Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database

Dominguez‐Valentin, Mev; Haupt, Saskia; Seppälä, Toni T.; Sampson, Julian R.; Sunde, Lone; Bernstein, Inge; Jenkins, Mark A.; Engel, Christoph; Aretz, Stefan; Nielsen, Maartje; Capellà, Gabriel; Balaguer, Francesc; Evans, D Gareth; Burn, John; Holinski‐Feder, Elke; Bertario, Lucio; Bonanni, Bernardo; Lindblom, Annika; Levi, Zohar; Macrae, Finlay; Winship, Ingrid; Plazzer, John‐Paul; Sijmons, Rolf H.; Laghi, Luigi; Valle, Adriana Della; Heinimann, Karl; Dębniak, Tadeusz; Fruscio, Robert; Lopez-Koestner, Francisco; Alvarez-Valenzuela, Karin; Katz, Lior H.; Laish, Ido; Vainer, E; Vaccaro, Carlos; Carraro, Dirce Maria; Monahan, Kevin; Half, Elizabeth E.; Stakelum, Áine; Winter, D. C.; Kennelly, Rory; Gluck, Nathan; Sheth, Harsh; Abu‐Freha, Naim; Greenblatt, Marc S.; Rossi, Benedito Mauro; Bohórquez, Mábel; Cavestro, Giulia Martina; Lino‐Silva, Leonardo S.; Horisberger, Karoline; Tibiletti, Maria Grazia; Nascimento, Ivana; Thomas, Huw; Rossi, Norma Teresa; Silva, Leandro Apolinário da; Zaránd, Attila; Ruíz-Bañobre, Juan; Heuveline, Vincent; Mecklin, Jukka‐Pekka; Pylvänäinen, Kirsi; Renkonen–Sinisalo, Laura; Lepistö, Anna; Peltomäki, Païvi; Therkildsen, Christina; Madsen, Mia Gebauer; Burgdorf, Stefan Kobbelgaard; Hopper, John L.; Win, Aung Ko; Haile, Robert W.; Lindor, Noralane M.; Gallinger, Steven; Marchand, Loı̈c Le; Newcomb, Polly A.; Figueiredo, Jane C.; Buchanan, Daniel D.; Thibodeau, Stephen N.; Doeberitz, Magnus von Knebel; Loeffler, Markus; Rahner, Nils; Schröck, Evelin; Steinke‐Lange, Verena; Schmiegel, Wolff; Vangala, Deepak; Perne, Claudia; Hüneburg, Robert; Redler, Silke; Büttner, Reinhard; Weitz, Jürgen; Pineda, Marta; Dueñas, Nuria; Vidal, J; Moreira, Letícia; Sánchez, Ariadna; Hovig, Eivind; Nakken, Sigve; Green, Kate; Lalloo, Fiona; Hill, James A.; Crosbie, Emma J.; Mints, Miriam; Goldberg, Yael; Tjandra, Douglas; Broeke, Sanne W. ten; Kariv, Revital; Rosner, Guy; Advani, Suresh H.; Thomas, Lidiya; Shah, Pankaj; Shah, Mithun Vinod; Neffa, Florencia; Esperón, Patricia; Pavicic, Walter Hernán; Torrezan, Giovana Tardin; Bassaneze, Thiago; Martin, Claudia; Möslein, Gabriela; Møller, Pål

doi:10.1016/j.eclinm.2023.101909

Cited by 21 publications

(9 citation statements)

References 28 publications

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“…Despite differences in ascertainment between UKB and LS cohorts, CRC cumulative incidence estimates from UKB are similar to those in the literature 13,16,23 . Using PLSD as an example, the cumulative CRC incidence by age 70 for male carriers of path_MLH1 is 53.5% (95% CI: 34.7 - 74.7) in UKB and 52.8% (46.1 – 59.8) in PLSD; for path_MSH2 , 31.0% (14.9 – 57.32) vs 51.0% (42.8 – 59.7); for path_MSH6 , 14.6% (9.1 – 23.0) vs 13.5% (7.1 – 24.8) and for path_PMS2 3.4% (1.3 – 9.0) vs 10.5% (2.7 – 36.0) (Figure S1).…”

Section: Discussionsupporting

confidence: 73%

“…The analysis of carriers of InSiGHT classified path_MMR in UKB replicates known differences in the CRC and EC risk conferred by pathogenic variants in different MMR genes. EC risk is greater than CRC risk in path_MSH6 carriers 13,15 . CRC risk is less and generally later onset in path_MSH6 carriers than path_MLH1 and path_MSH2 carriers 13,15,16 .…”

Section: Discussionmentioning

confidence: 99%

“…EC risk is greater than CRC risk in path_MSH6 carriers 13,15 . CRC risk is less and generally later onset in path_MSH6 carriers than path_MLH1 and path_MSH2 carriers 13,15,16 . EC and CRC risk is notably less for path_PMS2 carriers compared to carriers of path_MMR in other genes 13 .…”

