Does cancer originate in utero?

Abstract

The purpose of the present thesis was to evaluate Trichopoulos' hypothesis that breast cancer can originate in utero, and to examine the role of antenatal estrogen exposure in the etiology of testicular cancer.

First, we used data from a Swedish-Norwegian cohort study on risk factors for small-for-gestational-age births to identify markers for antenatal estrogen exposure. A total of 1,945 parous women were followed during gestation, and the follow-up included blood samples taken at 17, 25, 33 and 37 weeks of gestation. After delivery, 234 women who delivered at term (>=37 weeks) were selected for estriol analysis. Of these, 188 had been assessed three or more times during gestation. We calculated the cumulative estriol level for each woman and analyzed the associations between pregnancy characteristics, fetal and matemal anthropometrics and the cumulative levels of estriol. We found a strong positive association between birth weight and cumulative estriol. We also found that smoking decreases estriol throughout the duration of gestation with 20 to 30%, whereas matemal age and pregnancy weight gain were not associated with estriol.

Second, we used the obtained markers (birth weight and matemal smoking) in studies on risk factors for breast and testicular cancer. In a population based case-control study on breast cancer among female twins from opposite-sexed twin pairs, we found birth weight strongly associated with breast cancer risk. Compared with women with a birth weight below 2,000 grams, women with a birth weight of more than 3,500 grams had a more than tenfold increase in breast cancer risk.

As a marker for matemal smoking during gestation we used a matemal diagnosis of lung cancer. Through the use of the Swedish Cancer Register and the Swedish Generation Register we identified the offspring of women who had developed lung cancer between 1958 and 1997. We restricted the analysis to lung cancer subtypes with a known association to smoking. Of the 22,158 women who developed lung cancer during the study period, 19,869 were included. Of these, 11, 115 had a total of 23,530 children born after 1941. We found that male offspring of women with lung cancer had an almost twofold increase in testicular cancer risk, but we found no association between matemal lung cancer and risk of breast cancer.

The last study of the thesis was a retrospective cohort study on preterm and small-for-gestational-age birth and subsequent cancer risk. By manually reviewing approximately 250,000 birth records from the period 1925 to 1949 at four major delivery units, we identified 3,361 infants who were born small for gestational age or before the 35th week of gestation. We assessed incident cancer cases in the cohort through the Swedish Cancer Register. We found no increased risk for cancer overall in the cohort, but infants with a birth weight of less than 2,000 grams had an almost fourfold increase in testicular cancer risk. The association was independent of gestational age. Women with a gestational duration of 33 to 34 weeks and a birth weight of 3,000 grams or more had a threefold increase in breast cancer risk, and among women born before 32 weeks, a birth weight of less than 2,000 grams was associated with a relative risk of 1.7.

The association between birth weight and breast cancer suggests the role of antenatal hormonal exposures, but could be due to other factors. The strong association between birth weight and breast cancer among females from opposite-sexed twin pairs, much stronger than previously reported from same-sexed pairs in the same population, is, however, unlikely to be due to anything other than hormonal exposures in utero. Trichopoulos' hypothesis is therefore valid, but hormones other than estrogen must be of importance.

In contradiction to the hypothesis on the role of estrogens in testicular carcinogenesis, we found markers for low estrogen levels during pregnancy being associated with an increased risk for testicular cancer.