50≥50
No.FRR95% CINo.FRR95% CINo.FRR95% CI
<50 9.6 4.13–17.55 2.7 0.26–7.92 10 5.7 1.91 –12.02 
≥50 28 3.2 2.16–4.58 38 2.9 2.10–3.99 66 3.0 2.13–4.24 
Total 36 3.8 2.34–5.72 40 2.9 2.00–4.20 76 3.3 2.14–4.85 
a

FRR based on age-adjusted rate, daughters whose mother without endometrial cancer are the reference group.

Table 2

SIR for endometrial cancer in daughters by maternal cancers and in mothers by daughters’ cancers

CancersiteEndometrial cancer indaughtersEndometrial cancer in mothers
OESIR95% CIOESIR95% CI
No cancer 1395    12491    
Stomach 25 20.1 1.2 0.81–1.78 6.0 1.0 0.36–1.98 
Small intestine 2.1 1.9 0.50–4.23 1.7 1.1 0.11–3.35 
Colon 57 39.5 1.4a 1.09–1.84a 38 22.6 1.6a 1.19–2.26a 
Rectum 23 18.0 1.2 0.81–1.85 16 12.0 1.3 0.76–2.07 
Liver 19 19.4 0.9 0.59–1.47 4.1 0.7 0.14–1.78 
Pancreas 16 16.3 0.9 0.56–1.52 3.1 0.6 0.06–1.83 
Lung 19 17.0 1.1 0.67–1.68 21 15.2 1.3 0.85–2.03 
Breast 109 97.9 1.1 0.91–1.33 260 236.8 1.1 0.97–1.24 
Cervix 21 20.9 1.0 0.62–1.48 58 53.2 1.0 0.83–1.39 
Endometrial 76 23.8 3.1a 2.51 –3.95a 76 27.4 2.7a 2.19 –3.44a 
Ovary 32 23.3 1.3 0.94–1.89 49 41.1 1.1 0.88–1.55 
Other female genitals 4.9 1.2 0.44–2.41 3.9 1.0 0.26 –2.26 
Kidney 17 15.4 1.1 0.64 –1.69 9.0 0.8 0.38–1.61 
Urinary bladder 12 11.0 1.0 0.56–1.80 8.0 1.0 0.43 –1.81 
Melanoma 15 9.1 1.6 0.92 –2.59 56 55.7 1.0 0.76–1.29 
Skin 20 13.4 1.4 0.91–2.22 8.2 0.4 0.13 –1.08 
Nervous system 16 13.7 1.1 0.67 –1.81 48 39.3 1.2 0.90–1.59 
Thyroid glands 10 5.1 1.9 0.94–3.37 26 20.8 1.2 0.82 –1.78 
Endocrine gland 14 10.9 1.2 0.70 –2.04 21 23.5 0.8 0.55–1.32 
Connective tissue 3.0 0.6 0.06 –1.90 7.1 0.9 0.39 –1.86 
Lymphoma 14.3 0.4 0.15 –0.82 21 23.4 0.9 0.55–1.32 
Leukemia 10 12.3 0.8 0.39 –1.39 16 15.7 1.0 0.58–1.58 
Total of above sites 529 411.4 1.2a 1.18 –1.40a 750 637.7 1.1a 1.07 –1.23a 
CancersiteEndometrial cancer indaughtersEndometrial cancer in mothers
OESIR95% CIOESIR95% CI
No cancer 1395    12491    
Stomach 25 20.1 1.2 0.81–1.78 6.0 1.0 0.36–1.98 
Small intestine 2.1 1.9 0.50–4.23 1.7 1.1 0.11–3.35 
Colon 57 39.5 1.4a 1.09–1.84a 38 22.6 1.6a 1.19–2.26a 
Rectum 23 18.0 1.2 0.81–1.85 16 12.0 1.3 0.76–2.07 
Liver 19 19.4 0.9 0.59–1.47 4.1 0.7 0.14–1.78 
Pancreas 16 16.3 0.9 0.56–1.52 3.1 0.6 0.06–1.83 
Lung 19 17.0 1.1 0.67–1.68 21 15.2 1.3 0.85–2.03 
Breast 109 97.9 1.1 0.91–1.33 260 236.8 1.1 0.97–1.24 
Cervix 21 20.9 1.0 0.62–1.48 58 53.2 1.0 0.83–1.39 
Endometrial 76 23.8 3.1a 2.51 –3.95a 76 27.4 2.7a 2.19 –3.44a 
Ovary 32 23.3 1.3 0.94–1.89 49 41.1 1.1 0.88–1.55 
Other female genitals 4.9 1.2 0.44–2.41 3.9 1.0 0.26 –2.26 
Kidney 17 15.4 1.1 0.64 –1.69 9.0 0.8 0.38–1.61 
Urinary bladder 12 11.0 1.0 0.56–1.80 8.0 1.0 0.43 –1.81 
Melanoma 15 9.1 1.6 0.92 –2.59 56 55.7 1.0 0.76–1.29 
Skin 20 13.4 1.4 0.91–2.22 8.2 0.4 0.13 –1.08 
Nervous system 16 13.7 1.1 0.67 –1.81 48 39.3 1.2 0.90–1.59 
Thyroid glands 10 5.1 1.9 0.94–3.37 26 20.8 1.2 0.82 –1.78 
Endocrine gland 14 10.9 1.2 0.70 –2.04 21 23.5 0.8 0.55–1.32 
Connective tissue 3.0 0.6 0.06 –1.90 7.1 0.9 0.39 –1.86 
Lymphoma 14.3 0.4 0.15 –0.82 21 23.4 0.9 0.55–1.32 
Leukemia 10 12.3 0.8 0.39 –1.39 16 15.7 1.0 0.58–1.58 
Total of above sites 529 411.4 1.2a 1.18 –1.40a 750 637.7 1.1a 1.07 –1.23a 

