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

Broeke, Sanne W. ten; Rodríguez-Girondo, Mar; Suerink, Manon; Aretz, Stefan; Bernstein, Inge; Capellà, Gabriel; Engel, Christoph; Gómez-García, Encarna B.; Hest, Liselotte P. van; Doeberitz, Magnus von Knebel; Lagerstedt‐Robinson, Kristina; Letteboer, Tom G.W.; Møller, Pål; Os, Theo A.M. van; Pineda, Marta; Rahner, Nils; Olderode-Berends, Maran J. W.; Salomé, Jenny von; Schackert, Hans K.; Spruijt, Liesbeth; Steinke‐Lange, Verena; Wagner, Anja; Tops, Sophie; Nielsen, Maartje

doi:10.1158/1055-9965.epi-18-0576

Cited by 6 publications

(3 citation statements)

References 27 publications

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“…A European multicentre segregation analysis that estimated CRC incidence in path_PMS2 carriers [13] demonstrated an increased incidence in carriers under 50 years of age, similar to the findings reported in the IMRC series. In a subsequent report [14] the same group confirmed that the apparent anticipation observed was a statistical artifact caused by birth cohorts. The PLSD design eliminates such artificial anticipation.…”

Section: Discussionmentioning

confidence: 80%

Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Møller

Seppälä

Dowty

et al. 2022

Hered Cancer Clin Pract

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Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.

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Section: Discussionmentioning

confidence: 80%

Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Møller

Seppälä

Dowty

et al. 2022

Hered Cancer Clin Pract

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“…It has been proposed that LS families show genetic anticipation, with the first cancer appearing at an earlier age in successive generations. This hypothesis is controversial [14] with some studies showing evidence that supports genetic anticipation, in particular in families with MSH2 mutations, while data from other studies indicating that such observations may be explained by other factors [15,16]. The controversy persists partly because there is inadequate evidence for a biological mechanism that could cause genetic anticipation in LS [14].…”

Section: Introductionmentioning

confidence: 99%

Telomere Instability in Lynch Syndrome Families Leads to Some Shorter Telomeres in MSH2+/- Carriers

Garrido-Navas

Tippins

Barwell

et al. 2020

Life

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Lynch syndrome (LS) is an inherited predisposition to early onset of various cancers, caused by mutation in a DNA mismatch repair (MMR) gene. In heterozygous MMR+/− carriers, somatic mutation, loss or silencing of the wild type allele increases the mutation rate, facilitating the initiation of MMR-defective cancers. These cancers are characterized by instability at short tandem repeats (STRs) and in telomeric DNA. We have investigated telomere length in saliva DNA from LS and control families, using single telomere analysis at XpYp and 12q and by qPCR to measure total telomeric DNA. Single telomere analysis showed a trend for shorter XpYp telomeres in MSH2+/− carriers compared to MLH1+/− carriers or controls, but this was masked in the comparative analysis of total telomeric DNA. Comparison of age-adjusted telomere length within families showed that neither MSH2+/− or MLH1+/− children had consistently shorter or longer telomeres than their MMR+/− parent, indicating the absence of an inter-generational effect on telomere length. Unexpectedly however, wildtype children in families with MSH2 mutations, had significantly longer XpYp telomeres than their MMR+/− parent. Altogether our data suggest that MMR insufficiency, particularly in MSH2+/− carriers, increases telomere instability and somatic cell turnover during the lifetime of LS mutation carriers but has minimal consequences for telomere length in the germline.

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“…In these syndromes the genetic defect is transmitted without alterations. Partly due to the lack of generally accepted explanatory biological mechanism and a high risk of bias in this field of research, some publications suggested this observation to be the result of different forms of bias (15)(16)(17). To our knowledge, data about genetic anticipation within MEN1 families are limited to 1 study, describing a MEN1 family of 5 generations with clinical expression suggestive of anticipation (18).…”

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confidence: 99%

Clues For Genetic Anticipation In Multiple Endocrine Neoplasia Type 1

Broek

Nesselrooij

Pieterman

et al. 2020

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary disease caused by the loss of function of the MEN1 gene, a tumor-suppressor gene that encodes the protein menin. It is characterized by the occurrence of primary hyperparathyroidism (pHPT), duodenopancreatic neuroendocrine tumors (dpNET), pituitary tumors (PIT), adrenal adenomas, and bronchopulmonary (bp-NET), thymic, and gastric neuroendocrine tumors. More insight into factors influencing the age-related penetrance of MEN1 manifestations could provide clues for more personalized screening programs. Objective To investigate whether genetic anticipation plays a role in the largest known MEN1 families in the Netherlands. Methods All Dutch MEN1 families with ≥ 10 affected members in ≥ 2 successive generations were identified. Age at detection of the different MEN1-related manifestations were compared among generations using regression analyses adjusted for competing risks. To correct for the beneficial effect of being under surveillance, manifestations occurring during surveillance were also separately compared. Results A total of 152 MEN1 patients from 10 families were included. A significantly decreased age at detection of pHPT, dpNET, PIT, and bp-NET was found in successive generations (P < 0.0001). Adjusted analyses led to the same results. Conclusions These results suggest the presence of genetic anticipation. However, due to a risk of residual bias, the results must be interpreted with caution. After independent validation in other cohorts and further translational research investigating the molecular mechanisms explaining this phenomenon in MEN1, the results might add to future, more personalized, screening protocols and earlier screening for future generations of MEN1 patients.

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

Cited by 6 publications

References 27 publications

Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Telomere Instability in Lynch Syndrome Families Leads to Some Shorter Telomeres in MSH2+/- Carriers

Clues For Genetic Anticipation In Multiple Endocrine Neoplasia Type 1

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