An alternative approach to establishing unbiased colorectal cancer risk estimation in Lynch syndrome

Suerink, Manon; Rodríguez-Girondo, Mar; Klift, Heleen M. van der; Colas, Chrystelle; Brugières, Laurence; Lavoine, Noémie; Jongmans, Marjolijn C.J.; Munar, Gabriel Capellà; Evans, D. Gareth; Farrell, Michael; Genuardi, Maurizio; Goldberg, Yael; Gómez-García, Encarna B.; Heinimann, Karl; Hoell, Jessica I.; Aretz, Stefan; Jasperson, Kory; Kedar, Inbal; Modi, Manisha P; Nikolaev, Sergey I.; Os, Theo A.M. van; Ripperger, Tim; Rueda, Daniel; Senter, Leigha; Sjursen, Wenche; Sunde, Lone; Therkildsen, Christina; Tibiletti, Maria Grazia; Trainer, Alison H.; Vos, Yvonne J.; Wagner, Anja; Winship, Ingrid; Wimmer, Katharina; Zimmermann, Stefanie; Vasen, Hans F. A.; Asperen, Christi J. van; Houwing-Duistermaat, Jeanine J.; Broeke, Sanne W. ten; Nielsen, Maartje

doi:10.1038/s41436-019-0577-z

Cited by 16 publications

(4 citation statements)

References 40 publications

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“…Notably, these families almost never meet traditional selection criteria due to a very mild phenotype. Our group has gathered a large cohort of CMMR-D-ascertained LS families and found similar results to the previously published cancer risks, 8.7% (95% CI 4.3–12.7%) up to age 70 years for both sexes combined ( 30 ), which confirms previous reports of low cancer risks for PMS2 -LS patients. The great advantage of this method is that it provides cancer risks similar to the retrospective approach, i.e.…”

Section: Pastsupporting

confidence: 90%

PMS2-associated Lynch syndrome: Past, present and future

et al. 2023

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Carriers of any pathogenic variant in one of the MMR genes (path_MMR carriers) were traditionally thought to be at comparable risk of developing a range of different malignancies, foremost colorectal cancer (CRC) and endometrial cancer. However, it is now widely accepted that their cancer risk and cancer spectrum range notably depending on which MMR gene is affected. Moreover, there is increasing evidence that the MMR gene affected also influences the molecular pathogenesis of Lynch syndrome CRC. Although substantial progress has been made over the past decade in understanding these differences, many questions remain unanswered, especially pertaining to path_PMS2 carriers. Recent findings show that, while the cancer risk is relatively low, PMS2-deficient CRCs tend to show more aggressive behaviour and have a worse prognosis than other MMR-deficient CRCs. This, together with lower intratumoral immune infiltration, suggests that PMS2-deficient CRCs might have more in common biologically with sporadic MMR-proficient CRCs than with other MMR-deficient CRCs. These findings could have important consequences for surveillance, chemoprevention and therapeutic strategies (e.g. vaccines). In this review we discuss the current knowledge, current (clinical) challenges and knowledge gaps that should be targeted by future studies.

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Section: Pastsupporting

confidence: 90%

PMS2-associated Lynch syndrome: Past, present and future

et al. 2023

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“…Path_PMS2 variants associated with a milder heterozygous phenotype may be overrepresented, since it was shown that heterozygous relatives of CMMRD patients had a lower cumulative colon cancer risk (8.7%) than reported for path_PMS2 as a whole by the PLSD and others [1,31]. A difference in age at CRC diagnosis was found for path_PMS2 carriers when stratifying variants into those that lead to loss of RNA expression compared to those for which expression was preserved [32,33], but a similar relationship was not observed in a CMMRD family cohort. Host immune factors may also be involved in determining cancer incidence in LS.…”

Section: Discussionmentioning

confidence: 98%

No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study

Dominguez‐Valentin

Plazzer

Sampson

et al. 2021

JCM

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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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“…According to a meta-analysis by Wang et al [ 75 ], which assessed the risk of developing colorectal cancer by age 70, for carriers of pathogenic variants of MLH1 , MSH2 , and MSH6 , the risk was 44%, 54%, and 12%, respectively, for men, and 37%, 39%, and 12%, respectively, for women. For carriers of pathogenic PMS2 variants, this risk is about 8–20% [ 76 , 77 , 78 ]. There is significant heterogeneity of the reported risks in the literature [ 63 , 64 , 65 ], as well as in the NCCN guidelines [ 79 ].…”

Section: Lynch Syndrome-associated Cancer Risksmentioning

confidence: 99%

Microsatellite Instability: A Review of Molecular Epidemiology and Implications for Immune Checkpoint Inhibitor Therapy

Kavun¹,

Veselovsky

Lebedeva³

et al. 2023

Cancers

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Microsatellite instability (MSI) is one of the most important molecular characteristics of a tumor, which occurs among various tumor types. In this review article, we examine the molecular characteristics of MSI tumors, both sporadic and Lynch-associated. We also overview the risks of developing hereditary forms of cancer and potential mechanisms of tumor development in patients with Lynch syndrome. Additionally, we summarize the results of major clinical studies on the efficacy of immune checkpoint inhibitors for MSI tumors and discuss the predictive role of MSI in the context of chemotherapy and checkpoint inhibitors. Finally, we briefly discuss some of the underlying mechanisms causing therapy resistance in patients treated with immune checkpoint inhibitors.

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An alternative approach to establishing unbiased colorectal cancer risk estimation in Lynch syndrome

Cited by 16 publications

References 40 publications

PMS2-associated Lynch syndrome: Past, present and future

PMS2-associated Lynch syndrome: Past, present and future

No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study

Microsatellite Instability: A Review of Molecular Epidemiology and Implications for Immune Checkpoint Inhibitor Therapy

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