O, observed; E, expected.

a

SIR 95% CI did not include 1.00.

Table 3

SIR for cancer in offspring by maternal endometrial cancer and age at diagnosis

Offspring’s cancer siteIn daughters by maternal age at diagnosis of endometrial cancerIn sons by maternal age at diagnosis of endometrial cancer
<50≥50<50≥50
OESIR95% CIOESIR95% CIOESIR95% CIOESIR95% CI
No cancer 2031    15033    2139    15901    
Stomach 0.4 2.3 0.00–9.07 5.2 0.9 0.30–1.97 0.5 2.1 0.00–8.41 6.2 1.2 0.55–2.35 
Smallintestine     1.4 1.3 0.13–3.97     2.3 1.7 0.46–3.93 
Colon 1.7 3.5a 1.28–6.98a 32 20.0 1.6a 1.10–2.21a 1.3 5.5a 2.20–10.43a 33 16.1 2.0a 1.41–2.81a 
Rectum 0.6 1.5 0.00–6.17 15 8.9 1.6 0.95–2.66 0.7 6.1a 1.59–13.55a 12 9.6 1.2 0.64–2.06 
Liver     3.7 0.8 0.15–2.00 0.3 3.3 0.00–13.02 3.6 1.1 0.29–2.49 
Pancreas     2.9 0.7 0.07–2.00 0.3 11.2a 2.12–27.54a 11 3.7 2.9a 1.48–5.00a 
Lung 1.0 2.8 0.54–7.04 18 14.0 1.2 0.76–1.95 1.0 1.9 0.19–5.66 14 13.8 1.0 0.55–1.61 
Kidney     7.9 1.1 0.52–2.00     10 12.2 0.8 0.39–1.40 
Urinary bladder     7.0 1.1 0.49–2.08     22 19.0 1.1 0.72–1.69 
Melanoma 4.6 1.7 0.75–3.17 49 51.5 0.9 0.70–1.24 3.2 0.9 0.18–2.33 37 38.3 0.9 0.68–1.30 
Skin     7.2 0.5 0.14–1.23     15 10.4 1.4 0.80–2.26 
Nervous system 10 3.8 2.6a 1.26–4.55a 39 36.4 1.0 0.76–1.43 3.9 1.2 0.40–2.66 45 36.3 1.2 0.90–1.63 
Thyroid glands 1.8 2.2 0.57–4.91 22 18.8 1.1 0.73–1.71     5.9 1.0 0.37–1.99 
Endocrine gland 1.8 1.6 0.32–4.14 18 20.9 0.8 0.51–1.30     17 13.6 1.2 0.73–1.92 
Connective tissue     6.4 1.1 0.44–2.07     6.6 1.3 0.62–2.41 
Lymphoma 2.1 1.4 0.27–3.51 18 21.5 0.8 0.50–1.27 3.4 0.8 0.17–2.19 33 34.4 0.9 0.66–1.32 
Leukemia 1.8 0.5 0.00–2.24 15 14.2 1.0 0.59–1.66 2.3 2.2 0.69–4.54 15 19.2 0.7 0.44–1.23 
Breast 27 16.0 1.6a 1.11–2.38a 249 214.8 1.1a 1.02–1.31a         
Cervix 4.4 1.5 0.63–2.97 51 47.8 1.0 0.79–1.38         
Endometrial 10 1.5 6.8a 3.27–11.76a 66 22.4 2.9a 2.28–3.70a         
Ovary 3.0 2.9a 1.35–5.25a 41 35.6 1.1 0.82–1.53         
Other female genitals 0.3 3.4 0.00–13.66 3.5 0.8 0.16–2.10         
Prostate             17 12.3 1.3 0.81–2.12 
Testis         3.4 0.5 0.06–1.70 30 32.6 0.9 0.62–1.28 
Other male genital             2.1 1.4 0.27 –3.45 