Section: Discussionmentioning

confidence: 99%

“…An example is Prospective Lynch Syndrome Database (PLSD), which collects data on carriers of path_MMR from the point of genetic diagnosis. At last publication, the database included 8,500 carriers: path_MLH1 (36.8%) and path_MSH2 (37.3%) carriers are most common, followed by path_MSH6 (19.4%), and the fewest carriers are observed for path_PMS2 (6.5%) 13 .…”

Section: Discussionmentioning

confidence: 99%

“…Cumulative cancer incidence was estimated using a modified form of Nelson-Aalen survival analysis as described in Dominguez-Valentin et al 13 . Incidence rates were estimated for five-year intervals from age 25 to age 74, assuming no cancers occurred prior to the age of 25.…”

Section: Methodsmentioning

confidence: 99%

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Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank

Fummey,

Navarro,

Plazzer

et al. 2023

Preprint

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BackgroundLynch syndrome (LS) is an inherited cancer predisposition syndrome caused by genetic variants affecting DNA mismatch repair (MMR) genesMLH1,MSH2,MSH6, andPMS2. Cancer risk in LS is estimated from cohorts of individuals ascertained by family history of cancer, which is known to upwardly bias estimates.MethodsThe InSiGHT Database classifies MMR gene variants by pathogenicity through expert panel review of published evidence. 830 carriers of pathogenic or likely pathogenic (path_MMR) MMR gene variants from InSiGHT were identified in 454,756 UK Biobank participants using whole exome sequence. Nelson-Aalen survival analysis was used to estimate cumulative incidence of colorectal, endometrial, and breast cancer.ResultsCumulative incidence of colorectal and endometrial cancer by age 70 was elevated inpath_MMRcarriers compared to non-carriers (colorectal: 11.8% (95% CI: 9.5 - 14.6) vs. 1.7% (1.6 - 1.7), endometrial: 13.4% (10.2 - 17.6) vs. 1.0% (0.9 - 1.0)), but the magnitude of this increase differed between genes. Cumulative breast cancer incidence by age 70 was not elevated inpath_MMRcarriers compared to non-carriers (8.9% (6.3 - 12.4) vs. 7.5% (7.4 - 7.6)). Cumulative cancer incidence estimates in UK Biobank were similar to estimates from the Prospective Lynch Syndrome Database for all genes and cancers, except there was no evidence for elevated endometrial cancer risk in carriers of pathogenicPMS2variants in UK Biobank.ConclusionThese results can be used to inform the management of incidentally identified cases of LS. For example, they support the application of existing colorectal cancer surveillance strategies for LS in incidentally identified cases.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank

Fummey,

Navarro,

Plazzer

et al. 2023

Preprint

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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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Codesign of Lynch Choices^TM: Using implementation science to create a clinically deliverable patient decision support website to transform cancer genetics care pathways

Kohut,

Morton,

Turner

et al. 2024

Psycho-Oncology

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BackgroundResources including Patient Decision Aids (PtDA) are useful and valued by patients and clinicians to provide information and complement shared decision‐making. Despite their promise, few PtDA exist for patients with genetic cancer susceptibility facing difficult decisions about risk management. We aimed to fill this gap, partnering with patients to codesign Lynch ChoicesTM, a PtDA website for families with Lynch Syndrome. In addition to a Patient Reference Panel, we purposively invited an international stakeholder panel including charities, public bodies, clinical and academic experts. Implementation strategies and frameworks were employed to optimise translation of research findings to improve care.MethodsPatient/stakeholder suggestions were incorporated in a transparent Table of Changes and prioritised using the Person‐Based Approach throughout planning and codesign of Lynch ChoicesTM. An interactive stakeholder meeting was convened to identify barriers and facilitators to clinical implementation of the PtDA.ResultsPatient and stakeholder partnerships drove the direction of the research throughout codesign, resulting in several iterative refinements to the PtDA prior to roll out including the addition of illustrations/videos, clearer presentation of cancer risks and increased accessibility for lower literacy. Barriers and facilitators identified from stakeholders were used to create an implementation process map.ConclusionsCreating an effective, engaging PtDA is not enough. Systematic uptake in real world clinical practice, with its resource limitations, is needed to optimise benefit to patients and clinicians. Assessment of speed and breadth of dissemination and usage will be collected to further evidence the benefit of embedding implementation science methods from the outset to translate research findings into clinical practice.

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Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database

Cited by 21 publications

References 28 publications

Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank

Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank

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

Codesign of Lynch Choices^TM: Using implementation science to create a clinically deliverable patient decision support website to transform cancer genetics care pathways

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Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database

Cited by 21 publications

References 28 publications

Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank

Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank

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

Codesign of Lynch ChoicesTM: Using implementation science to create a clinically deliverable patient decision support website to transform cancer genetics care pathways

Contact Info

Product

Resources

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Codesign of Lynch Choices^TM: Using implementation science to create a clinically deliverable patient decision support website to transform cancer genetics care pathways