Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer

Facista, Alexander; Nguyen, Huy; Lewis, Cristy; Prasad, Anil; Ramsey, Lois; Zaitlin, Beryl; Nfonsam, Valentine; Krouse, Robert S.; Bernstein, Harris; Payne, Claire M.; Stern, Stephen; Oatman, Nicole; Banerjee, Bhaskar; Bernstein, Carol

doi:10.1186/2041-9414-3-3

Cited by 41 publications

(39 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore there are likely 11 to 22 million stem cells in the grossly unremarkable colonic mucosal epithelium shown in Figure 3. Evidence reported by Facista et al [35] , listed in Table 1 and illustrated in Figure 4, indicates that in many such resections, most of the crypts, and thus the stem cells in such an area up to 10 cm distant (in each direction) from a colon cancer (such as in the grossly unremarkable area shown in Figure 3), and the majority of their differentiated daughter cells, are epigenetically deficient for protein expression of the DNA repair genes ERCC1 and PMS2, although the epithelium is histologically normal.…”

Section: Dna Damage As a Primary Cause Of Cancermentioning

confidence: 85%

“…Agrelo et al [31] WRN (CGI) 38% Shen et al [32] MGMT (CGI) 46% MGMT (CGI) 23% Psofaki et al [33] MGMT (CGI) 90% Psofaki et al [33] MLH1 (CGI) 65% Truninger et al [29] MLH1 (CGI) 96% Lee et al [34] MLH1 (CGI) 2% Lee et al [34] MSH2 (CGI) 13% MSH2 (CGI) 5% Lee et al [34] MGMT (CGI) 47% MGMT (CGI) 11% Facista et al [35] ERCC1 100% ERCC1 60% Facista et al [35] PMS2 88% PMS2 50% Facista et al [35] XPF 55% XPF 40%…”

Section: Dna Damage As a Primary Cause Of Cancermentioning

confidence: 99%

“…Furthermore, high expression of miR-155 was found in colon cancers in which protein expression of MLH1 was reduced and the MLH1 gene was neither mutated nor hypermethylated [30] . Some of the epigenetic alterations in DNA repair genes found in colon cancers, as well as in their associated field defects, are summarized in Table 1 [31][32][33][34][35] . Deficiencies in DNA repair genes cause increased mutation rates in MMR defective cells [36,37] and in homologous recombinational repair (HRR) defective cells [38] .…”

Section: Dna Damage As a Primary Cause Of Cancermentioning

confidence: 99%

See 2 more Smart Citations

Epigenetic field defects in progression to cancer

Bernstein

Nfonsam²,

Prasad³

et al. 2013

WJGO

Self Cite

View full text Add to dashboard Cite

A field defect is a field of pre-malignant tissue in which a new cancer is likely to arise. Field defects often appear to be histologically normal under the microscope. Recent research indicates that cells within a field defect characteristically have an increased frequency of epigenetic alterations and these may be fundamentally important as underlying factors in progression to cancer. However, understanding of epigenetic field defects is at an early stage, and the work of Katsurano et al published this year, is a key contribution to this field. One question examined by Katsurano et al was how early could the formation of an epigenetic field defect be detected in a mouse colitis model of tumorigenesis. They highlighted a number of measurable epigenetic alterations, detected very early in normal appearing tissue undergoing histologically invisible tumorigenesis. They also documented the increasing presence of the epigenetic alterations at successive times during progression to cancer. In this commentary, we offer a perspective on the changes they observed within a broader sequence of epigenetic events that occur in progression to cancer. In particular, we highlight the likely central role of epigenetic deficiencies in DNA repair gene expression that arise during progression to cancer.

show abstract

Section: Dna Damage As a Primary Cause Of Cancermentioning

confidence: 85%

Section: Dna Damage As a Primary Cause Of Cancermentioning

confidence: 99%

Section: Dna Damage As a Primary Cause Of Cancermentioning

confidence: 99%

See 1 more Smart Citation

Epigenetic field defects in progression to cancer

Bernstein

Nfonsam²,

Prasad³

et al. 2013

WJGO

Self Cite

View full text Add to dashboard Cite

show abstract

“…Facista et al (37) hypothesized that the molecular alterations associated with field cancerization progress outwards, and that the most extensive regions reflect the earliest event in carcinogenesis. If this is the case, then aberrant expression of CK7 would be the latest event for tumorigenesis in the colon and rectum.…”