Total of above sites 94 45 2.1a 1.70–2.55a 676 572.0 1.1a 1.09–1.27a 36 20.0 1.8a 1.26–2.43a 345 298.1 1.1a 1.04–1.28a 
Offspring’s cancer siteIn daughters by maternal age at diagnosis of endometrial cancerIn sons by maternal age at diagnosis of endometrial cancer
<50≥50<50≥50
OESIR95% CIOESIR95% CIOESIR95% CIOESIR95% CI
No cancer 2031    15033    2139    15901    
Stomach 0.4 2.3 0.00–9.07 5.2 0.9 0.30–1.97 0.5 2.1 0.00–8.41 6.2 1.2 0.55–2.35 
Smallintestine     1.4 1.3 0.13–3.97     2.3 1.7 0.46–3.93 
Colon 1.7 3.5a 1.28–6.98a 32 20.0 1.6a 1.10–2.21a 1.3 5.5a 2.20–10.43a 33 16.1 2.0a 1.41–2.81a 
Rectum 0.6 1.5 0.00–6.17 15 8.9 1.6 0.95–2.66 0.7 6.1a 1.59–13.55a 12 9.6 1.2 0.64–2.06 
Liver     3.7 0.8 0.15–2.00 0.3 3.3 0.00–13.02 3.6 1.1 0.29–2.49 
Pancreas     2.9 0.7 0.07–2.00 0.3 11.2a 2.12–27.54a 11 3.7 2.9a 1.48–5.00a 
Lung 1.0 2.8 0.54–7.04 18 14.0 1.2 0.76–1.95 1.0 1.9 0.19–5.66 14 13.8 1.0 0.55–1.61 
Kidney     7.9 1.1 0.52–2.00     10 12.2 0.8 0.39–1.40 
Urinary bladder     7.0 1.1 0.49–2.08     22 19.0 1.1 0.72–1.69 
Melanoma 4.6 1.7 0.75–3.17 49 51.5 0.9 0.70–1.24 3.2 0.9 0.18–2.33 37 38.3 0.9 0.68–1.30 
Skin     7.2 0.5 0.14–1.23     15 10.4 1.4 0.80–2.26 
Nervous system 10 3.8 2.6a 1.26–4.55a 39 36.4 1.0 0.76–1.43 3.9 1.2 0.40–2.66 45 36.3 1.2 0.90–1.63 
Thyroid glands 1.8 2.2 0.57–4.91 22 18.8 1.1 0.73–1.71     5.9 1.0 0.37–1.99 
Endocrine gland 1.8 1.6 0.32–4.14 18 20.9 0.8 0.51–1.30     17 13.6 1.2 0.73–1.92 
Connective tissue     6.4 1.1 0.44–2.07     6.6 1.3 0.62–2.41 
Lymphoma 2.1 1.4 0.27–3.51 18 21.5 0.8 0.50–1.27 3.4 0.8 0.17–2.19 33 34.4 0.9 0.66–1.32 
Leukemia 1.8 0.5 0.00–2.24 15 14.2 1.0 0.59–1.66 2.3 2.2 0.69–4.54 15 19.2 0.7 0.44–1.23 
Breast 27 16.0 1.6a 1.11–2.38a 249 214.8 1.1a 1.02–1.31a         
Cervix 4.4 1.5 0.63–2.97 51 47.8 1.0 0.79–1.38         
Endometrial 10 1.5 6.8a 3.27–11.76a 66 22.4 2.9a 2.28–3.70a         
Ovary 3.0 2.9a 1.35–5.25a 41 35.6 1.1 0.82–1.53         
Other female genitals 0.3 3.4 0.00–13.66 3.5 0.8 0.16–2.10         
Prostate             17 12.3 1.3 0.81–2.12 
Testis         3.4 0.5 0.06–1.70 30 32.6 0.9 0.62–1.28 
Other male genital             2.1 1.4 0.27 –3.45 
Total of above sites 94 45 2.1a 1.70–2.55a 676 572.0 1.1a 1.09–1.27a 36 20.0 1.8a 1.26–2.43a 345 298.1 1.1a 1.04–1.28a 
a

