The diverse molecular profiles of lynch syndrome-associated colorectal cancers are (highly) dependent on underlying germline mismatch repair mutations

Helderman, Noah C.; Broeke, Sanne W. Bajwa ten; Morreau, Hans; Suerink, Manon; Terlouw, Diantha; Lam, Anne-Sophie van der Werf-’ t; Wezel, Tom van; Nielsen, Maartje

doi:10.1016/j.critrevonc.2021.103338

Cited by 21 publications

(22 citation statements)

References 81 publications

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“…Furthermore, the spectra of mutations in APC of LS CRCs were correlated with MMRd mutational signatures in two independent studies [ 47 , 64 ]. Although further studies [ 65 , 66 ] indicate that in patients with PMS2 -associated LS, MMRd is not an initiating step in CRC pathogenesis, several characteristics of the early-MMRd pathway of LS colorectal tumorigenesis were observed in the CRC of our index patient. MMRd was detected in adjacent normal colorectal mucosa, and in the tumor, mainly somatic frameshift variants in APC were found, which likely result from unrepaired insertion/deletion loops due to MMRd.…”

Section: Discussionmentioning

confidence: 63%

“…MMRd was detected in adjacent normal colorectal mucosa, and in the tumor, mainly somatic frameshift variants in APC were found, which likely result from unrepaired insertion/deletion loops due to MMRd. Other mutations frequently found in LS-CRC with early MMRd, such as the hotspot KRAS mutations (G12D and G13D) [ 47 , 65 ], were absent in both tumors. All data taken together, the comprehensive molecular analysis of the patients’ tumors suggest that both developed with MMRd as an early event.…”

Section: Discussionmentioning

confidence: 99%

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Teenage-Onset Colorectal Cancers in a Digenic Cancer Predisposition Syndrome Provide Clues for the Interaction between Mismatch Repair and Polymerase δ Proofreading Deficiency in Tumorigenesis

et al. 2022

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Colorectal cancer (CRC) in adolescents and young adults (AYA) is very rare. Known predisposition syndromes include Lynch syndrome (LS) due to highly penetrant MLH1 and MSH2 alleles, familial adenomatous polyposis (FAP), constitutional mismatch-repair deficiency (CMMRD), and polymerase proofreading-associated polyposis (PPAP). Yet, 60% of AYA-CRC cases remain unexplained. In two teenage siblings with multiple adenomas and CRC, we identified a maternally inherited heterozygous PMS2 exon 12 deletion, NM_000535.7:c.2007-786_2174+493del1447, and a paternally inherited POLD1 variant, NP_002682.2:p.Asp316Asn. Comprehensive molecular tumor analysis revealed ultra-mutation (>100 Mut/Mb) and a large contribution of COSMIC signature SBS20 in both siblings’ CRCs, confirming their predisposition to AYA-CRC results from a high propensity for somatic MMR deficiency (MMRd) compounded by a constitutional Pol ẟ proofreading defect. COSMIC signature SBS20 as well as SBS26 in the index patient’s CRC were associated with an early mutation burst, suggesting MMRd was an early event in tumorigenesis. The somatic second hits in PMS2 were through loss of heterozygosity (LOH) in both tumors, suggesting PPd-independent acquisition of MMRd. Taken together, these patients represent the first cases of cancer predisposition due to heterozygous variants in PMS2 and POLD1. Analysis of their CRCs supports that POLD1-mutated tumors acquire hypermutation only with concurrent MMRd.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Teenage-Onset Colorectal Cancers in a Digenic Cancer Predisposition Syndrome Provide Clues for the Interaction between Mismatch Repair and Polymerase δ Proofreading Deficiency in Tumorigenesis

et al. 2022

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“…Some research has shown that APC mutations commonly occur after the onset of MMR deficiency, in support of the different variant frequencies of APC in this study 34 . A study on the relationship between the APC mutation frequency and LS has received substantial attention 35,36 . To our knowledge, the present work is the first investigation revealing that VEGF and Notch pathways are uniquely enriched in LS CRCs but not enriched in sporadic CRCs with dMMR_MSI-H.…”

Section: Discussionmentioning

confidence: 99%

Lynch syndrome pre-screening and comprehensive characterization in a multi-center large cohort of Chinese patients with colorectal cancer

