Differentiating Lynch-Like From Lynch Syndrome

Carethers, John M.

doi:10.1053/j.gastro.2014.01.041

Cited by 102 publications

(119 citation statements)

References 17 publications

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“…These five genes are MLH1, MSH2, MSH6, PMS2, and PMS1, where the most frequent mutations occur in the MLH1 and MSH2 genes. Colorectal cancer can be divided into MSI-H (high) when we obtained two or more MMR genes are mutated, and MSI-L (low) when obtained only one MMR gene that is mutated, known as microsatellite stable (MSS) (Carethers, 2014).…”

Section: Resultsmentioning

confidence: 99%

Cigarette Smoke Induces Colorectal Carcinogenesis in Wistar Rats by Decreasing The Expression of APC, MSH2 and MLH1

et al. 2017

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Colorectal carcinogenesis induced by cigarette smoke requires at least 30-40 years. This long time duration causes an animal research conducted becomes relevant. This research was carried out to observe colorectal carcinogenesis due to cigarette smoke exposure in Wistar Rat. The observations focused on changes in epithelial morphology and expression of APC, MSH2 and MLH1. Twenty male Wistar rats inbreed strain were randomly allocated into control group and experimental group exposure to cigarettes smoke for 14 weeks and 28 weeks sequentially. Colorectal epithelial morphology was assessed on the histopathology examination, whereas the expression of APC, MSH2 and MLH1 was assessed on aspect of immunohistochemistry. The comparative analysis between the two groups was performed using nonparametric Mann-Whitney U test. Histology of colorectal epithelium showed pattern of colitis associated cancer that was significant both in 14 weeks and 28 weeks of treatment. This research indicated negative expression of APC, MSH2 and MLH1 in the colorectal cancer that were significant at 28 weeks of exposure. This research implies that chronic exposure to cigarette smoke can induce colitis associated colorectal cancer through decreased expression of APC, MSH2 and MLH1.

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Section: Resultsmentioning

confidence: 99%

Cigarette Smoke Induces Colorectal Carcinogenesis in Wistar Rats by Decreasing The Expression of APC, MSH2 and MLH1

et al. 2017

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“…UMMRD comprises patients with both hereditary and sporadic cancers [9–14]. The only way to distinguish between these two groups is by sequencing the tumor’s DNA MMR genes, which is still not routinely done.…”

Section: Discussionmentioning

confidence: 99%

“…This group of patients has been classified as having as “Lynch-like syndrome (LLS)” or “tumor Lynch” [8, 9]. According to current literature these patients either have an undetected MMR mutation (LS with missed mutation), false positive screening or double somatic mutations (the last two groups are not caused by germline mutation and therefore are not part of the LS spectrum) [9–14]. Since the term LLS is misleading, we will refer to this group of patients with MMR deficiency but without detected germline mutations as “unexplained MMR deficiency (UMMRD)”.…”

Section: Introductionmentioning

confidence: 99%

“…Since the term LLS is misleading, we will refer to this group of patients with MMR deficiency but without detected germline mutations as “unexplained MMR deficiency (UMMRD)”. Clinically, UMMRD falls in the spectrum midway between LS and sporadic CRC [9]. Patients with LLS/UMMRD have a lower standardized incidence ratio of CRC compared to LS patients.…”

Section: Introductionmentioning

confidence: 99%

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Cancer screening behaviors and risk perceptions among family members of colorectal cancer patients with unexplained mismatch repair deficiency

et al. 2016

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Communication gaps in families with unexplained mismatch repair (MMR) deficiency (UMMRD) could negatively impact the screening behaviors of relatives of individual with UMMRD. We evaluated cancer risk perception, screening behaviors, and family communication among relatives of colorectal cancer (CRC) patients with UMMRD. Fifty-one family members of 17 probands with UMMRD completed a questionnaire about cancer risk perception, adherence to Lynch syndrome (LS) screening recommendations, and communication with relatives. Clinical data about the probands were obtained from medical records. Thirty-eight participants (78%) were worried from having cancer and twenty-one participants (42%) had undergone colonoscopy in the past 2 years, as recommended for LS families. In terms of screening for extracolonic cancers, only two eligible participants (3.9%) were screened for gastric, endometrial (10.0%), and ovarian (9.5%) cancers. Additionally, 5 participants (10%) underwent genetic counseling. Most participants were not told by anyone to be screened for extracolonic cancers (84, 85, and 95% for gastric, ovarian, and endometrial cancers, respectively). A minority of family members of CRC patients with UMMRD follow cancer screening as recommended for LS families. Health care providers should encourage patients with UMMRD to share information on LS-related cancers screening, especially extracolonic cancers, with their relatives.