Section: Discussionmentioning

confidence: 99%

Altered expression of cytokeratin 7 and CD117 in transitional mucosa adjacent to human colorectal cancer

et al. 2017

View full text Add to dashboard Cite

The multi-step progression of colorectal cancer through precancerous lesions (adenoma and dysplasia) is associated with cumulative molecular alterations, a number of which have also been demonstrated to be present in morphologically normal transitional mucosa adjacent to colorectal cancer. The cytoskeletal protein cytokeratin 7 (CK7) and the receptor tyrosine kinase, KIT proto-oncogene receptor tyrosine kinase (CD117), encoded by the proto-oncogene c-Kit, are lacking in normal colorectal crypt epithelium and are aberrantly expressed in a subset of colorectal cancer. The aim of the present study was to evaluate the expression of CK7 and CD117 in morphologically normal transitional mucosa adjacent to colorectal cancer. Immunohistochemical staining for CK7 and CD117 was performed in the mucosa adjacent to five groups of surgically resected colorectal tumors [low-grade adenoma, high-grade adenoma, mucosal adenocarcinoma, small-sized invasive adenocarcinoma (≤2 cm) and large-sized invasive adenocarcinoma (>2 cm)]. CK7 was expressed in the mucosa adjacent to a subset of colorectal tumors, and the positivity ratio increased according to tumor grade from low-grade adenoma up to small-sized invasive adenocarcinoma (61.2%). However, the positivity ratio of CK7 in the mucosa adjacent to the large-sized invasive adenocarcinoma (25.0%) was significantly lower compared with that of the next lower grade. CD117 was also expressed in the mucosa adjacent to a subset of colorectal tumors. In contrast to CK7, the positivity ratio of CD117 increased according to tumor grade from low-grade adenoma all the way through to the large-sized invasive adenocarcinoma (45.0%). Based on these results, the mechanism of CK7 and CD117 expression in the transitional mucosa adjacent to colorectal cancer may be different, and analysis of their individual expression may provide novel insights into the development and progression of colorectal cancer.

show abstract

“…Altered expression of ERCC4 is common in colon cancer, where ~55% of cases have epigenetic repression of the gene (Facista, et al 2012). While it is not clear that ATM and ERCC4 cooperate in thyrocytes, such an interaction has been suggested in CLL cells in which co-occurrence of mutations in ERCC4 and ATM predicted synthetic lethality to ATR kinase inhibitors (Kwok, et al 2016).…”

Section: Dear Editormentioning

confidence: 99%

Genetic variants in thyroid cancer distant metastases

Justiniano¹,

McElroy²,

Yu³

et al. 2016

Endocrine-Related Cancer

View full text Add to dashboard Cite

Thyroid carcinoma is the most rapidly increasing solid tumor in the United States; although there has been a great emphasis on the analysis of primary tumors, predictors of both late-stage progression and response to therapy are more poorly defined due in part to the scarcity of progressive metastatic tissues. Therapeutic evidence of mixed responses in metastatic lesions and the limited available genomic data suggest that distant metastases in thyroid cancer are heterogeneous, driven by known oncogenes and other pathways that also might be therapeutic targets. We analyzed the genomes of a small number of rare surgically resected metastatic thyroid cancer lesions along with paired normal and primary tumor samples when available, in an effort to better characterize progressive distant metastases. The findings confirm the presence of mutations to known tumor drivers (BRAF and RAS) in metastatic samples. The results also identified the co-occurrence in predicted functional variants to the DNA damage repair (DDR) genes ATM and ERCC4 in metastatic lesions that did not show alterations of the MAPK pathway.\ud \ud We examined the exomes of 19 samples (including 5 paired normal tissues) from 11 follicular cell-derived thyroid cancer patients with surgically resected distant metastases by custom exomeSeq (Supplementary Materials and Methods, see section on supplementary data given at the end of this article). Tumors with different histopathologies were included and were confirmed by an expert thyroid pathologist (PW). All patients were treated with TSH suppression, eight of them received I-131 therapy and none of them received chemotherapy or kinase inhibitors. Overall, 19,299 unique variants in the 682 genes and genomic regions were identified by an exomeSeq custom panel. We sought to identify rare, conserved, exonic variants that were likely to have functional effects. Thus, we focused on 1742 exonic variants in exons of sequenced genes. We excluded synonymous variants and

show abstract

Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer

Cited by 41 publications

References 60 publications

Epigenetic field defects in progression to cancer

Epigenetic field defects in progression to cancer

Altered expression of cytokeratin 7 and CD117 in transitional mucosa adjacent to human colorectal cancer

Genetic variants in thyroid cancer distant metastases

Contact Info

Product

Resources

About