SIR 95% CI did not include 1.00.

Table 4

SIR for second cancer in females with endometrial cancer by follow-up intervals

Cancer site in femalesFollow-up interval (yr) since endometrial cancerTotal
<11–910–38
OESIR95% CIOESIR95% CIOESIR95% CIOESIR95% CI
No cancer 1414    7577    6224    15215    
Stomach 4.1 0.2 0.00–0.96 24 26.9 0.8 0.57–1.28 26 26.4 0.9 0.64–1.40 51 57.4 0.8 0.66 –1.15 
Small intestine 0.6 8.2a 2.59–16.96a 4.1 1.7 0.68–3.21 4.0 0.7 0.14 –1.83 15 8.7 1.7 0.96–2.70 
Colon 16 10.6 1.5 0.86–2.35 113 70.8 1.6a 1.32 –1.91a 139 74.5 1.8a 1.57 –2.19a 268 155.8 1.7a 1.52 –1.93a 
Rectum 11 5.1 2.1a 1.08 –3.64a 55 33.8 1.6a 1.23 –2.09a 61 33.8 1.8a 1.38 –2.29a 127 72.6 1.7a 1.46 –2.07a 
Liver 4.6 1.0 0.34 –2.23 18 31.3 0.5 0.34 –0.87 41 32.4 1.2 0.91 –1.68 64 68.3 0.9 0.72 –1.18 
Pancreas 4.1 0.7 0.14 –1.81 22 27.6 0.8 0.50 –1.17 37 28.6 1.2 0.91 –1.74 62 60.2 1.0 0.79 –1.30 
Lung 6.3 0.4 0.09 –1.16 44 42.7 1.0 0.75 –1.36 44 39.4 1.1 0.81 –1.47 91 88.4 1.0 0.83 –1.25 
Breast 46 34.8 1.3 0.97 –1.73 269 219.5 1.2a 1.08 –1.38a 190 178.8 1.0 0.92 –1.22 505 433.1 1.1a 1.07 –1.27a 
Cervix 12 4.0 2.9a 1.53 –4.90a 22.9 0.1 0.02 –0.32 14.6 0.1 0.01 –0.39 17 41.4 0.4 0.24 –0.63 
Ovary 169 7.5 22.5a 19.32 –26.13a 29 47.6 0.6 0.41 –0.85 36.2 0.1 0.08 –0.36 205 91.3 2.2a 1.95 –2.56a 
Other female genitals 1.2 1.6 0.16–4.82 7.8 1.1 0.52 –2.02 19 8.2 2.3a 1.39 –3.46a 30 17.3 1.7a 1.17 –2.42a 
Kidney 4.0 2.0 0.86 –3.66 34 26.5 1.2 0.89 –1.75 36 24.3 1.4a 1.04 –2.00a 78 54.8 1.4a 1.13 –1.76a 
Urinary bladder 3.2 1.2 0.33 –2.78 35 21.6 1.6a 1.13 –2.20a 52 22.3 2.3a 1.74 –3.00a 91 47.2 1.9a 1.55 –2.35a 
Melanoma     25 22.5 1.1 0.72 –1.59 28 18.9 1.4 0.98 –2.08 53 44.9 1.1 0.88 –1.52 
Skin 3.4 0.5 0.06 –1.70 29 21.8 1.3 0.89 –1.86 39 26.9 1.4a 1.03 –1.94a 70 52.1 1.3a 1.05 –1.68a 
Nervous system 4.3 0.7 0.13 –1.73 28 27.3 1.0 0.68 –1.44 24 21.7 1.1 0.71 –1.59 55 53.3 1.0 0.78 –1.32 
Thyroid     12 8.6 1.4 0.72 –2.30 6.7 0.7 0.24 –1.55 17 16.7 1.0 0.59 –1.56 
Endocrine glands 3.7 0.2 0.00 –1.06 26 24.7 1.0 0.69 –1.50 31 22.0 1.4 0.96 –1.95 58 50.4 1.1 0.87 –1.47 
Connective tissue 0.8 1.1 0.00 –4.67 14 5.4 2.5a 1.41 –4.11a 5.0 1.6 0.68 –2.90 23 11.3 2.0a 1.29 –2.96a 
Lymphoma 4.1 1.2 0.39 –2.55 29 27.0 1.0 0.72–1.50 30 27.0 1.1 0.75 –1.54 64 58.1 1.1 0.85 –1.39 
Leukemia 3.2 1.5 0.50 –3.26 29 21.0 1.3 0.93 –1.93 22 20.7 1.0 0.67 –1.55 56 44.8 1.2 0.94 –1.60 
Total of above cancers 302 114.4 2.6a 2.35 –2.95a 854 741.2 1.1a 1.08 –1.23a 844 672.4 1.2a 1.17 –1.34a 2000 1527.9 1.3a 1.25 –1.37a 