Li¹,

Fan²,

Zheng³

et al. 2022

Cancer Biology & Medicine

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Objective: Lynch syndrome (LS) pre-screening methods remain under-investigated in colorectal cancers (CRCs) in Asia. Here, we aimed to systematically investigate LS pre-screening and comprehensively characterize LS CRCs. Methods: Microsatellite instability (MSI) and germline variants of DNA mismatch repair (MMR) genes were examined in 406 deficient MMR (dMMR) and 250 proficient MMR CRCs. The genetic differences between LS and sporadic CRCs were studied with whole exome sequencing analysis. Results: The incidence of dMMR in Chinese patients with CRCs was 13.8%. Consistency analysis between MMR immunohistochemistry (IHC) and MSI testing showed the kappa value was 0.758. With next-generation sequencing (NGS), germline variants were detected in 154 CRCs. Finally, 88 patients with CRC were identified as having LS by Sanger sequencing. Among them, we discovered 21 previously unreported pathogenic germline variants of MMR genes. Chinese patients with LS, compared with sporadic CRCs, tended to be early-onset, right-sided, early-stage and mucinous. Overall, the performance of MMR IHC and MSI testing for LS pre-screening was comparable: the area under the ROC curve for dMMR, MSI-H, and MSI-H/L was 0.725, 0.750, and 0.745, respectively. dMMR_MSI-H LS and sporadic CRCs showed substantial differences in somatic genetic characteristics, including different variant frequencies of APC, CREBBP, and KRAS, as well as different enriched pathways of VEGF, Notch, TGFβR, mTOR, ErbB, and Rac protein signal transduction. Conclusions: MMR IHC and MSI testing were effective methods for LS pre-screening. The revealed clinical and somatic genetic characteristics in LS CRCs may have the potential to improve the performance of LS pre-screening in combination with dMMR/MSI.

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“…22 2. 6 | General steps for processing EPIC array data across cohorts Samples were excluded if they did not pass sex or ethnicity checks performed in SeSAMe. 23 Samples were processed in minfi using a detection P value of <0.01 for probe removal.…”

Section: Preprocessing Of Dna Methylation Microarray Data In Colon Or...mentioning

confidence: 99%

“…Individuals with LS often present with earlier onset cancers. Differences in lifetime risk estimates for LS subjects are thought to be driven by disease variant pathogenicity, the specific MMR gene involved, and other factors 6–8 . One challenge for the clinical management of LS is the need to identify additional molecular markers driving risk.…”

Section: Introductionmentioning

confidence: 99%

Multi‐omic analysis in normal colon organoids highlightsMSH4as a novel marker of defective mismatch repair in Lynch syndrome and microsatellite instability

et al. 2023

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Introduction Lynch syndrome (LS) is a hereditary condition that increases the risk of colorectal (CRC) and extracolonic cancers that exhibit microsatellite instability (MSI‐H). MSI‐H is driven by defective mismatch repair (dMMR), and approximately 15% of nonhereditary CRCs also exhibit MSI‐H. Here, we aimed to better define mechanisms underlying tumor initiation in LS and MSI‐H cancers through multi‐omic analyses of LS normal colon organoids and MSI‐H tumors. Methods Right (n = 35) and left (n = 23) colon organoids generated from normal colon biopsies at routine colonoscopy of LS and healthy individuals were subjected to Illumina EPIC array. Differentially methylated region (DMR) analysis was performed by DMRcate. RNA‐sequencing (n = 16) and bisulfite‐sequencing (n = 15) were performed on a subset of right colon organoids. CRISPR‐cas9‐mediated editing of MMR genes in colon organoids of healthy individuals was followed by quantitative PCR of MSH4. The relationship between MSH4 expression and tumor mutational burden was further explored in three independent tumor data sets. Results We identified a hypermethylated region of MSH4 in both the right and left colon organoids of LS versus healthy controls, which we validated using bisulfite‐sequencing. DMR analysis in three gastrointestinal and one endometrial data set revealed that this region was also hypermethylated in MSI‐H versus microsatellite stable (MSS) tumors. MSH4 expression was increased in colon organoids of LS versus healthy subjects and in publicly available MSI‐H versus MSS tumors across four RNA‐seq and four microarray data sets. CRISPR‐cas9 editing of MLH1 and MSH2, but not MSH6, in normal colon organoids significantly increased MSH4 expression. MSH4 expression was significantly associated with tumor mutational burden in three publicly available data sets. Conclusions Our findings implicate DNA methylation and gene expression differences of MSH4 as a marker of dMMR and as a potential novel biomarker of LS. Our study of LS colon organoids supports the hypothesis that dMMR exists in the colons of LS subjects prior to CRC.

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The diverse molecular profiles of lynch syndrome-associated colorectal cancers are (highly) dependent on underlying germline mismatch repair mutations

Cited by 21 publications

References 81 publications

Teenage-Onset Colorectal Cancers in a Digenic Cancer Predisposition Syndrome Provide Clues for the Interaction between Mismatch Repair and Polymerase δ Proofreading Deficiency in Tumorigenesis

Teenage-Onset Colorectal Cancers in a Digenic Cancer Predisposition Syndrome Provide Clues for the Interaction between Mismatch Repair and Polymerase δ Proofreading Deficiency in Tumorigenesis

Lynch syndrome pre-screening and comprehensive characterization in a multi-center large cohort of Chinese patients with colorectal cancer

Multi‐omic analysis in normal colon organoids highlightsMSH4as a novel marker of defective mismatch repair in Lynch syndrome and microsatellite instability

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