Peltomäki P, Olkinuora A, Nieminen TT
Introduction: Up to one third of colorectal cancers show familial clustering and 5% are hereditary single-gene disorders. Hereditary non-polyposis colorectal cancer comprises DNA mismatch repair-deficient and -proficient subsets, represented by Lynch syndrome (LS) and familial colorectal cancer type X (FCCTX), respectively. Accurate knowledge of molecular etiology and genotype-phenotype correlations are critical for tailored cancer prevention and treatment.
Areas covered: The authors highlight advances in the molecular dissection of hereditary non-polyposis colorectal cancer, based on recent literature retrieved from PubMed. Future possibilities for novel gene discoveries are discussed.
Expert commentary: LS is molecularly well established, but new information is accumulating of the associated clinical and tumor phenotypes. FCCTX remains poorly defined, but several promising candidate genes have been discovered and share some preferential biological pathways. Multi-level characterization of specimens from large patient cohorts representing multiple populations, combined with proper bioinformatic and functional analyses, will be necessary to resolve the outstanding questions.
Keywords: DNA mismatch repair; Hereditary non-polyposis colorectal cancer; constitutional epimutation; familial colorectal cancer type X; genomic instability; germline mutation; lynch syndrome.
Expert Rev Gastroenterol Hepatol. 2020 Aug 5;1-14.
Olkinuora A, Gylling A, Almusa H, Eldfors S, Lepistö A, Mecklin J P, Nieminen T T., & Peltomäki P.
Some 10-50% of Lynch-suspected cases with abnormal immunohistochemical (IHC) staining remain without any identifiable germline mutation of DNA mismatch repair (MMR) genes. MMR proteins form heterodimeric complexes, giving rise to distinct IHC patterns when mutant. Potential reasons for not finding a germline mutation include involvement of an MMR gene not predicted by the IHC pattern, epigenetic mechanism of predisposition, primary mutation in another DNA repair or replication-associated gene, and double somatic MMR gene mutations. We addressed these possibilities by germline and tumor studies in 60 Lynch-suspected cases ascertained through diagnostics (n = 55) or research (n = 5). All cases had abnormal MMR protein staining in tumors but no point mutation or large rearrangement of the suspected MMR genes in the germline. In diagnostic practice, MSH2/MSH6 (MutS Homolog 2/MutS Homolog 6) deficiency prompts MSH2 mutation screening; in our study, 3/11 index individuals (27%) with this IHC pattern revealed pathogenic germline mutations in MSH6. Individuals with isolated absence of MSH6 are routinely screened for MSH6 mutations alone; we found a predisposing mutation in MSH2 in 1/7 such cases (14%). Somatic deletion of the MSH2-MSH6 region, joint loss of MSH6 and MSH3 (MutS Homolog 3) proteins, and hindered MSH2/MSH6 dimerization offered explanations to misleading IHC patterns. Constitutional epimutation hypothesis was pursued in the MSH2 and/or MSH6-deficient cases plus 38 cases with MLH1 (MutL Homolog 1)-deficient tumors; a primary MLH1 epimutation was identified in one case with an MLH1-deficient tumor. We conclude that both MSH2 and MSH6 should be screened in MSH2/6- and MSH6-deficient cases. In MLH1-deficient cases, constitutional epimutations of MLH1 warrant consideration.
Keywords: DNA mismatch repair; Lynch syndrome; colorectal cancer; deep sequencing.
Cancers (Basel) 2020 Jul 9;12(7):E1853.
Mariann Kasela, M.Sc. will defend the doctoral dissertation entitled “Reduced mismatch repair gene expression and functional deficiency as indicators of Lynch syndrome” in the Faculty of Biological and Environmental Sciences, University of Helsinki, on 26 June 2020 at 12:00. The public examination will take place at the following address: Porthania, P673, Yliopistonkatu 3.
Professor Karl Heinimann, University of Basel, Switzerland, will serve as the opponent, and Professor Minna Nyström as the custos.