Cancer site in femalesFollow-up interval (yr) since endometrial cancerTotal
<11–910–38
OESIR95% CIOESIR95% CIOESIR95% CIOESIR95% CI
No cancer 1414    7577    6224    15215    
Stomach 4.1 0.2 0.00–0.96 24 26.9 0.8 0.57–1.28 26 26.4 0.9 0.64–1.40 51 57.4 0.8 0.66 –1.15 
Small intestine 0.6 8.2a 2.59–16.96a 4.1 1.7 0.68–3.21 4.0 0.7 0.14 –1.83 15 8.7 1.7 0.96–2.70 
Colon 16 10.6 1.5 0.86–2.35 113 70.8 1.6a 1.32 –1.91a 139 74.5 1.8a 1.57 –2.19a 268 155.8 1.7a 1.52 –1.93a 
Rectum 11 5.1 2.1a 1.08 –3.64a 55 33.8 1.6a 1.23 –2.09a 61 33.8 1.8a 1.38 –2.29a 127 72.6 1.7a 1.46 –2.07a 
Liver 4.6 1.0 0.34 –2.23 18 31.3 0.5 0.34 –0.87 41 32.4 1.2 0.91 –1.68 64 68.3 0.9 0.72 –1.18 
Pancreas 4.1 0.7 0.14 –1.81 22 27.6 0.8 0.50 –1.17 37 28.6 1.2 0.91 –1.74 62 60.2 1.0 0.79 –1.30 
Lung 6.3 0.4 0.09 –1.16 44 42.7 1.0 0.75 –1.36 44 39.4 1.1 0.81 –1.47 91 88.4 1.0 0.83 –1.25 
Breast 46 34.8 1.3 0.97 –1.73 269 219.5 1.2a 1.08 –1.38a 190 178.8 1.0 0.92 –1.22 505 433.1 1.1a 1.07 –1.27a 
Cervix 12 4.0 2.9a 1.53 –4.90a 22.9 0.1 0.02 –0.32 14.6 0.1 0.01 –0.39 17 41.4 0.4 0.24 –0.63 
Ovary 169 7.5 22.5a 19.32 –26.13a 29 47.6 0.6 0.41 –0.85 36.2 0.1 0.08 –0.36 205 91.3 2.2a 1.95 –2.56a 
Other female genitals 1.2 1.6 0.16–4.82 7.8 1.1 0.52 –2.02 19 8.2 2.3a 1.39 –3.46a 30 17.3 1.7a 1.17 –2.42a 
Kidney 4.0 2.0 0.86 –3.66 34 26.5 1.2 0.89 –1.75 36 24.3 1.4a 1.04 –2.00a 78 54.8 1.4a 1.13 –1.76a 
Urinary bladder 3.2 1.2 0.33 –2.78 35 21.6 1.6a 1.13 –2.20a 52 22.3 2.3a 1.74 –3.00a 91 47.2 1.9a 1.55 –2.35a 
Melanoma     25 22.5 1.1 0.72 –1.59 28 18.9 1.4 0.98 –2.08 53 44.9 1.1 0.88 –1.52 
Skin 3.4 0.5 0.06 –1.70 29 21.8 1.3 0.89 –1.86 39 26.9 1.4a 1.03 –1.94a 70 52.1 1.3a 1.05 –1.68a 
Nervous system 4.3 0.7 0.13 –1.73 28 27.3 1.0 0.68 –1.44 24 21.7 1.1 0.71 –1.59 55 53.3 1.0 0.78 –1.32 
Thyroid     12 8.6 1.4 0.72 –2.30 6.7 0.7 0.24 –1.55 17 16.7 1.0 0.59 –1.56 
Endocrine glands 3.7 0.2 0.00 –1.06 26 24.7 1.0 0.69 –1.50 31 22.0 1.4 0.96 –1.95 58 50.4 1.1 0.87 –1.47 
Connective tissue 0.8 1.1 0.00 –4.67 14 5.4 2.5a 1.41 –4.11a 5.0 1.6 0.68 –2.90 23 11.3 2.0a 1.29 –2.96a 
Lymphoma 4.1 1.2 0.39 –2.55 29 27.0 1.0 0.72–1.50 30 27.0 1.1 0.75 –1.54 64 58.1 1.1 0.85 –1.39 
Leukemia 3.2 1.5 0.50 –3.26 29 21.0 1.3 0.93 –1.93 22 20.7 1.0 0.67 –1.55 56 44.8 1.2 0.94 –1.60 
Total of above cancers 302 114.4 2.6a 2.35 –2.95a 854 741.2 1.1a 1.08 –1.23a 844 672.4 1.2a 1.17 –1.34a 2000 1527.9 1.3a 1.25 –1.37a 
a

