Publications by authors named "Taina Nieminen"

21 Publications

  • Page 1 of 1

Feasibility of preoperative adrenalectomy risk score in center with low operation-specific volume.

Minerva Surg 2021 May 4. Epub 2021 May 4.

Department of Surgery, Central Finland Central Hospital, Jyväskylä, Finland.

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http://dx.doi.org/10.23736/S2724-5691.21.08892-4DOI Listing
May 2021

A novel essential splice site variant in SPTB in a large hereditary spherocytosis family.

Mol Genet Genomic Med 2021 May 4;9(5):e1641. Epub 2021 May 4.

Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA.

Background: We studied a large family with 22 individuals affected with autosomal dominant hereditary spherocytosis (HS).

Methods: Genome-wide linkage, whole-genome sequencing (WGS), Sanger sequencing, RT-PCR, and ToPO TA cloning analyses were performed.

Results: We revealed a heterozygous G>A transition in the 14q23 locus, at position +1 of the intron 8 donor splice site of the spectrin beta, erythrocytic (SPTB) gene. This splice variant (SPTB c.1064+1G>A) was confirmed by Sanger sequencing and showed complete co-segregation with HS in the family. Further RT-PCR reactions and sequencing analysis indicated that the variant leads to the exclusion of exon 8 and subsequent frameshift in exon 9 and a premature stop codon in SPTB. Translation of the altered allele would lead to a truncation with a loss of all spectrin repeat domains in SPTB protein.

Conclusion: This variant is novel and has not been found in any databases. We propose that this splice variant explains the spherocytosis phenotype observed in this large family.
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http://dx.doi.org/10.1002/mgg3.1641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172196PMC
May 2021

Updates in the field of hereditary nonpolyposis colorectal cancer.

Expert Rev Gastroenterol Hepatol 2020 Aug 5;14(8):707-720. Epub 2020 Aug 5.

Department of Medical and Clinical Genetics, University of Helsinki , Helsinki, Finland.

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.
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http://dx.doi.org/10.1080/17474124.2020.1782187DOI Listing
August 2020

Molecular Basis of Mismatch Repair Protein Deficiency in Tumors from Lynch Suspected Cases with Negative Germline Test Results.

Cancers (Basel) 2020 Jul 9;12(7). Epub 2020 Jul 9.

Department of Medical and Clinical Genetics, University of Helsinki, 00014 Helsinki, Finland.

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 ( = 55) or research ( = 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 mutation screening; in our study, 3/11 index individuals (27%) with this IHC pattern revealed pathogenic germline mutations in . Individuals with isolated absence of MSH6 are routinely screened for mutations alone; we found a predisposing mutation in in 1/7 such cases (14%). Somatic deletion of the - 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 epimutation was identified in one case with an MLH1-deficient tumor. We conclude that both and should be screened in MSH2/6- and MSH6-deficient cases. In MLH1-deficient cases, constitutional epimutations of warrant consideration.
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http://dx.doi.org/10.3390/cancers12071853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408769PMC
July 2020

Thyroid Carcinomas That Occur in Familial Adenomatous Polyposis Patients Recurrently Harbor Somatic Variants in , , and .

Thyroid 2020 03;30(3):380-388

Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Familial adenomatous polyposis (FAP) is a condition typically caused by pathogenic germline mutations in the gene. In addition to colon polyps, individuals with FAP have a substantially increased risk of developing papillary thyroid cancer (PTC). Little is known about the events underlying this association, and the prevalence of somatic "second-hit" mutations in is controversial. Whole-genome sequencing was performed on paired thyroid tumor and normal DNA from 12 FAP patients who developed PTC. Somatic mutation profiles were compared with clinical characteristics and previously sequenced sporadic PTC cases. Germline variant profiling was performed to assess the prevalence of variants in genes previously shown to have a role in PTC predisposition. All 12 patients harbored germline mutations in , consistent with FAP. Seven patients also had somatic mutations in , and seven patients harbored somatic mutations in , which encodes a lysine methyl transferase. Mutation of these genes is extremely rare in sporadic PTCs. Notably, only two of the tumors harbored the somatic p.V600E mutation, which is the most common driver mutation found in sporadic PTCs. Six tumors displayed a cribriform-morular variant of PTC (PTC-CMV) histology, and all six had somatic mutations in . Additionally, nine FAP-PTC patients had rare germline variants in genes that were previously associated with thyroid carcinoma. Our data indicate that FAP-associated PTCs typically have distinct mutations compared with sporadic PTCs. Roughly half of the thyroid cancers that arise in FAP patients have somatic "second-hits" in , which is associated with PTC-CMV histology. Somatic p.V600E variants also occur in some FAP patients, a novel finding. We speculate that in carriers of heterozygous pathogenic mutations of tumor suppressor genes such as , a cooperating second-hit somatic variant may occur in a different gene such as or , leading to differences in phenotypes. The role of germline variance in genes other than APC (9 of the 12 patients in this series) needs further research.
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http://dx.doi.org/10.1089/thy.2019.0561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080217PMC
March 2020

