Sequencing of Lynch syndrome tumors reveals the importance of epigenetic alterations

Porkka, Noora; Valo, Satu; Nieminen, Taina T.; Olkinuora, Alisa; Mäki-Nevala, Satu; Eldfors, Samuli; Peltomäki, Païvi

doi:10.18632/oncotarget.22445

Cited by 19 publications

(43 citation statements)

References 47 publications

(61 reference statements)

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“…). We previously profiled 18 LS tumors from the national LS registry on the same sequencing platform as the present LLS tumors . These tumors were now re‐analyzed by the same bioinformatics pipeline as our LLS tumors and used for comparison.…”

Section: Resultsmentioning

confidence: 99%

“…Setting the cut‐off at 4 of 14 tumors (29%) mutant for a given gene (in analogy to Ref. ), 13 top mutant genes were detected in LLS tumors (Fig. a ).…”

Section: Resultsmentioning

confidence: 99%

“…Sixteen colorectal cancer samples in which MLH1 methylation or LS registry information did not explain the dMMR phenotype, and their corresponding normal samples were included in CCP sequencing. Sequencing was conducted in the Institute for Molecular Medicine Finland (FIMM; Helsinki, Finland), as described . Nimblegen Comprehensive Cancer Panel (Roche Diagnostics) was used to target 578 cancer‐related genes with a 4 Mb design compiled from the Sanger Institute Cancer Gene Census Database and the NCBI Gene tests databases.…”

Section: Methodsmentioning

confidence: 99%

“…For each of the 578 genes targeted, we determined the proportion of tumors in which a particular gene was mutant according to our criteria for non‐synonymous somatic mutations described above. To identify top mutated genes, the cut‐off method developed earlier was applied . Based on the distribution of mutated genes across the tumors, a cut‐off of 29% (LLS) or 28% (LS) was set, as described in detail in Supporting Information Table below.…”

Section: Methodsmentioning

confidence: 99%

“…The relative shares of LS, MLH1 ‐hypermethylated and LLS fractions of colorectal cancers were determined. For the LLS tumors, the somatic mutation profiles of 578 cancer‐associated genes were established and compared to those of LS colorectal tumors from our previous investigation . Our study provides important new information of the molecular epidemiology and underlying developmental mechanisms of LLS.…”

Section: Introductionmentioning

confidence: 99%

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Epidemiological, clinical and molecular characterization of Lynch‐like syndrome: A population‐based study

Porkka

Lahtinen

Ahtiainen

et al. 2019

Intl Journal of Cancer

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Colorectal carcinomas that are mismatch repair (MMR)‐deficient in the absence of MLH1 promoter methylation or germline mutations represent Lynch‐like syndrome (LLS). Double somatic events inactivating MMR genes are involved in the etiology of LLS tumors. Our purpose was to define the clinical and broader molecular hallmarks of LLS tumors and the population incidence of LLS, which remain poorly characterized. We investigated 762 consecutive colorectal carcinomas operated in Central Finland in 2000–2010. LLS cases were identified by a stepwise protocol based on MMR protein expression, MLH1 methylation and MMR gene mutation status. LLS tumors were profiled for CpG Island Methylator Phenotype (CIMP) and somatic mutations in 578 cancer‐relevant genes. Among 107 MMR‐deficient tumors, 81 (76%) were attributable to MLH1 promoter methylation and 9 (8%) to germline mutations (Lynch syndrome, LS), leaving 14 LLS cases (13%) (3 remained unclassified). LLS carcinomas were diagnosed at a mean age of 65 years (vs. 44 years in LS, p < 0.001), had a proximal to distal ratio of 1:1, and all were BRAF V600E‐negative. Two somatic events in MMR genes were identifiable in 11 tumors (79%). As novel findings, the tumors contained an average of 31 nonsynonymous somatic mutations/Mb and 13/14 were CIMP‐positive. In conclusion, we establish the epidemiological, clinical and molecular characteristics of LLS in a population‐based study design. Significantly more frequent CIMP‐positivity and lower rates of somatic mutations make a distinction to LS. The absence of BRAF V600E mutation separates LLS colorectal carcinomas from MLH1‐methylated colorectal carcinomas with CIMP‐positive phenotype.