SIR 95% CI did not include 1.00.

Table 5

SIR for endometrial cancer in daughters and mothers by colorectal and endometrial cancers in family

Family member with endometrial cancerFamily member with colorectal cancerSIR for endometrial cancerOESIR95% CI for SIRMedian age at diagnosisQuantities
2.5%97.5%
Nonea None In daughters 1,684    51 34 59 
None Mother  77 56.3 1.3 1.08 –1.69 51 35 59 
None Father  90 57.3 1.5 1.26 –1.91 49 31 58 
None Sister  39 10.0 3.9 2.77 –5.22 50 31 61 
None Brother  3.1 2.8 1.30 –5.04 48 31 58 
Mother None  63 21.2 2.9 2.29 –3.76 51 31 60 
Mother Mother  0.8 6.0 1.90 –12.49 44 39 44 
Mother Father  0.7 5.4 1.41 –12.03 39 26 48 
Mother Sister  0.2 31.4 11.30 –61.55 47 30 53 
Mother Brother  0.1 18.9 0.01 –74.34 44 44 44 
None None In mothers 16,929    61 43 82 
None Daughter  50 35.7 1.4 1.04 –1.81 61 44 79 
None Son  49 32.5 1.5 1.12 –1.96 58 40 77 
None Husband  482 504.0 0.9 0.87 –1.04 63 45 83 
Daughterb None  63 24.5 2.5 1.97 –3.24 58 43 86 
Daughter Daughter  0.6 10.9 3.92 –21.37 52 43 65 
Daughter Son  0.2 6.4 0.00 –25.35 52 52 52 
Daughter Husband  1.4 2.8 0.74 –6.36 68 43 76 
Family member with endometrial cancerFamily member with colorectal cancerSIR for endometrial cancerOESIR95% CI for SIRMedian age at diagnosisQuantities
2.5%97.5%
Nonea None In daughters 1,684    51 34 59 
None Mother  77 56.3 1.3 1.08 –1.69 51 35 59 
None Father  90 57.3 1.5 1.26 –1.91 49 31 58 
None Sister  39 10.0 3.9 2.77 –5.22 50 31 61 
None Brother  3.1 2.8 1.30 –5.04 48 31 58 
Mother None  63 21.2 2.9 2.29 –3.76 51 31 60 
Mother Mother  0.8 6.0 1.90 –12.49 44 39 44 
Mother Father  0.7 5.4 1.41 –12.03 39 26 48 
Mother Sister  0.2 31.4 11.30 –61.55 47 30 53 
Mother Brother  0.1 18.9 0.01 –74.34 44 44 44 
None None In mothers 16,929    61 43 82 
None Daughter  50 35.7 1.4 1.04 –1.81 61 44 79 
None Son  49 32.5 1.5 1.12 –1.96 58 40 77 
None Husband  482 504.0 0.9 0.87 –1.04 63 45 83 
Daughterb None  63 24.5 2.5 1.97 –3.24 58 43 86 
Daughter Daughter  0.6 10.9 3.92 –21.37 52 43 65 
Daughter Son  0.2 6.4 0.00 –25.35 52 52 52 
Daughter Husband  1.4 2.8 0.74 –6.36 68 43 76 
a

Note that the categories are not mutually exclusive.

b

Not including five mothers who had both endometrial and colorectal cancer.