A Truncating Germline Mutation of in Individuals with Thyroid Cancer or Melanoma Results in Longer Telomeres.

Thyroid 2020 02;30(2):204-213

Human Cancer Genetics Program and Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Our genome sequencing analysis revealed a frameshift mutation in the shelterin gene in a large family with individuals affected with papillary thyroid carcinoma (PTC) and melanoma. Here, we further characterized the mutation and screened for coding variants in the 6 shelterin genes in 24 families. Sanger sequencing was performed to screen for the mutation in the key family. Quantitative reverse transcription-polymerase chain reaction (PCR) was used for gene expression analysis. Exogenous expression and co-immunoprecipitation techniques were used for assessing TINF2 binding to TERF1. Relative telomere length (RTL) was quantified in DNAs from lymphocytes by using quantitative real-time PCR. Whole exome sequencing (WES) was performed in seven families with individuals affected with PTC and other cancer types. Screening for DNA variants in shelterin genes was performed by using whole genome sequencing data from 17 families and WES data from 7 further families. The mutation (TINF2 p.Trp198fs) showed complete co-segregation with PTC and melanoma in the key family. The mutation is not reported in databases and not identified in 23 other families we screened. The expression of was borderline reduced in individuals with the mutation. The truncated TINF2 protein showed abolished binding to TERF1. The RTL in the individuals with the mutation was significantly longer when compared with those without the mutation from the same family as well as compared with 62 healthy controls. Among the 24 families, we identified 3 missense and 1 synonymous variant(s) in 2 shelterin genes ( and ). The rare frameshift mutation in the gene and the associated longer telomere length suggest that dysregulated telomeres could be a mechanism predisposing to PTC and melanoma. DNA coding variants in shelterin genes are rare. Further studies are required to evaluate the roles of variants in shelterin genes in thyroid cancer and melanoma.
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http://dx.doi.org/10.1089/thy.2019.0156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047085PMC
February 2020

Identification of Rare Variants Predisposing to Thyroid Cancer.

Thyroid 2019 07 13;29(7):946-955. Epub 2019 May 13.

1Human Cancer Genetics Program and Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Familial non-medullary thyroid cancer (NMTC) accounts for a relatively small proportion of thyroid cancer cases, but it displays strong genetic predisposition. So far, only a few NMTC susceptible genes and low-penetrance variants contributing to NMTC have been described. This study aimed to identify rare germline variants that may predispose individuals to NMTC by sequencing a cohort of 17 NMTC families. Whole-genome sequencing and genome-wide linkage analysis were performed in 17 NMTC families. MendelScan and BasePlayer were applied to screen germline variants followed by customized filtering. The remaining candidate variants were subsequently validated by Sanger sequencing. A panel of 277 known cancer predisposition genes was also screened in these families. A total of 41 rare coding candidate variants in 40 genes identified by whole-genome sequencing are reported, including 24 missense, five frameshift, five splice change, and seven nonsense variants. Sanger sequencing confirmed all 41 rare variants and proved their co-segregation with NMTC in the extended pedigrees. functional analysis of the candidate genes using Ingenuity Pathway Analysis showed that cancer was the top category of "Diseases and Disorders." Additionally, a targeted search displayed six variants in known cancer predisposition genes, including one frameshift variant and five missense variants. The data identify rare germline variants that may play important roles in NMTC predisposition. It is proposed that in future research including functional characterization, these variants and genes be considered primary candidates for thyroid cancer predisposition.
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http://dx.doi.org/10.1089/thy.2018.0736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6648188PMC
July 2019

Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition.

Genet Med 2019 08 21;21(8):1868-1873. Epub 2018 Dec 21.

Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.