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Section: Resultsmentioning

confidence: 99%

“…Setting the cut‐off at 4 of 14 tumors (29%) mutant for a given gene (in analogy to Ref. ), 13 top mutant genes were detected in LLS tumors (Fig. a ).…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epidemiological, clinical and molecular characterization of Lynch‐like syndrome: A population‐based study

Porkka

Lahtinen

Ahtiainen

et al. 2019

Intl Journal of Cancer

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A computational model for investigating the evolution of colonic crypts during Lynch syndrome carcinogenesis

et al. 2021

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Lynch syndrome (LS), the most common inherited colorectal cancer (CRC) syndrome, increases the cancer risk in affected individuals. LS is caused by pathogenic germline variants in one of the DNA mismatch repair (MMR) genes, complete inactivation of which causes numerous mutations in affected cells.As CRC is believed to originate in colonic crypts, understanding the intra-crypt dynamics caused by mutational processes is essential for a complete picture of LS CRC and may have significant implications for cancer prevention.We propose a computational model describing the evolution of colonic crypts during LS carcinogenesis. Extending existing modeling approaches for the non-Lynch scenario, we incorporated MMR deficiency and implemented recent experimental data demonstrating that somatic CTNNB1 mutations are common drivers of LS-associated CRCs, if affecting both alleles of the gene. Further, we simulated the effect of different mutations on the entire crypt, distinguishing non-transforming and transforming mutations. As an example, we analyzed the spread of mutations in the genes APC and CTNNB1, which are frequently mutated in LS tumors, as well as of MMR deficiency itself. We quantified each mutation's potential for monoclonal conversion and investigated the influence of the cell location and of stem cell dynamics on mutation spread. The in silico experiments underline the importance of stem cell dynamics for the overall crypt evolution. Further, simulating different mutational processes is essential in LS since mutations without survival advantages (the MMR deficiency-inducing second hit) play a key role. The effect of other mutations can be simulated with the proposed model. Our results provide first mathematical clues towards more effective surveillance protocols for LS carriers.

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Somatic mutation profiles as molecular classifiers of ulcerative colitis‐associated colorectal cancer

Mäki-Nevala

Ukwattage

Olkinuora

et al. 2021

Intl Journal of Cancer

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Ulcerative colitis increases colorectal cancer risk by mechanisms that remain incompletely understood. We approached this question by determining the genetic and epigenetic profiles of colitis-associated colorectal carcinomas (CA-CRC). The findings were compared to Lynch syndrome (LS), a different form of cancer predisposition that shares the importance of immunological factors in tumorigenesis. CA-CRCs (n = 27) were investigated for microsatellite instability, CpG island methylator phenotype and somatic mutations of 999 cancer-relevant genes ("Pan-cancer" panel). A subpanel of "Pan-cancer" design (578 genes) was used for LS colorectal tumors (n = 28). Mutational loads and signatures stratified CA-CRCs into three subgroups: hypermutated microsatellite-unstable (Group 1, n = 1), hypermutated microsatellite-stable (Group 2, n = 9) and nonhypermutated microsatellite-stable (Group 3, n = 17). The Group 1 tumor was the only one with MLH1 promoter hypermethylation and exhibited the mismatch repair deficiency-associated Signatures 21 and 15. Signatures 30 and 32 characterized Group 2, whereas no prominent single signature existed in Group 3. TP53, the most common mutational target in CA-CRC (16/27, 59%), was similarly affected in Groups 2 and 3, but DNA repair genes and Wnt signaling genes were mutated significantly more often in Group 2. In LS tumors, the degree of hypermutability exceeded that of the hypermutated CA-CRC Groups 1 and 2, and somatic mutational profiles and signatures were different. In conclusion, Groups 1 (4%) and 3 (63%) comply with published studies, whereas Group 2 (33%) is novel. The existence of molecularly distinct subgroups within CA-CRC may guide clinical management, such as therapy options.

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Sequencing of Lynch syndrome tumors reveals the importance of epigenetic alterations

Cited by 19 publications

References 47 publications

Epidemiological, clinical and molecular characterization of Lynch‐like syndrome: A population‐based study

Epidemiological, clinical and molecular characterization of Lynch‐like syndrome: A population‐based study

A computational model for investigating the evolution of colonic crypts during Lynch syndrome carcinogenesis

Somatic mutation profiles as molecular classifiers of ulcerative colitis‐associated colorectal cancer

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