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“…And there is yet another group of tumors with an MSI phenotype (also referred as "Lynch-like" tumors) that exhibit loss of expression of 1 or more of the MMR genes but lack a germline MMR mutation or promoter hypermethylation of the MLH1 gene. 9 It is believed that at least some of these patients harbor somatically acquired MMR mutations leading to MSI. In this regard, the current study by Billingsley and colleagues suggests that some of these "Lynch-like" tumors may exhibit somatic inactivation of MMR genes because of POLE EDMs.…”

mentioning

confidence: 99%

POLE mutations as an alternative pathway for microsatellite instability in endometrial cancer: Implications for Lynch syndrome testing

Konstantinopoulos

Matulonis

2014

Cancer

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Further elucidation of the genomics of endometrial cancer has the capability and promise of much needed understanding of causative factors of this disease and its hereditary predisposition, development of more effective therapeutics, and improved predictive indicators for use of chemotherapy and radiation therapy. Significant strides toward these goals have been accomplished by The Cancer Genome Atlas (TCGA) project, which has genomically characterized and distilled endometrial cancer into 4 major groups based on microsatellite instability (MSI), somatic copy number alterations (SCNAs), and somatic nucleotide substitutions. 1 These groups include: 1) an ultramutated group with a unique nucleotide change spectrum of increased cysteine-toalanine (C!A) transversion frequency; 2) a hypermutated group of cancers with MSI, most of which had mutL homolog 1 (MLH1) promoter methylation (MSI group); 3) a group of cancers with microsatellite stability (MSS) that had a relatively lower mutation frequency and low SCNAs; and 4) a serous-like group comprised of cancers with serous or mixed histology and a few high-grade endometrioid cancers, all of which harbored extensive SCNAs and a low mutation rate. 1 The ultramutated group included 17 tumors (7% of all tumors in the TCGA data set), all of which harbored mutations in the exonuclease domain of polymerase e (POLE), and was associated with improved progression-free survival (PFS) compared with all other groups, and the largest difference was observed when this ultramutated group was compared with the serous-like group.POLE and polymerase d (POLD1) belong to the B family of polymerases and are responsible for synthesizing the leading and lagging strands in eukaryotic DNA replication. 2 POLE and POLD1 form the major catalytic and proofreading units of Pole and Pold enzyme complexes, which ensure the high fidelity of DNA replication. Both POLE and POLD1 exhibit the greatest homology over their proofreading exonuclease domain (residues 268-471 and 304-517, respectively), which exhibit a high level of evolutionary conservation. It is estimated that their proofreading 3 0 to 5 0 exonuclease activity, which locates and replaces erroneous bases in the daughter strand, helps protect against genomic instability by improving the fidelity of DNA replication by at least 10-fold. 3 Several cancer genome sequencing efforts have consistently demonstrated that a small fraction of colorectal and endometrial cancers contain somatic mutations within the exonuclease domains of POLE (3% and 7% in the TCGA colorectal and uterine projects, respectively). 1,4 Contrary to POLE, very few somatic POLD1 exonuclease domain mutations (EDMs) have been detected in human cancers, whereas both germline POLD1 and POLE mutations have been reported in association with a high risk of multiple colorectal adenomas and carcinomas, whereas germline POLD1 mutations also predispose to endometrial cancers. 5 Somatic POLE EDMs in endometrial and colorectal cancers have demonstrated significant overlap; and codons 286 (a c...

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Differentiating Lynch-Like From Lynch Syndrome

Cited by 102 publications

References 17 publications

Cigarette Smoke Induces Colorectal Carcinogenesis in Wistar Rats by Decreasing The Expression of APC, MSH2 and MLH1

Cigarette Smoke Induces Colorectal Carcinogenesis in Wistar Rats by Decreasing The Expression of APC, MSH2 and MLH1

Cancer screening behaviors and risk perceptions among family members of colorectal cancer patients with unexplained mismatch repair deficiency

POLE mutations as an alternative pathway for microsatellite instability in endometrial cancer: Implications for Lynch syndrome testing

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