Worldwide variations in sex ratio of cancer incidence : temporal and geographic patterns

Context: International comparisons of cancer incidence rates are important sources of evidence for generating hypotheses about cancer etiology. The estimates of geographic variation in cancer incidence can be compromised by artifacts such as imperfect accuracy and completeness of available cancer incidence data among several others. The artifacts associated with incidence rates, can be potentially misleading when interpreting and comparing trends across cancer registries. The Sex Ratio (defined as the male-to-female cancer incidence rate) is one measure that can be less susceptible to ambiguity of interpretations by these artifacts, provided that the ascertainment of cancer cases is similar in males and females.  Objectives: Hence, the main aim of this study is to infer as to potential causes that drive sex ratio variability (i.e., the ratio of male to female incidence rates), of type specific cancers across time and geography, generating hypotheses. The secondary aim is to explore the extent to which country-level gender inequalities can provide clues on quality of cancer registries for selected cancer types through sex ratios. Methods: Cancer Incidence in Five Continents (CI-5), a database of population-based cancer registries obtained from International Agency for Research on Cancer (IARC), was used to access incidence data on 30 different cancers in 3 time-periods (i.e., 1974-77; 1988-92 and 2003-07) from 77, 142 and 281 cancer registries. Descriptive methods were used with recourse to mixed-effect regression methods for studying temporal trends and geographic variations in sex ratios. To explore gender bias, sex ratios for cancers of lung, bladder, esophagus, and larynx were tallied with two statistics namely UN’s Gender Inequality Index and WHO’s global tobacco prevalence estimates. Results: In the mixed-effect regression analysis using equal number of 76 long-standing cancer registries in each year from 1983 to 2007, and after adjusting for geographic variation in sex ratio, lung cancer had the highest sex ratio on average in the baseline year (i.e.,  9.9), followed by esophagus (7.8), bladder (5.1), liver (3.8), pancreas (2.1), kidney (1.9) leukemia (1.8), non-Hodgkin’s lymphoma (1.8), brain (1.6), rectum and anus (1.5), colon (1.2), eye (1.2), melanoma of skin (0.9), gallbladder (0.6), and thyroid (0.5). In registries belonging to countries, with low gender inequality and similar smoking prevalence in men and women (Sweden, Norway and Denmark), the sex ratio for lung cancer was relatively very low (1.2, 1.3 and 1.6). Whereas Spain with similar prevalence of smoking in men and women, showed an unusually high sex ratio for lung (7.1) as well as for other smoking associated cancers (bladder: 14.9; esophagus: 10.7; and larynx: 28.2). The results of our study also highlight several cancer types, in particular, kidney for which acknowledged and well-known risk factors are unlikely to fully explain the consistently stable male-female ratio of almost 2:1 across time and regions. Conclusions: The well-established risk factors in literature whose prevalence varies worldwide in both sexes, does not seem to decipher the curiously stable sex ratios in cancer of kidney maintained over three decades. This observation has made us to tentatively hypothesize that some endogenous factor such as a gene or gene variant might be able to explain the stable sex ratio of this cancer. Another cancer type, multiple myeloma is also consistently stable across time and place, and where the role of vitamin D has previously been postulated. The study points towards gaps in our understanding of causes of cancer risk in populations.

Keyphrases: Cancer, Mixed effect models, Registries, Incidence, Sex Ratios, Worldwide, Spatial autocorrelations