On the nature of susceptibility to cancer. The presidential address

Abstract

The most prominent factor determining susceptibility to cancer is age. However, there is little evidence that the aging process per se increases susceptibility to cancer. Rather, age provides the time necessary for the accumulation of cellular events required for the development of neoplasia. The variations in the patterns of cancer incidence rates seen with age can be explained by alterations in conditions of exposure to carcinogenic stimuli. There is no evidence that the pool of susceptible individuals in a population is limited. Cancer occurs as a random event in a population with greater or lesser frequency according to the presence of risk factors. In populations with an increased frequency of cancer such as those with genetic abnormalities, immune deficiency syndromes, or altered hormonal states, the risk of developing cancer is never generalized to all tissues but is characteristic of particular tissues at risk. Any circumstance of internal or external origin that disturbs homeostasis of particular tissues at risk. Any circumstance of internal or external origin that disturbs homeostasis over a prolonged period of time increases the susceptibility to cancer for the tissue concerned. Susceptibility to cancer does not mean that cancer is inevitable. Only a small number of those susceptible to cancer by virtue of a special risk factor develop the disease. Furthermore, most patients who develop cancer have no determinable risk factors. Although all evidence points to a multifactorial, multistage process, the rate of somatic mutation appears to be the key determinant factor in susceptibility to cancer. This concept is supported by research studies showing that the onset of atherosclerosis is initiated by somatic mutations, and the finding that the same chemical mutagens can advance the development of both diseases.

Loss of p16 pathways stabilizes EWS/FLI1 expression and complements EWS/FLI1 mediated transformation

“…It is estimated that the incidence of cancer in humans increases between 10 3 ± 10 7 times with advancing age (Miller, 1980). Such clinical observations prompted the multi-hit hypothesis of oncogenesis, which states that cellular transformation is due to an accumulation of somatic mutations.…”

Genomic and Epigenomic Alterations in Cancer

“…It is suggested that the breast, colorectal, and prostate require five to seven driver mutations for cancer initiation and progression, whereas hematological malignancies may require fewer. 6 Some of the well-characterized genes carrying mutations include TP53, RB1, EGFR, and KRAS, which are frequently mutated in various cancer types, whereas others are rare and/or restricted to one cancer. 2 Apart from genomic events that are evident during cancer progression, modifications of the nucleotides, particularly that of the cytosine and post-translational histone modifications, are common in cancer ( Figure 1).…”

From tumor size andHER2status to systems oncology for very early breast cancer treatment

“…Extensive genetic studies and statistical models estimate that the number of 'driver' mutations -alterations that causatively contribute to cancer development -depends on the tumor stage. The number of these events varies from five to seven mutations in at least six genes required to convert a normal cell into a cancer cell [29,30] and approximately 80-100 genetic alterations in advanced breast, colorectal and other common solid cancer types [31,32]. Somewhere between these cutoff values, for example 20-40 mutations, may be the number of mutations in pT1a,bN0M0 tumors.…”