Annual National HNPCC meeting

The Annual Meeting of the Finnish collaborative HNPCC reseach groups was organized in Haikko, Porvoo on 9th of June 2018.

Prof. Päivi Pelomäki gave an overview of the on-going research projects including an overview of the current status of the collaborative project initiated together with Prof. Jukka-Pekka Mecklin and Prof. Minna Nyström funded by Jane and Aatos Erkko Foundation in aim to recognize molecular mechanisms of colon cancer susceptibility. Noora Porkka, M.Sc and Satu Mäki-Nevala, PhD, presented projects related to epigenetic and genetic characterization of Lynch and Lynch-like syndrome cancer. Minttu Kansikas, PhD, and Marjaana Pussila, PhD, from Prof. Minna Nyströms lab presented on-going projects related to the development and validation of a non-invasive test to detect Lynch syndrome (http://www.lscancerdiag.com/) and assessment of the effects of MLH1 gene deficiency in normal colon mucosa on colon cancer chromosome stability.

M.Mc, Noora Porkka

PhD, Satu Mäki-Nevala

PhD, Minttu Kansikas

Mlh1 deficiency in normal mouse colon mucosa associates with chromosomally unstable colon cancer.

Pussila M, Törönen P, Einarsdottir E, Katayama S, Krjutškov K, Holm L, Kere J, Peltomäki P, Mäkinen MJ, Linden J, Nyström M.

Colorectal cancer (CRC) genome is unstable and different types of instabilities, such as chromosomal instability (CIN) and microsatellite instability (MSI) are thought to reflect distinct cancer initiating mechanisms. Although 85% of sporadic CRC reveal CIN, 15% reveal mismatch repair (MMR) malfunction and MSI, the hallmarks of Lynch syndrome with inherited heterozygous germline mutations in MMR genes. Our study was designed to comprehensively follow genome-wide expression changes and their implications during colon tumorigenesis. We conducted a long-term feeding experiment in the mouse to address expression changes arising in histologically normal colonic mucosa as putative cancer preceding events, and the effect of inherited predisposition (Mlh1+/-) and Western-style diet (WD) on those. During the 21-month experiment, carcinomas developed mainly in WD-fed mice and were evenly distributed between genotypes. Unexpectedly, the heterozygote (B6.129-Mlh1tm1Rak) mice did not show MSI in their CRCs. Instead, both wildtype and heterozygote CRC mice showed a distinct mRNA expression profile and shortage of several chromosomal segregation gene-specific transcripts (Mlh1, Bub1, Mis18a, Tpx2, Rad9a, Pms2, Cenpe, Ncapd3, Odf2 and Dclre1b) in their colon mucosa, as well as an increased mitotic activity and abundant numbers of unbalanced/atypical mitoses in tumours. Our genome-wide expression profiling experiment demonstrates that cancer preceding changes are already seen in histologically normal colon mucosa and that decreased expressions of Mlh1 and other chromosomal segregation genes may form a field-defect in mucosa, which trigger MMR-proficient, chromosomally unstable CRC.

Carcinogenesis. 2018 May 28;39(6):788-797.

Pubmed ID:29701748

Molecular Alterations of Endometrial and Ovarian Tumorigenesis in Lynch Syndrome Mutation Carriers and the General Population

Public PhD defence on 18th of May 2018, at 12 noon

Biomedicum Helsinki, Lecture hall 2

Docent Annika Auranen, M.Sc. Anni Niskakoski and Prof. Päivi Peltomäki

Author: M.Sc. Anni Niskakoski

Department of Medical and Clinical Genetics, University of Helsinki

Opponent: Docent Annika Auranen, M.D, Ph.D

Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland

Converging endometrial and ovarian tumorigenesis in Lynch syndrome: Shared origin of synchronous carcinomas

Niskakoski A, Pasanen A, Porkka N, Eldfors S, Lassus H, Renkonen-Sinisalo L, Kaur S, Mecklin JP, Bützow R, Peltomäki P.

