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- Dominguez-Valentin, M, et al.
(författare)
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No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study
- 2021
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Ingår i: Journal of clinical medicine. - : MDPI AG. - 2077-0383. ; 10:13
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Tidskriftsartikel (refereegranskat)abstract
- Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.
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- Dehasque, Marianne, et al.
(författare)
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Inference of natural selection from ancient DNA
- 2020
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Ingår i: Evolution Letters. - : JOHN WILEY & SONS LTD. - 2056-3744. ; 4:2, s. 94-108
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Evolutionary processes, including selection, can be indirectly inferred based on patterns of genomic variation among contemporary populations or species. However, this often requires unrealistic assumptions of ancestral demography and selective regimes. Sequencing ancient DNA from temporally spaced samples can inform about past selection processes, as time series data allow direct quantification of population parameters collected before, during, and after genetic changes driven by selection. In this Comment and Opinion, we advocate for the inclusion of temporal sampling and the generation of paleogenomic datasets in evolutionary biology, and highlight some of the recent advances that have yet to be broadly applied by evolutionary biologists. In doing so, we consider the expected signatures of balancing, purifying, and positive selection in time series data, and detail how this can advance our understanding of the chronology and tempo of genomic change driven by selection. However, we also recognize the limitations of such data, which can suffer from postmortem damage, fragmentation, low coverage, and typically low sample size. We therefore highlight the many assumptions and considerations associated with analyzing paleogenomic data and the assumptions associated with analytical methods.
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- Lindberg, L. J., et al.
(författare)
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Benefit from extended surveillance interval on colorectal cancer risk in Lynch syndrome
- 2020
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Ingår i: Colorectal Disease. - : Wiley. - 1462-8910 .- 1463-1318. ; 22:5, s. 529-536
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Although patients with Lynch syndrome have an increased risk of developing colorectal cancer, surveillance can reduce morbidity and mortality. Whether or not affected individuals benefit from lifetime surveillance depends on individual factors and patient adherence, and these may vary, complicating risk modelling. The aim of this study was to identify individual factors which influence patient adherence to surveillance programmes and whether extended surveillance interval influenced their risk of developing colorectal cancer. Method: Demographics and survival data were obtained from patients (n = 1223) with Lynch syndrome, identified by interrogating the Danish Hereditary Non-Polyposis Colorectal Cancer Register. These data were linked to patient surveillance interval data which had been divided into three subsets (< 27 months, adherent to the recommended biennial programme; > 27 months, extended surveillance interval; and no surveillance) to estimate the cumulative risks and hazard ratios (HRs) for colorectal cancer. Results: In all, 147 colorectal cancers (99 first; 48 metachronous) were identified in 1223 patients. Factors associated with adherence to surveillance were female sex, a previous history of cancer and age < 75 years. The cumulative incidence for colorectal cancer was 38% (95% CI 27%–50%) for surveillance intervals < 27 months, 48% (95% CI 29%–67%) for intervals > 27 months and 72% (95% CI 61%–83%) with no surveillance. Adjusted HRs were 0.22 for surveillance intervals < 27 months and 0.32 for surveillance intervals > 27 months. Extended surveillance intervals > 27 months had a non-significant benefit with an HR of 1.51 (95% CI 0.83–2.75) compared to surveillance intervals < 27 months. Conclusion: This study demonstrates that adherence to colonoscopic surveillance in Lynch syndrome varies with age, sex and cancer history and demonstrates a consistent benefit from colorectal cancer surveillance, though it might be lower for individuals with extended intervals.
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