Hereditary susceptibility has been increasingly recognized to be an important etiological factor in many cancers. Familial aggregation is one of the phenotypes reflecting the contribution of genetic factors in carcinogenesis [1–4]. Genetic influences on cancer onset can also present as geographic and racial aggregation in some cancers. For example, nasopharyngeal carcinoma (NPC) has the highest incidence rate in southern China and Southeast Asia in populations with similar racial/ethnic backgrounds [5, 6].
In a study comparing the age of cancer onset, Brandt and colleagues found that cancers in individuals with a family history occur 2.6-16.3 years earlier than in sporadic patients . The early onset in familial cases is observed in a variety of malignancies, including leukemia, non-Hodgkin lymphoma, and cancers arising in the cervix, breast, nasopharynx, ovary, nervous system, colorectum, endometrium, bladder, lung, prostate, skin, stomach, and pancreas [7, 8]. These findings strengthen the notion that genetic susceptibility plays an important role in the carcinogenesis of a variety of cancers.
Thanks to advances in molecular technology, especially genome-wide association studies (GWAS), one could expect that in the near future susceptibility gene(s) could be identified in more malignancies . However, another important question is then raised: if the genetic trait is the main culprit, why does it show up so late for the most common cancers arising in epithelial tissue, with the average age of onset being 40-70 years old even in the familial cancers, although the affected individual carries the gene(s) from day 1 of his/her life?
The commonly accepted explanation for the delayed onset of cancer is that accumulation of the genetic alterations is needed for carcinogenesis. The multiple mutation theory has been widely acknowledged for tumor initiation . Genetic variety inside a solid tumor correlating with different invasiveness of the cells  further supports the theory that multiple genetic alterations might be needed for cancer formation and progression. If the accumulation of multiple genetic alterations is needed, the remarkable variety of age of onset within each type of epithelial cancer suggests that the speed of this genetic accumulation is different, probably controlled by a molecular postponing system functioning at different efficiencies. On another hand, the multiple mutation theory is also challenged by the fact that a particular type of cancer only develops in a small proportion of a population heavily exposed to known chemical carcinogens , suggesting that a postponing mechanism could be functioning to prevent tumorigenesis in the lifetime of the exposed population.
Another hypothetical explanation for the delayed onset of cancer is that the immune system in the patient prevents the disease onset in his/her childhood and adolescence. However, most cancer patients, especially those with early-stage disease, do not show impaired immune function, weakening the rationale of the explanation. Other unknown mechanism(s) in human body may be acting to delay the cancer onset.