Associations Between Mutations in MSH6 and PMS2 and Risk of Surveillance-detected Colorectal Cancer

Lamba, Mehul; Wakeman, Chris; Ebel, Rosy; Hamilton, Sarah; Frampton, Chris; Kiesanowski, Maxene; Griffiths, Ben; Keating, John P.; Parry, Susan; Chalmers-Watson, Teresa

doi:10.1016/j.cgh.2020.03.048

Cited by 8 publications

(6 citation statements)

References 32 publications

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“…The results show that MLH1 and MSH2 carriers have higher odds of CRC development during surveillance than MSH6, PMS2, and EPCAM carriers and patients with a mixed genotype. In accordance with these results, other studies have found that MLH1 and MSH2 carriers have a higher risk of developing CRC than MLH6 carriers ( 25 ), as well as PMS2 carriers ( 14 – 16 ), which could also be explained by the more rapid CRC development amongst MLH1 and MSH2 carriers ( 6 ). This finding could be used to bring forward a more individualized approach towards LS surveillance in which genotype is taken into consideration when an appropriate surveillance interval is recommended, which has previously been proposed by Goverde et al.…”

Section: Discussionsupporting

confidence: 84%

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Endoscopic surveillance of Lynch syndrome at a highly specialized center in Sweden: An observational study of interval colorectal cancer and individual risk factors

et al. 2023

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IntroductionLynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC). In order to detect CRCs amongst LS patients, regular colonoscopies are recommended. However, an international agreement on an optimal surveillance interval has not yet been reached. In addition, few studies have investigated factors that could potentially increase the CRC risk amongst LS patients.AimsThe primary aim was to describe the frequency of CRCs detected during endoscopic surveillance and to estimate the interval from a clean colonoscopy to CRC detection amongst LS patients. The secondary aim was to investigate individual risk factors, including sex, LS genotype, smoking, aspirin use and body mass index (BMI), on CRC risk amongst patients that develop CRC before and during surveillance.Material and methodsClinical data and colonoscopy findings from 366 LS patients’ 1437 surveillance colonoscopies were collected from medical records and patient protocols. Logistic regression and Fisher’s exact test were used to investigate associations between individual risk factors and CRC development. Mann-Whitney U test was used to compare the distribution of TNM stages of CRC detected before surveillance and after index.ResultsCRC was detected in 80 patients before surveillance and in 28 patients during surveillance (10 at index and 18 after index). During the surveillance programme, CRC was detected within 24 months in 65% of the patients, and after 24 months within 35% of the patients. CRC was more common amongst men, previous and current smokers, and the odds of developing CRC also increased with an increasing BMI. CRCs were more often detected amongst MLH1 and MSH2 carriers during surveillance, compared to the other genotypes.ConclusionsWe found that 35% of the CRC cases detected during surveillance were found after 24 months. MLH1 and MSH2 carriers were at higher risk of developing CRC during surveillance. Additionally, men, current or previous smokers, and patients with a higher BMI were at higher risk of developing CRC. Currently, LS patients are recommended a “one-size-fits-all” surveillance program. The results support the development of a risk-score whereby individual risk factors should be taken into consideration when deciding on an optimal surveillance interval.

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Section: Discussionsupporting

confidence: 84%

“…For instance, some studies suggest that MLH1 carriers are at a higher risk of developing CRC than PMS2 carriers ( 13 – 15 ). Meanwhile, MLH1 and MSH2 carriers are estimated to have a similar risk for CRC, and MSH6 carriers present an intermediate risk in the genetic spectrum ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

Endoscopic surveillance of Lynch syndrome at a highly specialized center in Sweden: An observational study of interval colorectal cancer and individual risk factors

et al. 2023

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“…Additionally, rare mutations in EPCAM causes loss of MSH2 and also causes Lynch syndrome. [28][29][30][31] Results of genetic testing subsequently guides family germline testing as well as guides risk stratification and personalized screening.…”

Section: Germline Genetic Testingmentioning

confidence: 99%

Hereditary Colorectal Cancer: From Diagnosis to Surgical Options

Aoun,

Kalady

2024

Clin Colon Rectal Surg

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Hereditary colorectal cancer (CRC) syndromes account for up to 5% of CRC. Patients have an increased risk of CRC and extracolonic cancers, both of which develop at an early age. The main polyposis syndromes include familial adenomatous polyposis, MYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, and PTEN hamartoma syndrome. The non-polyposis syndromes include Lynch syndrome and familial colorectal cancer type X. Each of the syndromes have distinct but sometimes overlapping phenotypes. Clinical evaluation and ultimately the underlying germline genetic pathogenic variants define the syndromes. Each syndrome has polyp, CRC, and extracolonic risks and management is based on early and timely surveillance with therapeutic and often extended prophylactic surgery. Surgical intervention strategies are individualized, considering not only the earlier onset of malignancies and heightened risks for metachronous cancers but also the patient's needs and quality of life. This article reviews the different diagnostic approaches to hereditary CRC and highlights subsequent disease-specific management and surgical decision-making strategies.

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“…The following are available online at https://www.mdpi.com/article/10 .3390/cancers13092081/s1, Table S1: Studies evaluating cumulative CRC risk in Lynch syndrome in relation to germline mutations in MMR gene; Table S2: Studies evaluating somatic mutations in sporadic CRC. References [49][50][51][52]58,59,63,68,69,74] are cited in the Supplementary Material. Funding: This research was funded by the AIRC Foundation for Cancer Research (Grant number: IG 21723 to L.R.…”

Section: Conflicts Of Interestmentioning

confidence: 99%

“…Recent findings have shown distinct associations between MMR mutations and cancer risks [ 49 , 50 ] ( Supplementary Table S1 ). A prospective study demonstrated that carriers of MSH2 mutations show the highest risk of developing adenomas and advanced adenomas, probably as a consequence of the association between germline MSH2 alterations and somatic APC gene mutations which may contribute to accelerate the colonic malignant transformation [ 49 ].…”

Section: Hereditary Settingsmentioning

confidence: 99%

Discovering the Mutational Profile of Early Colorectal Lesions: A Translational Impact

Alquati

Prossomariti

Piazzi

et al. 2021

Cancers

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Colorectal cancer (CRC) develops through a multi-step process characterized by the acquisition of multiple somatic mutations in oncogenes and tumor-suppressor genes, epigenetic alterations and genomic instability. These events lead to the progression from precancerous lesions to advanced carcinomas. This process requires several years in a sporadic setting, while occurring at an early age and or faster in patients affected by hereditary CRC-predisposing syndromes. Since advanced CRC is largely untreatable or unresponsive to standard or targeted therapies, the endoscopic treatment of colonic lesions remains the most efficient CRC-preventive strategy. In this review, we discuss recent studies that have assessed the genetic alterations in early colorectal lesions in both hereditary and sporadic settings. Establishing the genetic profile of early colorectal lesions is a critical goal in the development of risk-based preventive strategies.

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Associations Between Mutations in MSH6 and PMS2 and Risk of Surveillance-detected Colorectal Cancer

Cited by 8 publications

References 32 publications

Endoscopic surveillance of Lynch syndrome at a highly specialized center in Sweden: An observational study of interval colorectal cancer and individual risk factors

Endoscopic surveillance of Lynch syndrome at a highly specialized center in Sweden: An observational study of interval colorectal cancer and individual risk factors

Hereditary Colorectal Cancer: From Diagnosis to Surgical Options

Discovering the Mutational Profile of Early Colorectal Lesions: A Translational Impact

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