Body Weight, Physical Activity, and Risk of Cancer in Lynch Syndrome

Sievänen, Tero; Törmäkangas, Timo; Laakkonen, Eija K.; Mecklin, Jukka‐Pekka; Pylvänäinen, Kirsi; Seppälä, Toni T.; Peltomäki, Païvi; Sipilä, Sarianna; Sillanpää, Elina

doi:10.3390/cancers13081849

Cited by 11 publications

(15 citation statements)

References 51 publications

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“…In conjunction with the clinical data provided for the Tunisian carrier patients, this information enables classification of two variants in class 4 (likely pathogenic). This allows a diagnosis to be established for carriers of these variants in Tunisia and elsewhere, and enables predictive testing for family members as well as better targeted surveillance measures and life style counselling [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of MLH1 missense variants unveils mechanisms of pathogenicity and clarifies role in cancer

et al. 2022

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Lynch syndrome is a heritable condition caused by a heterozygous germline inactivating mutation of the DNA mismatch repair (MMR) genes, most commonly the MLH1 gene. However, one third of the identified alterations are missense variants, for which the clinical significance is unclear in many cases. We have identified three MLH1 missense alterations (p.(Glu736Lys), p.(Pro640Thr) and p.(Leu73Pro)) in six individuals from large Tunisian families. For none of these alterations, a classification of pathogenicity was available, consequently diagnosis, predictive testing and targeted surveillance in affected families was impossible. We therefore performed functional laboratory testing using a system testing stability as well as catalytic activity that includes clinically validated reference variants. Both p.(Leu73Pro) and p.(Pro640Thr) were found to be non-functional due to severe defects in protein stability and catalytic activity. In contrast, p.(Glu736Lys) was comparable to the wildtype protein and therefore considered a neutral substitution. Analysis of residue conservation and of the structural roles of the substituted residues corroborated these findings. In conjunction with the available clinical data, two variants fulfil classification criteria for class 4 “likely pathogenic”. The findings of this work clarify the mechanism of pathogenicity of two unclear MLH1 variants and enables predictive testing and targeted surveillance in members of carrier families worldwide.

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Section: Introductionmentioning

confidence: 99%

Functional characterization of MLH1 missense variants unveils mechanisms of pathogenicity and clarifies role in cancer

et al. 2022

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“…Some variants in our cohort were close to codon 1317. Furthermore, confounders that have a proven influence on (colorectal) cancer development, 6 such as lifestyle, diet, aspirin use, 26–28 or low penetrant genetic risk modifiers, 29 were not taken into account. However, cultural and environmental differences were minimized by including almost all identified Dutch families with known (likely) disease‐causing MSH6 variants.…”

Section: Discussionmentioning

confidence: 99%

“…Some variants in our cohort were close to codon 1317. Furthermore, confounders that have a proven influence on (colorectal) cancer development, 6 such as lifestyle, diet, aspirin use, [26][27][28] or low penetrant genetic risk modifiers, 29 were not T A B L E 3 Hazard ratios for genotype effect and POE.…”

Section: Discussionmentioning

confidence: 99%

Delineating genotype and parent‐of‐origin effect on the phenotype in MSH6‐associated Lynch syndrome

van der Werf‐'t Lam,

Rodriguez‐Girondo,

Villasmil

et al. 2024

Genes Chromosomes & Cancer

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BackgroundThis study investigates the potential influence of genotype and parent‐of‐origin effects (POE) on the clinical manifestations of Lynch syndrome (LS) within families carrying (likely) disease‐causing MSH6 germline variants.Patients and MethodsA cohort of 1615 MSH6 variant carriers (310 LS families) was analyzed. Participants were categorized based on RNA expression and parental inheritance of the variant. Hazard ratios (HRs) were calculated using weighted Cox regression, considering external information to address ascertainment bias. The findings were cross‐validated using the Prospective Lynch Syndrome Database (PLSD) for endometrial cancer (EC).ResultsNo significant association was observed between genotype and colorectal cancer (CRC) risk (HR = 1.06, 95% confidence interval [CI]: 0.77–1.46). Patients lacking expected RNA expression exhibited a reduced risk of EC (Reference Cohort 1: HR = 0.68, 95% CI: 0.43–1.03; Reference Cohort 2: HR = 0.63, 95% CI: 0.46–0.87). However, these results could not be confirmed in the PLSD. Moreover, no association was found between POE and CRC risk (HR = 0.78, 95% CI: 0.52–1.17) or EC risk (Reference Cohort 1: HR = 0.93, 95% CI: 0.65–1.33; Reference Cohort 2: HR = 0.8, 95% CI: 0.64–1.19).Discussion and ConclusionNo evidence of POE was detected in MSH6 families. While RNA expression may be linked to varying risks of EC, further investigation is required to explore this observation.

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“…However, a limitation of their study was the lack of subcategories amongst tobacco users, as current smokers were not distinguished from previous smokers. In terms of BMI, several studies suggest that male sex combined with higher BMI leads to an increased CRC risk, whereas this association could not be found amongst females with higher BMI and LS ( 10 – 12 ).…”

Section: Introductionmentioning

confidence: 97%

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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Body Weight, Physical Activity, and Risk of Cancer in Lynch Syndrome

Cited by 11 publications

References 51 publications

Functional characterization of MLH1 missense variants unveils mechanisms of pathogenicity and clarifies role in cancer

Functional characterization of MLH1 missense variants unveils mechanisms of pathogenicity and clarifies role in cancer

Delineating genotype and parent‐of‐origin effect on the phenotype in MSH6‐associated Lynch syndrome

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

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