1
Centre for Epidemiology. Cancer Incidence in Sweden 1996 The National Board of Health and Welfare Stockholm  
1998
.
2
Hedrick L. Endometrial cancer Vogelstein B. Kinzler K. eds. .
The Genetic Basis of Human Cancer
,
:
621
-629, McGraw-Hill New York  
1998
.
3
Burke T., Eifel P., Muggia F. Cancer of the uterine body DeVita V. Hellman S. Rosenberg S. eds. .
Cancer: Principles and Practice of Oncology
,
:
1478
-1499, Lippincott-Raven Philadelphia  
1997
.
4
IARC. Some pharmaceutical drugs. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 66, pp. 260–280. Lyon, France: IARC, 1996.
5
Kumar V., Cotran R., Robbins S. .
Basic Pathology
,
607
-612, W. B. Saunders Philadelphia  
1997
.
6
Shoff S., Newcomb P. Diabetes, body size, and risk of endometrial cancer.
Am. J. Epidemiol.
,
148
:
234
-40,  
1998
.
7
Olson S., Vena L., Dorn J., Marshall J., Zielezny M., Laughlin R., Graham S. Excercise, occupational activity, and risk of endometrial cancer.
Ann. Epidemiol.
,
1997
:
46
-53,  
1997
.
8
Moradi T., Nyren O., Bergström R., Gridley G., Linet M., Wolk A., Dosemeci M., Adami H-O. Risk for endometrial cancer in relation to occupational physical activity: a nationwide cohort study in Sweden.
Int. J. Cancer
,
76
:
665
-670,  
1998
.
9
World Cancer Research Fund. Food, Nutrition and the Prevention of Cancer: A Global Perspective American Institute for Cancer Research Washington DC  
1997
.
10
Lynch H., Smyrk T. Hereditary nonpolyposis colorectal cancer (Lynch syndrome).
Cancer (Phila.)
,
78
:
1149
-1167,  
1996
.
11
Aaltonen L., Salovaara R., Kristo P., Canzzian F., Hemminki A., Peltomäki P., Chadwick R., Kääriäinen H., Eskelinen M., Järvinen H., Mecklin J-P., De La Chapelle A. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease.
N. Engl. J. Med.
,
338
:
14811
-14817,  
1998
.
12
Aarnio M., Mecklin J-P., Aaltonen L., Nyström-Lahti M., Järvinen H. Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome.
Int. J. Cancer
,
64
:
430
-3,  
1995
.
13
Boland C. Hereditary nonpolyposis colorectal cancer Vogelstein B. Kinzler K. eds. .
The Genetic Basis of Human Cancer
,
:
333
-46, McGraw-Hill New York  
1998
.
14
Aarnio M., Sankila R., Pukkala E., Salovaara R., Aaltonen L., De La Chapelle A., Peltomäki P., Mecklin J-P., Järvinen H. Cancer risk in mutation carriers of DNA-mismatch-repair genes.
Int. J. Cancer
,
81
:
214
-8,  
1999
.
15
Pal T., Flanders T., Mitchell-Lehman M., MacMillan A., Brunet J., Narod S., Foulkes W. Genetic implications of double primary cancers of the colorectum and endometrium.