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.
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http://dx.doi.org/10.1038/s41436-018-0405-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752675PMC
August 2019

Sequencing of Lynch syndrome tumors reveals the importance of epigenetic alterations.

Oncotarget 2017 Dec 14;8(64):108020-108030. Epub 2017 Nov 14.

Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.

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 and (62 % of colorectal tumors) and (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.
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http://dx.doi.org/10.18632/oncotarget.22445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746122PMC
December 2017

Pseudoexons provide a mechanism for allele-specific expression of APC in familial adenomatous polyposis.

Oncotarget 2016 Oct;7(43):70685-70698

University of Helsinki, Medical and Clinical Genetics, Helsinki, Finland.

Allele-specific expression (ASE) of the Adenomatous Polyposis Coli (APC) gene occurs in up to one-third of families with adenomatous polyposis (FAP) that have screened mutation-negative by conventional techniques. To advance our understanding of the genomic basis of this phenomenon, 54 APC mutation-negative families (21 with classical FAP and 33 with attenuated FAP, AFAP) were investigated. We focused on four families with validated ASE and scrutinized these families by sequencing of the blood transcriptomes (RNA-seq) and genomes (WGS). Three families, two with classical FAP and one with AFAP, revealed deep intronic mutations associated with pseudoexons. In all three families, intronic mutations (c.646-1806T>G in intron 6, c.1408+729A>G in intron 11, and c.1408+731C>T in intron 11) created new splice donor sites resulting in the insertion of intronic sequences (of 127 bp, 83 bp, and 83 bp, respectively) in the APC transcript. The respective intronic mutations were absent in the remaining polyposis families and the general population. Premature stop of translation as the predicted consequence as well as co-segregation with polyposis supported the pathogenicity of the pseudoexons. We conclude that next generation sequencing on RNA and genomic DNA is an effective strategy to reveal and validate pseudoexons that are regularly missed by traditional screening methods and is worth considering in apparent mutation-negative polyposis families.
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http://dx.doi.org/10.18632/oncotarget.12206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342583PMC
October 2016

Desmoid tumor patients carry an elevated risk of familial adenomatous polyposis.

J Surg Oncol 2016 Feb 10;113(2):209-12. Epub 2015 Dec 10.

Department of Colorectal Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland.

Background: The prevalence of desmoid tumors among patients with familial adenomatous polyposis (FAP) is at least 10%, and the prevalence of FAP among desmoid patients varies between 7.5-16%.

Methods: Data included 106 desmoid patients identified from the database of the Department of Pathology, Helsinki University Hospital, years 2000-2012. We evaluated the risk of FAP among patients by using endoscopy and we identified individuals with attenuated FAP by APC gene mutation test. We compared sporadic desmoid patients' and FAP patients' clinical characteristics.

Results: Ten of 106 patients already had FAP diagnosis before the desmoid. Eleven patients had had FAP screening already earlier due to desmoid and three of them were found to have FAP. Total of 52 patients participated into prospective screening of FAP. No new cases of FAP were found. The risk of FAP among desmoid tumor patients was 4.8%. In the FAP desmoid group, there were more males and patients were younger than in the sporadic group. Intra-abdominal desmoids were more common in the FAP group.

Conclusions: Patients with desmoid carry an elevated risk of FAP and therefore screening is indicated. Asymptomatic patients with desmoid situated in extra truncal region may not need to be screened.
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http://dx.doi.org/10.1002/jso.24117DOI Listing
February 2016

Methyltransferase expression and tumor suppressor gene methylation in sporadic and familial colorectal cancer.

Genes Chromosomes Cancer 2015 Dec 25;54(12):776-87. Epub 2015 Aug 25.

Department of Medical and Clinical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.

