The Global Health Observatory of the World Health Organization reported that 13% of all deaths originate from cancer. Colorectal cancer is the third most common cancer in the world, and it is one of the most common causes of cancer mortality in women followed by lung and breast cancer (Ferlay, 2013). Statistics from Korea and Japan indicate that colorectal cancer is the number one cause of cancer morbidity in women 65 years and older (Jung et al., 2012; Matsuda et al., 2014).
Dietary guidelines for cancer prevention represent an essential strategy to lower the burden of cancer. Despite sex- and gender-associated differences in dietary risk factors, few studies take these factors into account.
Gendered Innovation 1: Understanding Sex-Related Differences in Colorectal Cancer Risk
Women have a higher risk then men of developing right-sided (proximal) colon cancer (Pal et al., 2010), which is associated with poor prognosis. A major cohort study involving 17,641 patients compared right-sided colon cancer to left-sided colon cancer for clinical and histological characteristics, progress after the operation, and survival (Benedix et al., 2010). Proximal colon cancer is associated with more aggressive form of neoplasia compared to left-sided (distal) colon cancer (Hansen et al., 2012)—see Figure below. The results revealed worse outcomes for women, especially older women.
A recent cohort study has indicated that the risk of developing proximal large polyps as a proportion of all large polyps is higher in women. African Americans in the U.S. are more likely to develop proximal large polyps compared to whites and Hispanics (Lieberman et al., 2014). Although the effect of tumor location on survival remains uncertain, more information on pathophysiological differences in relation to sex is needed to plan strategies for screening and treatment of colorectal cancer.
Certain genetic and epigenetic differences between women and men may contribute to colorectal cancer risk. Microsatellite instability (MSI)-high, CpG island methylator phenotype (CIMP)-high, and BRAF mutation are often observed in right-sided colon cancer. By contrast, chromosomal instability, which is associated with 60-70% of colon cancer, is more often observed in left-sided colon cancer (Markowitz et al., 2009). Defective genes include APC, K-ras, DCC and p53.
CIMP-high was increased from the rectum to the cecum, with a higher percentage of females developing tumors in the cecum (Bae, J. M. et al., 2013). An earlier study reported that a methylated CpG island in the 5’ region of the p161NK4a tumor suppressor was positively associated with females (Wiencke et al., 1999). Another study showed that the vascular endothelial growth factor (VEGF) 936 polymorphism increased the risk of colon cancer in women only (Bae, S. J. et al., 2008). Also, the PIK3CA mutation occurs more frequently in females and in proximal colon cancer, which is associated with poorer survival (Phipps et al., 2013).
Differences in women and men’s patterns of colon cancer (discussed above) require understanding of sex-related biological factors that affect segment-specific colon tumor formation. Many of these factors can be studied in animal models. Animal studies, however, have preferred male animals. A literature search for experimental CRC studies using rodent models in Pubmed between 2012 and 2014 found 335 studies. Among those, 52% used only male animals, 18% used only female animals, and 30% used both sexes. More studies employing animals of both sexes are needed to investigate the molecular mechanisms of colon cancer development, responses to environmental stresses, and efficacy of treatments—and how these may differ by sex.