Gender effects in familial cancer

In their paper on gender effects in familial cancer, Hemminki and Li1 reported that, among 15 cancer sites considered, only thyroid cancer showed a significant difference in the relative risk (RR) for concordant cancer by gender. Based on the nation-wide Swedish Family-Cancer Database, which included 10.2 million individuals and over 1 million cancers, the RR of thyroid cancer was 16.4 (95% confidence interval [CI] = 11.3–23.8) in the male but 6.6 (95% CI = 4.9–9.0) in the female offspring of thyroid cancer cases. Thus, the ratio observed for male compared to female offspring was 2.48 (95% CI = 1.5–4.0). Notably, women had a 2–3-fold higher thyroid cancer incidence rate compared to men in the general population of Sweden and most other countries.2 Because thyroid cancer is rare among men, the majority of our knowledge on thyroid cancer comes from data on women. In a pooled analysis of 12 case-control studies on thyroid cancer, which includes all ten published studies that have males, there were 2,094 female cases, but only 425 male cases (3,248 female and 928 male controls, respectively3). The only risk factor that appeared to be stronger in males than in females was a personal history of benign thyroid diseases (RR for goitre = 38.3, 95% CI = 5.0–291.2 in men and 5.9; 95% CI = 4.2–8.1 in women; RR for history of benign nodules/adenomas = infinity, 95% CI = 9.2-infinity in men and 29.9, 95% CI = 14.5–62.0 in women). The gender difference in the RRs resulted mainly from the rarity of goiter (1/836) and benign nodules/adenomas (0/531) among male controls. A history of goiter or benign nodules/adenomas was reported, respectively, by 1.8% and 0.3% of female controls.3 The similarity in the gender effect for family history of thyroid cancer and personal history of benign thyroid disease suggests that both factors can be considered markers of increased individual susceptibility to thyroid cancer. Lower RR for markers of individual susceptibility among women than men supports the suggestion4 that the greater risk of cancers of the thyroid in the general female population is chiefly attributable to female-specific environmental risk factors (e.g., female hormones, greater functional demand of iodine and thyroid hormones during reproductive years, etc.2). Conversely, in men, a greater proportion of thyroid cancer may be the result of genetic factors. The genetic bases for the commonest types of thyroid cancer (i.e., non-medullary forms) are not well understood.5 Linkage studies have identified a few genes (MNG1,6 TCO,7 PTC8), but single genes seem to explain only a minority of cases. Non-medullary thyroid cancer is thus likely to be a polygenic disease.9 Although surveillance bias may explain some of the findings related to benign thyroid disease,3 because women tend to undergo general medical examinations more frequently than men, it is unlikely to account for the gender-related difference in the influence of family history of thyroid cancer.1 Also in another cancer site, the breast, where the female excess is even greater than for the thyroid, a marker of individual susceptibility (history of contralateral breast cancer) showed a clear difference between the gender-specific RRs.10 The RR of contralateral breast cancer among men was 29.6 (95% CI = 15.5–52.4) compared to 1.8 (95% CI = 1.7–1.8) among women. In conclusion, the findings from Hemminki and Li1 and our own3 illustrate well the strong influence of non-genetic risk factors on the apparent strength of the RRs for genetic markers. As a consequence of a weaker “dilution effect” from non-genetic risk factors, family history of thyroid cancer and previous occurrence of goitre and benign nodules/adenomas can, however, distinguish high-risk men more accurately than high-risk women. The contribution of the Italian Association for Cancer Research, Milan, Italy is gratefully acknowledged. Yours sincerely, Silvia Franceschi*, Eva Negri , Carlo La Vecchia , * International Agency for Research on Cancer, Lyon, France, Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy, Istituto di Statistica Medica e Biometria, Università degli Studi di Milano, Milan, Italy