Molecular mechanisms underlying coordinated hypermethylation of multiple CpG islands in cancer remain unclear and studies of methyltransferase enzymes have arrived at conflicting results. We focused on DNMT1 and DNMT3B, DNA methyltransferases responsible for (de novo) methylation, and EZH2, histone (H3K27) methyltransferase, and examined their roles in tumor suppressor gene (TSG) methylation patterns we have previously established in sporadic and familial cancers. Our investigation comprised 165 tumors, stratified by tissue of origin (117 colorectal and 48 endometrial carcinomas) and sporadic vs. familial disease (57 sporadic vs. 60 familial, mainly Lynch syndrome, colorectal carcinomas). By immunohistochemical evaluation, EZH2 protein expression was associated with a TSG methylator phenotype. DNMT1, DNMT3B, and EZH2 were expressed at significantly higher levels in tumor vs. normal tissues. DNMT1 and EZH2 expression were positively correlated and higher in microsatellite-unstable vs. microsatellite-stable tumors, whether sporadic or hereditary. Ki-67 expression mirrored the same pattern. Promoter methylation of the methyltransferase genes themselves was addressed as a possible cause behind their altered expression. While DNMT1 or EZH2 did not show differential methylation between normal and tumor tissues, DNMT3B analysis corroborated the regulatory role of a distal promoter region. Our study shows that methyltransferase expression in cancer depends on the tissue of origin, microsatellite-instability status, cellular proliferation, and--in the case of DNMT3B--promoter methylation of the respective gene. Translation of methyltransferase expression into DNA methylation appears complex as suggested by the fact that except for EZH2, no clear association between methyltransferase protein expression and TSG methylation was observed.
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http://dx.doi.org/10.1002/gcc.22289DOI Listing
December 2015

Reply: To PMID 24941021.

Gastroenterology 2015 Jan 22;148(1):259. Epub 2014 Nov 22.

Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.

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http://dx.doi.org/10.1053/j.gastro.2014.11.028DOI Listing
January 2015

Promoter-specific alterations of APC are a rare cause for mutation-negative familial adenomatous polyposis.

Genes Chromosomes Cancer 2014 Oct 20;53(10):857-64. Epub 2014 Jun 20.

Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland; Laboratorio de Citogenética y Mutagénesis, Instituto Multidisciplinario de Biología Celular (IMBICE-CONICET-CICPBA), La Plata, Argentina.

n familial adenomatous polyposis (FAP), 20% of classical and 70% of attenuated/atypical (AFAP) cases remain mutation-negative after routine testing; yet, allelic expression imbalance may suggest an APC alteration. Our aim was to determine the proportion of families attributable to genetic or epigenetic changes in the APC promoter region. We studied 51 unrelated families/cases (26 with classical FAP and 25 with AFAP) with no point mutations in the exons and exon/intron borders and no rearrangements by multiplex ligation-dependent probe amplification (MLPA, P043-B1). Promoter-specific events of APC were addressed by targeted resequencing, MLPA (P043-C1), methylation-specific MLPA, and Sanger sequencing of promoter regions. A novel 132-kb deletion encompassing the APC promoter 1B and upstream sequence occurred in a classical FAP family with allele-specific APC expression. No promoter-specific point mutations or hypermethylation were present in any family. In conclusion, promoter-specific alterations are a rare cause for mutation-negative FAP (1/51, 2%). The frequency and clinical correlations of promoter 1B deletions are poorly defined. This investigation provides frequencies of 1/26 (4%) for classical FAP, 0/25 (0%) for AFAP, and 1/7 (14%) for families with allele-specific expression of APC. Clinically, promoter 1B deletions may associate with classical FAP without extracolonic manifestations.
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http://dx.doi.org/10.1002/gcc.22197DOI Listing
October 2014

Germline mutation of RPS20, encoding a ribosomal protein, causes predisposition to hereditary nonpolyposis colorectal carcinoma without DNA mismatch repair deficiency.

Gastroenterology 2014 Sep 15;147(3):595-598.e5. Epub 2014 Jun 15.

Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.

Little is known about the genetic factors that contribute to familial colorectal cancer type X (FCCX), characterized by hereditary nonpolyposis colorectal carcinoma with no mismatch repair defects. Genetic linkage analysis, exome sequencing, tumor studies, and functional investigations of 4 generations of a FCCX family led to the identification of a truncating germline mutation in RPS20, which encodes a component (S20) of the small ribosomal subunit and is a new colon cancer predisposition gene. The mutation was associated with a defect in pre-ribosomal RNA maturation. Our findings show that mutations in a gene encoding a ribosomal protein can predispose individuals to microsatellite-stable colon cancer. Evaluation of additional FCCX families for mutations in RPS20 and other ribosome-associated genes is warranted.
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http://dx.doi.org/10.1053/j.gastro.2014.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155505PMC
September 2014

Loss of p15INK⁴b expression in colorectal cancer is linked to ethnic origin.

