Malignant transformation

Colon cancer provides one example of the mechanisms by which diet, the top factor listed in the table, is an external factor in cancer. The Western diet of African Americans in the United States is associated with a yearly colon cancer rate of 65 per 100,000 individuals, while the high fiber/low fat diet of rural Native Africans in South Africa is associated with a yearly colon cancer rate of <5 per 100,000.[4] Feeding the Western diet for two weeks to Native Africans increased their secondary bile acids, including carcinogenic deoxycholic acid,[5] by 400%, and also changed the colonic microbiota.[4] Evidence reviewed by Sun and Kato[6] indicates that differences in human colonic microbiota play an important role in the progression of colon cancer.

A second example, relating a dietary component to a cancer, is illustrated by lung cancer. Two large population-based studies were performed, one in Italy and one in the United States.[7] In Italy, the study population consisted of two cohorts: the first, 1721 individuals diagnosed with lung cancer and no severe disease, and the second, 1918 control individuals with absence of lung cancer history or any advanced diseases. All individuals filled out a food frequency questionnaire including consumption of walnuts, hazelnuts, almonds, and peanuts, and indicating smoking status. In the United States, 495,785 members of AARP were questioned on consumption of peanuts, walnuts, seeds, or other nuts in addition to other foods and smoking status. In this U.S. study 18,533 incident lung cancer cases were identified during up to 16 years of follow-up. Overall, individuals in the highest quintile of frequency of nut consumption had a 26% lower risk of lung cancer in the Italian study and a 14% lower risk of lung cancer in the U.S. study. Similar results were obtained among individuals who were smokers.

In 2002 the World Health Organizations International Agency for Research on Cancer[10] estimated that 11.9% of human cancers are caused by one of seven viruses (see Oncovirus overview table). These are Epstein-Barr virus (EBV or HHV4); Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8); Hepatitis B and Hepatitis C viruses (HBV and HCV); Human T-lymphotrophic virus 1 (HTLV-1); Merkel cell polyomavirus (MCPyV); and a group of alpha Human papillomaviruses (HPVs).[11]

In 1995 epidemiologic evidence indicated that Helicobacter pylori infection increases the risk for gastric carcinoma.[12] More recently, experimental evidence showed that infection with Helicobacter pylori cagA-positive bacterial strains results in severe degrees of inflammation and oxidative DNA damage, leading to progression to gastric cancer.[13]

Perera et al.[14] referred to a number of articles pointing to roles of bacteria in other cancers. They pointed to single studies on the role of Chlamydia trachomatis in cervical cancer, Salmonella typhi in gallbladder cancer, and both Bacteroides fragilis and Fusobacterium nucleatum in colon cancer. Meurman has recently summarized evidence connecting oral microbiota with carcinogenesis.[15] Although suggestive, these studies need further confirmation.

One underlying commonality in cancers is genetic mutation, acquired either by inheritance, or, more commonly, by mutations in one's somatic DNA over time. The mutations considered important in cancers are those that alter protein coding genes (the exome). As Vogelstein et al. point out, a typical tumor contains two to eight exome "driver gene" mutations, and a larger number of exome mutations that are "passengers" that confer no selective growth advantage.[16]

Cancers also generally have genome instability, that includes a high frequency of mutations in the noncoding DNA that makes up about 98% of the human genome. The average number of DNA sequence mutations in the entire genome of breast cancer tissue is about 20,000.[17] In an average melanoma (where melanomas have a higher exome mutation frequency[16]) the total number of DNA sequence mutations is about 80,000.[18]

A second underlying commonality in cancers is altered epigenetic regulation of transcription. In cancers, loss of gene expression occurs about 10 times more frequently by epigenetic transcription silencing (caused, for example, by promoter hypermethylation of CpG islands) than by mutations. As Vogelstein et al.[16] point out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker, or passenger, mutations.[16] In contrast, the frequency of epigenetic alterations is much higher. In colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in promoters of genes in the tumors while the corresponding CpG islands are not methylated in the adjacent mucosa.[19][20][21] Such methylation turns off expression of a gene as completely as a mutation would. Around 60–70% of human genes have a CpG island in their promoter region.[22][23] In colon cancers, in addition to hypermethylated genes, several hundred other genes have hypomethylated (under-methylated) promoters, thereby causing these genes to be turned on when they ordinarily would be turned off.[21]

Epigenetic alterations are also carried out by another major regulatory element, that of microRNAs (miRNAs). In mammals, these small non-coding RNA molecules regulate about 60% of the transcriptional activity of protein-encoding genes.[24] Epigenetic silencing or epigenetic over-expression of miRNA genes, caused by aberrant DNA methylation of the promoter regions controlling their expression, is a frequent event in cancer cells. Almost one third of miRNA promoters active in normal mammary cells were found to be hypermethylated in breast cancer cells, and that is a several fold greater proportion of promoters with altered methylation than is usually observed for protein coding genes.[25] Other microRNA promoters are hypomethylated in breast cancers, and, as a result, these microRNAs are over-expressed. Several of these over-expressed microRNAs have a major influence in progression to breast cancer. BRCA1 is normally expressed in the cells of breast and other tissue, where it helps repair damaged DNA, or destroy cells if DNA cannot be repaired.[26] BRCA1 is involved in the repair of chromosomal damage with an important role in the error-free repair of DNA double-strand breaks.[27] BRCA1 expression is reduced or undetectable in the majority of high grade, ductal breast cancers.[28] Only about 3–8% of all women with breast cancer carry a mutation in BRCA1 or BRCA2.[29] BRCA1 promoter hypermethylation was present in only 13% of unselected primary breast carcinomas.[30] However, breast cancers were found to have an average of about 100-fold increase in miR-182, compared to normal breast tissue.[31] In breast cancer cell lines, there is an inverse correlation of BRCA1 protein levels with miR-182 expression.[32] Thus it appears that much of the reduction or absence of BRCA1 in high grade ductal breast cancers may be due to over-expressed miR-182. In addition to miR-182, a pair of almost identical microRNAs, miR-146a and miR-146b-5p, also repress BRCA1 expression. These two microRNAs are over-expressed in triple-negative tumors and their over-expression results in BRCA1 inactivation.[33] Thus, miR-146a and/or miR-146b-5p may also contribute to reduced expression of BRCA1 in these triple-negative breast cancers.

Post-transcriptional regulation by microRNA occurs either through translational silencing of the target mRNA or through degradation of the target mRNA, via complementary binding, mostly to specific sequences in the three prime untranslated region of the target gene's mRNA.[34] The mechanism of translational silencing or degradation of target mRNA is implemented through the RNA-induced silencing complex (RISC).