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Colon cancer: pathology and natural history
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
These traditional tumor suppressors are joined by an increasing number of susceptibility genes that indirectly suppress neoplasia. The prototypes for this class of genes encode DNA repair proteins that act as ‘caretakers’ of the genome (Figure 2). Inactivation of a caretaker gene results in a greatly increased mutation rate and is equivalent to a constant exposure to mutagens. These indirectly acting genes are not required for neoplasia. In fact, most non-hereditary (sporadic) tumors will evolve without them.
Methods for Genetic Testing I
Published in Peter G. Shields, Cancer Risk Assessment, 2005
Haruhiko Sugimura, Peter G. Shields
An individual’s risk for cancer is a function of their genetical predisposition (preinherited mutations found in the germline) and environmental exposures. This is then added to by acquired mutations that occur as a result of those gene-environment interactions, such as a mutation in a caretaker gene. We believe that mutations are nonrandom profiles of what caused a particular cancer. Nonrandomness of the mutations of certain genes (p53, ATM, Brca1, APC, and others) help us understand what causes cancer, especially when studied in animal and in vitro cell culture models. This so-called “carcinogen fingerprint,” as methodologies are further developed, is considered among the best ways of determining carcinogenic etiologies.
GENETIC CHANGES IN CANCER
Published in James Bishop, Cancer Facts, 1999
More recently, the 2 hit model has been expanded to include up to 4 hits. This follows from the proposition that genes can function asgatekeepers or caretakers (entry no. 600185 in ref. 3). Gate- keepers are genes that directly regulate tumour growth through effects on growth or apoptosis, e.g. RB1 gene. Each cell has a very limited number of gatekeepers. Inactivation of both gatekeeper al�eles produces a tissue-specific tumour. Caretaker genes, on the other hand, have a more subtle and indirect effect, since mutations in them enable the development and accumulation of other defects, which might involve a range of genes including gatekeepers and those required for DNA repair. Thus, a mutation in a caretaker gene, e.g. BRCA1, BRCA2 and one of the HNPCC genes described earlier, is unlikely to be found in sporadic cancers because up to 4 hits would be required, i.e. 2 caretaker and 2 gatekeeper genes. The two breast cancer genes mentioned are considered examples of caretakers because of their complex functional domains.
Known epigenetic biomarkers for prostate cancer detection and management: exploring the potential of blood-based liquid biopsies
Published in Expert Review of Molecular Diagnostics, 2019
Vera Constâncio, Daniela Barros-Silva, Carmen Jerónimo, Rui Henrique
To date, GSPT1 promoter hypermethylation is the foremost reported epigenetic alteration in cell-free DNA from PCa patients [21–30]. This caretaker gene is a family member of Glutathione-S transferases (GSTs), which are enzymes involved in DNA protection from electrophilic metabolites of carcinogens and reactive oxygen species by catalyzing the conjugation of chemically reactive electrophiles with reduced glutathione [31]. The silencing of GSTP1 by methylation is a frequent and early event in prostate carcinogenesis, being largely reported for its cancer-specific nature in prostate tissues, making it an outstanding putative biomarker to detect in body fluids, although it is also present in other cancer types [31,32]. A meta-analysis of 10 studies published until 2010, evaluated the performance of GSTP1 hypermethylation for PCa detection in plasma/serum, finding a pooled specificity of 90% (non-qMSP) and 96% (qMSP-based detection), although with modest sensitivity of 40% (non-qMSP) and 36% (qMSP-based detection) [33]. In another study, Dumache et al. detected GSTP1 promoter hypermethylation in 93% of plasma samples from PCa patients, compared to only 11% from controls [28], emphasizing the ability to discriminate PCa patients from healthy men. Because epigenetic alterations are usually multiple and not necessarily overlapped, multigene panels are key to increase the modest sensitivity of GSTP1 promoter methylation. Indeed, Sunami et al. demonstrated that GSTP1, RASSF1, and RARβ2 were hypermethylated in 13%, 24% and 12% of serum samples from PCa patients, respectively. However, when analyzed in combination, the three gene panel increased the detection rate to 29% [24]. In this study, none of those circulating methylated DNA markers were identified in healthy male donors [24]. Furthermore, Ellinger et al. reported that using a gene panel comprising GSTP1/PTGS2/RPRM/TIG1, PCa diagnostic coverage in serum samples increased from 42% (GSTP1 alone) to 47% (panel), keeping the 93% specificity [21]. More recently, the combination of GSTP1 and RASSF1A promoter methylation in a cohort of Mexican patients with biopsy-confirmed PCa enabled PCa detection with 73% positive predictive value (PPV) and 59.6% negative predictive value (NPV), which increased to 80.8% and 66.2%, respectively, when considering serum PSA also [29]. Besides GSTP1, either alone or in combination, other genes have also been tested as PCa biomarkers in serum/plasma. Indeed, serum GADD45a methylation in combination with PSA and free circulating DNA level yielded 88% specificity and 94% sensitivity for discriminating healthy subjects from PCa patients [34]. Taken together, these data suggest that due to lack of sensitivity of promoter DNA methylation from plasma/serum samples, these markers may better complement serum PSA testing rather than replace it. In that vein, these combinations would potentially increase both sensitivity and specificity of PCa detection, reducing the number of unnecessary biopsies. Finally, Brait et al. used a different gene panel (MCAM/ERα/ERβ) which demonstrated 75% sensitivity and 70% specificity for early PCa detection in serum [35].