OBJECTIVE: The diagnosis of carcinoma in both the uterus and the ovary simultaneously is not uncommon and raises the question of synchronous primaries vs. metastatic disease. Targeted sequencing of sporadic synchronous endometrial and ovarian carcinomas has shown that such tumors are clonally related and thus represent metastatic disease from one site to the other. Our purpose was to investigate whether or not the same applies to Lynch syndrome (LS), in which synchronous cancers of the gynecological tract are twice as frequent as in sporadic cases, reflecting inherited defects in DNA mismatch repair (MMR).

METHODS: MMR gene mutation carriers with endometrial or ovarian carcinoma or endometrial hyperplasia were identified from a nationwide registry. Endometrial (n = 35) and ovarian carcinomas (n = 23), including 13 synchronous carcinoma pairs, were collected as well as endometrial hyperplasias (n = 56) and normal endometria (n = 99) from a surveillance program over two decades. All samples were studied for MMR status, ARID1A and L1CAM protein expression and tumor suppressor gene promoter methylation, and synchronous carcinomas additionally for somatic mutation profiles of 578 cancer-relevant genes.

RESULTS: Synchronous carcinomas were molecularly concordant in all cases. Prior or concurrent complex (but not simple) endometrial hyperplasias showed a high degree of concordance with endometrial or ovarian carcinoma as the endpoint lesion.

CONCLUSIONS: Our investigation suggests shared origins for synchronous endometrial and ovarian carcinomas in LS, in analogy to sporadic cases. The similar degrees of concordance between complex hyperplasias and endometrial vs. ovarian carcinoma highlight converging pathways for endometrial and ovarian tumorigenesis overall.

Gynecol Oncol. 2018 Apr 28. doi: 10.1016/j.ygyno.2018.04.566. [Epub ahead of print]

PMID:29716739

Young researchers award for Anni Niskakoski

The Finnish Society of Medical Genetics (Suomen lääketieteellisen genetiikan yhdistys ry., SLGY) awarded the award for young researchers for M.Sc Anni Niskakoski from Prof. Päivi Peltomäki’s group. She received the award based on her excellent talk, entitled “Gynecological cancers in Lynch syndrome” in SLGY spring meeting in March the 23rd 2018.

Congratulations Anni.

M.Sc Anni Niskakoski

The best journal article prize for Denis Dermadi Bebek

PhD Denis Dermadi Bebek was awarded The best journal article prize for his article: Western Diet Deregulates Bile Acid Homeostasis, Cell Proliferation, and Tumorigenesis in Colon (Cancer Res. 2017 Jun 15;77(12):3352-3363. doi: 10.1158/0008-5472.CAN-16-2860. Epub 2017 Apr 17; PMID 28416481).

The Faculty of Biological and Environmental Sciences awarded article prizes for two young researchers (doctoral student and postdoctoral researcher) for the first time in April the 4th 2018. Denis Dermadi Bebek, from Prof. Minna Nyströms group, received the award for postdoctoral researches. The prize for doctoral students was awarded for Albert Spoljaric.

Congratulations.

https://www.helsinki.fi/en/news/life-science/best-journal-article-prizes-granted-to-albert-spoljaric-and-denis-dermadi-bebek

 

Molecular changes preceding endometrial and ovarian cancer: a study of consecutive endometrial specimens from Lynch syndrome surveillance

Niskakoski A, Pasanen A, Lassus H, Renkonen-Sinisalo L, Kaur S, Mecklin J-P, Bützow R and Peltomäki P

