Variation in Lynch Syndrome

Church, James M.; Kravochuck, Sara E.

doi:10.1097/dcr.0000000000000355

Cited by 2 publications

(2 citation statements)

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“…Genetic variation is the foundation of diversity observed in the human phenotype, and accounts for the large variety of susceptibilities to common diseases 7 . Differences in disease expression are not only observed between patients who harbour causative germline variants in different MMR genes, but also between patients carrying variants in the same gene and even in patients harbouring the same variant 8 , suggesting that other genetic and environmental factors, are likely to be involved in the disease process. The search for genetic variants that have a modifying effect on disease expression has been ongoing but without definitive results 9 – 12 .…”

Section: Introductionmentioning

confidence: 99%

A genetic variant in telomerase reverse transcriptase (TERT) modifies cancer risk in Lynch syndrome patients harbouring pathogenic MSH2 variants

Wiik

Evans

Belhadj

et al. 2021

Sci Rep

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Individuals with Lynch syndrome (LS), have an increased risk of developing cancer. Common genetic variants of telomerase reverse transcriptase (TERT) have been associated with a wide range of cancers, including colorectal cancer (CRC) in LS. We combined genotype data from 1881 LS patients, carrying pathogenic variants in MLH1, MSH2 or MSH6, for rs2075786 (G>A, intronic variant), 1207 LS patients for rs2736108 (C>T, upstream variant) and 1201 LS patients for rs7705526 (C>A, intronic variant). The risk of cancer was estimated by heterozygous/homozygous odds ratio (OR) with mixed-effects logistic regression to adjust for gene/gender/country of sample origin considering family identity. The AA genotype of SNP rs2075786 is associated with 85% higher odds at developing cancer compared to GG genotype in MSH2 pathogenic variant carriers (p = 0.0160). Kaplan–Meier analysis also shows an association for rs2075786; the AA allele for MSH2 variant carriers confers risk for earlier diagnosis of LS cancer (log-rank p = 0.0011). We report a polymorphism in TERT to be a possible modifier of disease risk in MSH2 pathogenic variant carriers. The rs2075786 SNP in TERT is associated with a differential risk of developing cancer for MSH2 pathogenic variant carriers. Use of this information has the potential to personalise screening protocols for LS patients.

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Section: Introductionmentioning

confidence: 99%

A genetic variant in telomerase reverse transcriptase (TERT) modifies cancer risk in Lynch syndrome patients harbouring pathogenic MSH2 variants

Wiik

Evans

Belhadj

et al. 2021

Sci Rep

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“…While the mean age of onset for colorectal cancer for PMS2-associated Lynch syndrome is around 60, some PMS2 carriers develop colorectal cancer as early as 23 (2)(3)(4). Several external and internal modifiers have been suggested as possible explanations, one of which, genetic anticipation, has been the subject of much debate (5)(6)(7)(8)(9). The phenomenon of genetic anticipation is clearly defined in genetic disorders involving trinucleotide repeats such as Huntington's disease, where expansion of the repeat in subsequent generations is a clear precursor of disease (10).…”

Section: Introductionmentioning

confidence: 99%

The Apparent Genetic Anticipation in PMS2-Associated Lynch Syndrome Families Is Explained by Birth-cohort Effect

Broeke

Rodríguez-Girondo

Suerink

et al. 2019

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: PMS2-associated Lynch syndrome is characterized by a relatively low colorectal cancer penetrance compared with other Lynch syndromes. However, age at colorectal cancer diagnosis varies widely, and a strong genetic anticipation effect has been suggested for PMS2 families. In this study, we examined proposed genetic anticipation in a sample of 152 European PMS2 families. Methods: The 152 families (637 family members) that were eligible for analysis were mainly clinically ascertained via clinical genetics centers. We used weighted Cox-type random effects model, adjusted by birth cohort and sex, to estimate the generational effect on the age of onset of colorectal cancer. Probands and young birth cohorts were excluded from the analyses. Weights represented mutation probabilities based on kinship coefficients, thus avoiding testing bias. Results: Family data across three generations, including 123 colorectal cancers, were analyzed. When compared with the first generation, the crude HR for anticipation was 2.242 [95% confidence interval (CI), 1.162-4.328] for the second generation and 2.644 (95% CI, 1.082-6.464) for the third generation. However, after correction for birth cohort and sex, the effect vanished [HR ¼ 1.302 (95% CI, 0.648-2.619) and HR ¼ 1.074 (95% CI, 0.406-2.842) for second and third generations, respectively]. Conclusions: Our study did not confirm previous reports of genetic anticipation in PMS2-associated Lynch syndrome. Birth-cohort effect seems the most likely explanation for observed younger colorectal cancer diagnosis in subsequent generations, particularly because there is currently no commonly accepted biological mechanism that could explain genetic anticipation in Lynch syndrome. Impact: This new model for studying genetic anticipation provides a standard for rigorous analysis of families with dominantly inherited cancer predisposition.

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Variation in Lynch Syndrome

Cited by 2 publications

References 1 publication

A genetic variant in telomerase reverse transcriptase (TERT) modifies cancer risk in Lynch syndrome patients harbouring pathogenic MSH2 variants

A genetic variant in telomerase reverse transcriptase (TERT) modifies cancer risk in Lynch syndrome patients harbouring pathogenic MSH2 variants

The Apparent Genetic Anticipation in PMS2-Associated Lynch Syndrome Families Is Explained by Birth-cohort Effect

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