The dissertation will be published in the series Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Unviersitatis Helsinkiensis.
The dissertation is also available in electronic form through the E-thesis service.
Porkka NK, Olkinuora A, Kuopio T, Ahtiainen M, Eldfors S, Almusa H, Mecklin JP, Peltomäki P.
Inherited DNA mismatch repair (MMR) defects cause predisposition to colorectal, endometrial, ovarian, and other cancers occurring in Lynch syndrome (LS). It is unsettled whether breast carcinoma belongs to the LS tumor spectrum. We approached this question through somatic mutational analysis of breast carcinomas from LS families, using established LS-spectrum tumors for comparison. Somatic mutational profiles of 578 cancer-relevant genes were determined for LS-breast cancer (LS-BC, n = 20), non-carrier breast cancer (NC-BC, n = 10), LS-ovarian cancer (LS-OC, n = 16), and LS-colorectal cancer (LS-CRC, n = 18) from the National LS Registry of Finland. Microsatellite and MMR protein analysis stratified LS-BCs into MMR-deficient (dMMR, n = 11) and MMR-proficient (pMMR, n = 9) subgroups. All NC-BCs were pMMR and all LS-OCs and LS-CRCs dMMR. All but one dMMR LS-BCs were hypermutated (> 10 non-synonymous mutations/Mb; average 174/Mb per tumor) and the frequency of MMR-deficiency-associated signatures 6, 20, and 26 was comparable to that in LS-OC and LS-CRC. LS-BCs that were pMMR resembled NC-BCs with respect to somatic mutational loads (4/9, 44%, hypermutated with average mutation count 33/Mb vs. 3/10, 30%, hypermutated with average 88 mutations/Mb), whereas mutational signatures shared features of dMMR LS-BC, LS-OC, and LS-CRC. Epigenetic regulatory genes were significantly enriched as mutational targets in LS-BC, LS-OC, and LS-CRC. Many top mutant genes of our LS-BCs have previously been identified as drivers of unselected breast carcinomas. In conclusion, somatic mutational signatures suggest that conventional MMR status of tumor tissues is likely to underestimate the significance of the predisposing MMR defects as contributors to breast tumorigenesis in LS.
DNA mismatch repair; Lynch syndrome; MSI; breast carcinoma; somatic mutation
Oncotarget. 2020 Apr 7;11(14):1244-1256.
PubMed ID: 32292574
Public PhD defence on 17th April 2020 at 12:00.
Due to the COVID-19 pandemia, event was arranged only among few individuals and streamed live for the audience via UniTube.
Professor Arto Mannermaa and M.Sc. Noora Porkka
Professor Päivi Peltomäki and M.Sc. Noora Porkka
Author: M.Sc. Noora Porkka
Department of Medical and Clinical Genetics, University of Helsinki
Opponent: Prof. Arto Mannermaa
Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
The 4th EHTG meeting was organized in Barcelona, Spain on 17th-19th October 2019.
Professor Minna Nyström gave a presentation about the DiagMMR®, a novel carrier test to detect inherited MMR deficiency.
Prof., Minna Nyström
PhD Satu Mäki-Nevala and M.Sc Noora Porkka from Professor Päivi Peltomäki’s group presented their latest studies in short oral presentations and as poster presentations.
Satu Mäki-Nevala was awarded a poster award for presenting one of the three best posters in the meeting. Congratulations Satu!
PhD, Satu Mäki-Nevala
PhD, Satu Mäki-Nevala with her award winning poster
M.Sc, Noora Porkka
M.Sc, Noora Porkka
The 7th biennial International Society for Gastrointestinal Hereditary tumors Incorporated (InSIGHT) meeting was organized in Auckland, New Zealand on 20-23rd of March.
M.Sc. Noora Porkka
Olkinuora A, Nieminen TT, Mårtensson E, Rohlin A, Ristimäki A, Koskenvuo L, Lepistö A, Swedish Extended Genetic Analysis of Colorectal Neoplasia (SWEN) Study Group, Gebre-Medhin S, Nordling M, Peltomäki P.