Molecular alterations preceding endometrial and ovarian cancer and the sequence of events are unknown. Consecutive specimens from lifelong surveillance for Lynch syndrome provides a natural setting to address such questions. To molecularly define the multistep gynecological tumorigenesis, DNA mismatch repair gene mutation carriers with endometrial or ovarian carcinoma or endometrial hyperplasia were identified from a nation-wide registry and endometrial biopsy specimens taken from these individuals during 20 years of screening were collected. A total of 213 endometrial and ovarian specimens from Lynch syndrome individuals and 197 histology-matched (non-serous) samples from sporadic cases were available for this investigation. The specimens were profiled for markers linked to endometrial and ovarian tumorigenesis, including ARID1A protein expression, mismatch repair status, and tumor suppressor gene promoter methylation. In Lynch syndrome-associated endometrial and ovarian carcinomas, ARID1A protein was lost in 61–100% and mismatch repair was deficient in 97–100%, compared to 0–17% and 14–44% in sporadic cases (P = 0.000). ARID1A loss appeared in complex hyperplasia and deficient mismatch repair and tumor suppressor gene promoter methylation in histologically normal endometrium. Despite quantitative differences between Lynch syndrome and sporadic cases, ARID1A expression, mismatch repair, and tumor suppressor gene promoter methylation divided endometrial samples from both patient groups into three categories of increasing abnormality, comprising normal endometrium and simple hyperplasia (I), complex hyperplasia with or without atypia (II), and endometrial cancer (III). Complex hyperplasias without vs. with atypia were molecularly indistinguishable. In conclusion, surveillance specimens from Lynch syndrome identify mismatch repair deficiency, tumor suppressor gene promoter methylation, and ARID1A loss as early changes in tumor development. Our findings are clinically relevant for the classification of endometrial hyperplasias and have potential implications in cancer prevention in Lynch syndrome and beyond.

Mod Pathol. 2018 Mar 27. doi: 10.1038/s41379-018-0044-4. [Epub ahead of print]

PMID: 29588532

 

Sequencing of Lynch syndrome tumors reveals the importance of epigenetic alterations

Porkka N, Valo S, Nieminen TT, Olkinuora A, Mäki-Nevala S, Eldfors S and Peltomäki P

Genomic instability and epigenetic aberrations are important classifiers of human tumors, yet, their interrelations are poorly understood. We used Lynch syndrome (LS) to address such relationships. Forty-five tumors (11 colorectal adenomas, 18 colorectal carcinomas, and 16 ovarian carcinomas) were profiled for CpG Island Methylator Phenotype (CIMP) and somatic mutations. All tumors showed high-degree microsatellite instability. Panel sequencing of 578 cancer-relevant genes revealed the average number of 1433, 1124, and 657 non-synonymous somatic mutations per colorectal adenoma, colorectal carcinoma, and ovarian carcinoma, respectively. Genes harboring mutations with allele frequency 25 % or higher in at least 31 % of tumors were regarded to be possible drivers. Among 72 and 10 such genes identified in colorectal and ovarian tumors, respectively, the most frequently mutated genes BRD4 and MLL2 (62 % of colorectal tumors) and ARID1A (50 % of ovarian carcinomas) are involved in epigenetic regulation. The total number of somatic mutations or mutant genes per tumor were significantly associated with CIMP. Our results suggest that even in an inherited disease, tumor type-specific epigenetic changes are significant and may result from regulatory changes (CIMP) or structural events (mutations of epigenetic regulatory genes). The findings are clinically relevant since many of the affected pathways can be therapeutically targeted.

Oncotarget, 2017

http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=22445&path%5B%5D=70979

eLS: Mismatch Repair Genes

Kansikas M, Nyström M & Peltomäki P.

The mismatch repair (MMR) system is necessary for the maintenance of genomic stability. The primary role of MMR is to correct errors such as base/base mismatches and small insertions/deletions that arise during DNA (deoxyribonucleic acid) synthesis. Loss of functional MMR results in increased rates of point mutations and microsatellite instability. Post-replicative MMR is strand-specific and serves mutation avoidance. Outside replication, discrimination between old and newly synthesised DNA strands is no longer necessary, and the MMR system can be mutagenic. Such non-canonical actions of MMR are required, for example, for the generation of immunoglobulin diversity. The anti-mutator and mutator activities of MMR play important roles in human diseases. Notably, germline mutations in MMR genes cause predisposition to Lynch syndrome, whereas epigenetic inactivation of the MMR gene MLH1 underlies 15% of sporadic colorectal and other cancers.

 

Link to updated article. eLS, 2017.