J. Med. Genet.
,
35
:
978
-984,  
1998
.
16
Risinger J., Haayes A., Berchuck A., Barrett J. PTEN/MMAC1 Mutations in endometrial cancer.
Cancer Res.
,
57
:
4736
-4738,  
1997
.
17
Gruber S., Thompson W., the Cancer and Steroid Hormone Study Group A population-based study of endometrial cancer and familial risk in younger women.
Cancer Epidemiol. Biomarkers Prev.
,
5
:
411
-417,  
1996
.
18
Fornasarig M., Campagnutta E., Talamini R., Franceschi S., Boz G., Scarabelli C., Andreaus C. M., Scozzari G., Valentini M. Risk factors for endometrial cancer according to familial susceptibility.
Int. J. Cancer
,
77
:
29
-32,  
1998
.
19
Hemminki K., Vaittinen P. Familial breast cancer in the Family-Cancer Database.
Int. J. Cancer
,
77
:
386
-391,  
1998
.
20
Hemminki K., Vaittinen P., Kyyrönen P. Age-specific familial risks in common cancers of the offspring.
Int. J. Cancer
,
78
:
172
-5,  
1998
.
21
Hemminki K., Vaittinen P. Familial cancers in a nation-wide family-cancer database: age distribution and prevalence.
Eur. J. Cancer
,
35
:
1109
-1117,  
1999
.
22
Vaittinen P., Hemminki K. Familial cancer risks in offspring from discordant parental cancers.
Int. J. Cancer
,
81
:
12
-19,  
1999
.
23
Hemminki K., Vaittinen P. Familial risks in in situ cancers from the Family-Cancer Database.
Cancer Epidemiol. Biomarkers Prev.
,
7
:
865
-868,  
1998
.
24
Hemminki K., Vaittinen P. National database of familial cancer in Sweden.
Genet. Epidemiol.
,
15
:
225
-236,  
1998
.
25
Esteve, J., Benhamou, E., Raymond, L. Statistical Methods in Cancer Research. IARC Scientific Publication. Lyon, France: IARC, 1994.
26
Parazzini F., La Vecchia C., Moroni S., Chatenoud L., Ricci E. Family history and the risk of endometrial cancer.
Int. J. Cancer
,
59
:
460
-462,  
1994
.
27
Nelson C. L., Sellers T. A., Rich S. S., Potter J. D., McGovern P. G., Kushi L. H. Familial clustering of colon, breast, uterine, and ovarian cancers as assessed by family history.
Genet. Epidemiol.
,
10
:
235
-244,  
1993
.
28
Hemminki K., Vaittinen P. Familial risks in second primary breast cancer based on the Family-Cancer Database.
Eur. J. Cancer
,
35
:
455
-458,  
1999
.
29
Bergfeldt K., Einhorn S., Rosendahl I., Hall P. Increased risk of second primary malignancies in patients with gynecological cancer.
Acta Oncol.
,
34
:
771
-777,  
1995
.
30
Vasen H., Mecklin J-P., Meera Khan P., Lynch H. The international collaborative group on hereditary non-polyposis colorectal cancer (ICG-HNPCC).
Dis. Colon Rectum
,
34
:
424
-425,  
1991
.