PURPOSE: Some 10% of familial adenomatous polyposis (FAP) and 80% of attenuated polyposis (AFAP) cases remain molecularly unexplained. We scrutinized such cases by exome-wide and targeted methods to search for novel susceptibility genes.
METHODS: Exome sequencing was conducted on 40 unexplained (mainly sporadic) cases with FAP or AFAP from Finland. The DNA mismatch repair (MMR) gene MLH3 (MutL Homolog 3) was pinpointed and prompted a subsequent screen of ~1000 Swedish patients referred to clinical panel sequencing for colon tumor susceptibility.
RESULTS: Three homozygous carriers of a truncating variant in MLH3, c.3563C>G, p.Ser1188Ter, were identified among the index cases from the Finnish series. An additional biallelic carrier of the same variant was present in the Swedish series. All four patients shared a 0.8-Mb core haplotype around MLH3, suggesting a founder variant. Colorectal polyps from variant carriers showed no instability at mono-, di-, tri-, or tetranucleotide repeats, in agreement with previous findings of a minor role of MLH3 in MMR. Multiple loci were affected by loss of heterozygosity, suggesting chromosomal instability.
CONCLUSION: Our results show that a biallelic nonsense variant of MLH3 underlies a novel syndrome with susceptibility to classical or attenuated adenomatous polyposis and possibly extracolonic tumors, including breast cancer.
Genet Med. 2018 Dec 21. [Epub ahead of print]
PubMed ID: 30573798
Noora Porkka, Laura Lahtinen, Maarit Ahtiainen, Jan Böhm, Teijo Kuopio, Samuli Eldfors, Jukka-Pekka Mecklin, Toni Seppälä, Päivi Peltomäki
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.
Int J Cancer. 2019 Jul 1;145(1):87-98.
PubMed ID 30575961
Satu Mäki-Nevala, Satu Valo, Ari Ristimäki, Virinder Sarhadi, Sakari Knuutila, Minna Nyström, Laura Renkonen-Sinisalo, Anna Lepistö, Jukka-Pekka Mecklin, Päivi Peltomäki.
Background: DNA mismatch repair (MMR) defects are a major factor in colorectal tumorigenesis in Lynch syndrome (LS) and 15% of sporadic cases. Some adenomas from carriers of inherited MMR gene mutations have intact MMR protein expression implying other mechanisms accelerating tumorigenesis. We determined roles of DNA methylation changes and somatic mutations in cancer-associated genes as tumorigenic events in LS-associated colorectal adenomas with intact MMR.Methods: We investigated 122 archival colorectal specimens of normal mucosae, adenomas and carcinomas from 57 LS patients. MMR-deficient (MMR-D, n = 49) and MMR-proficient (MMR-P, n = 18) adenomas were of particular interest and were interrogated by methylation-specific multiplex ligation-dependent probe amplification and Ion Torrent sequencing.Findings: Promoter methylation of CpG island methylator phenotype (CIMP)-associated marker genes and selected colorectal cancer (CRC)-associated tumor suppressor genes (TSGs) increased and LINE-1 methylation decreased from normal mucosa to MMR-P adenomas to MMR-D adenomas. Methylation differences were statistically significant when either adenoma group was compared with normal mucosa, but not between MMR-P and MMR-D adenomas. Significantly increased methylation was found in multiple CIMP marker genes (IGF2, NEUROG1, CRABP1, and CDKN2A) and TSGs (SFRP1 and SFRP2) in MMR-P adenomas already. Furthermore, certain CRC-associated somatic mutations, such as KRAS, were prevalent in MMR-P adenomas.
Interpretation: We conclude that DNA methylation changes and somatic mutations of cancer-associated genes might serve as an alternative pathway accelerating LS-associated tumorigenesis in the presence of proficient MMR.
EBioMedicine 2019 Jan;39:280-291.