DNA replication errors are responsible for two-thirds of the mutations in human cancers

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Cancer is developed due to Mutation

It is now widely known or accepted that cancer is result of mutation that successively increase the cell proliferation. But main question is that what causes these mutations? Environmental factors or Reloe of heredity or others. Now recently by researchers Tomasetti, Li and Vogelstein  develops their model of ‘other’ sources of DNA mutation that lead to tumour initiation further and explores how different sources of DNA mutation influence different cancer types.

But, there is a proportion of cancers — which varies by cancer type — that cannot be explained by these two sources of DNA mutation. So what causes them? Tomasetti et al. propose that the missing factor is endogenous mutagenesis: random DNA replication errors that occur in stem cells (because they are the only long-lived cells that divide) and thus also exist in their progeny. The existence of endogenous mutagenesis is widely accepted, as error-free DNA replication is incompatible with evolution.

Tomasetti et al. report an analysis of cancer incidence in 4.8 billion people from 69 countries. They analysed 17 different types of cancer for which data on stem cell divisions are available for their tissue of origin and again demonstrated a strong correlation between the lifetime risk of cancer in a tissue and stem cell divisions in that tissue.

DNA replication errors are responsible for two-thirds of the mutations in human cancers
Etiology of driver gene mutations in women with cancer. For each of 18 representative
cancer types, the schematic depicts the proportion of mutations that are inherited, due to environmental
factors, or due to errors in DNA replication (i.e., not attributable to either heredity or environment).The sum
of these three proportions is 100%. The color codes for hereditary, replicative, and environmental factors
are identical and span white (0%) to brightest red (100%). The numerical values used to construct this
figure, as well as the values for 14 other cancer types not shown in the figure, are provided in table S6. B,
brain; Bl, bladder; Br, breast; C, cervical; CR, colorectal; E, esophagus; HN, head and neck; K, kidney; Li, liver;
Lk, leukemia; Lu, lung; M, melanoma; NHL, non-Hodgkin lymphoma; O, ovarian; P, pancreas; S, stomach;
Th, thyroid; U, uterus. [Image: The Johns Hopkins University]
They developed a method to estimate the sources of the mutations in different cancers. Epidemiological studies suggest that ~90% of lung adenocarcinoma cases can be prevented through avoidance of exogenous mutagens (such as tobacco smoke); there is no evidence to date of inherited mutations in lung adenocarcinoma. Using epidemiological and genome-wide DNA sequencing data from hundreds of patients with lung adenocarcinoma they found that driver mutations in 90% of the patients were at least partially due to exogenous sources, while driver mutations in 10% of the patients were not attributable to exogenous sources at all. Therefore, the authors calculated that 35% of the driver mutations among all patients with lung adenocarcinoma are not due to exogenous (or inherited) sources and were proposed to be due to endogenous mutagenesis.

Assuming that the non-exogenous and non-inherited source of mutation in cancer is attributable to DNA replication error, Tomasetti et al. propose that these mutations may be derived from base pairing errors, DNA polymerase errors, base deamination and endogenous damage (for example, from reactive oxygen species). This model provides much food for thought and will likely stimulate further debate, and hopefully more research on tumour causation that could lead to improved prevention.

Source: Tomasetti, C. et al. Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science 355, 1330–1334 (2017)

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