Asian Pac J Cancer Prev 2014 ;15(5):2083-7

College of Health Sciences, University of Sharjah, and Sharjah Institute for Medical Research, Sharjah, United Arab Emirates E-mail :

Colorectal cancers remain to be a common cause of cancer-related death. Early-onset cases as well as those of various ethnic origins have aggressive clinical features, the basis of which requires further exploration. The aim of this work was to examine the expression patterns of p15INK4b and SMAD4 in colorectal carcinoma of different ethnic origins. Fifty-five sporadic colorectal carcinoma of Egyptian origin, 25 of which were early onset, and 54 cancers of Finnish origin were immunohistochemically stained with antibodies against p15INK4b and SMAD4 proteins. Data were compared to the methylation status of the p15INK4b gene promotor. p15INK4b was totally lost or deficient (lost in ≥ 50% of tumor cell) in 47/55 (85%) tumors of Egyptian origin as compared to 6/50 (12%) tumors of Finnish origin (p=7e-15). In the Egyptian cases with p15INK4b loss and available p15INK4b promotor methylation status, 89% of cases which lost p15INK4b expression were associated with p15INK4b gene promotor hypermethylation. SMAD4 was lost or deficient in 25/54 (46%) tumors of Egyptian origin and 28/48 (58%) tumors of Finnish origin. 22/54 (41%) Egyptian tumors showed combined loss/deficiency of both p15INK4b and SMAD4, while p15INK4b was selectively lost/deficient with positive SMAD4 expression in 24/54 (44%) tumors. Loss of p15INK4b was associated with older age at presentation (>50 years) in the Egyptian tumors (p=0.04). These data show for the first time that p15INK4b loss of expression marks a subset of colorectal cancers and ethnic origin may play a role in this selection. In a substantial number of cases, the loss was independent of SMAD4 but rather associated with p15INK4b gene promotor hypermethylation and old age which could be related to different environmental exposures.
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http://dx.doi.org/10.7314/apjcp.2014.15.5.2083DOI Listing
December 2014

Breast carcinoma and Lynch syndrome: molecular analysis of tumors arising in mutation carriers, non-carriers, and sporadic cases.

Breast Cancer Res 2012 Jun 12;14(3):R90. Epub 2012 Jun 12.

Department of Medical Genetics, Biomedicum Helsinki, P,O,Box 63 (Haartmaninkatu 8), University of Helsinki, Helsinki, Finland, FIN-00014.

Introduction: Breast carcinoma is the most common cancer in women, but its incidence is not increased in Lynch syndrome (LS) and studies on DNA mismatch repair deficiency (MMR) in LS-associated breast cancers have arrived at conflicting results. This study aimed to settle the question as to whether breast carcinoma belongs to the LS tumor spectrum.

Methods: MMR status and epigenetic profiles were determined for all available breast carcinomas identified among 200 LS families from a nation-wide registry (23 tumors from mutation carriers and 18 from non-carriers). Sporadic breast carcinomas (n = 49) and other cancers (n = 105) from MMR gene mutation carriers were studied for comparison.

Results: The proportion of breast carcinomas that were MMR-deficient based on absent MMR protein, presence of microsatellite instability, or both was significantly (P = 0.00016) higher among breast carcinomas from mutation carriers (13/20, 65%) compared to non-carriers (0/14, 0%). While the average age at breast carcinoma diagnosis was similar in carriers (56 years) and non-carriers (54 years), it was lower for MMR-deficient versus proficient tumors in mutation carriers (53 years versus 61 years, P = 0.027). Among mutation carriers, absent MMR protein was less frequent in breast carcinoma (65%) than in any of seven other tumor types studied (75% to 100%). Tumor suppressor promoter methylation patterns were organ-specific and similar between breast carcinomas from mutation carriers and non-carriers.

Conclusions: Breast carcinoma from MMR gene mutation carriers resembles common breast carcinoma in many respects (for example, general clinicopathological and epigenetic profiles). MMR status makes a distinction: over half are MMR-deficient typical of LS spectrum tumors, while the remaining subset which is MMR-proficient may develop differently. The results are important for appropriate surveillance in mutation carriers and may be relevant for LS diagnosis in selected cases.
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http://dx.doi.org/10.1186/bcr3205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3446353PMC
June 2012

LINE-1 hypomethylation in familial and sporadic cancer.

J Mol Med (Berl) 2012 Jul 8;90(7):827-35. Epub 2012 Jan 8.

Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, PO Box 63 00014, Finland.

Increased and decreased methylation at specific sequences (hypermethylation and hypomethylation, respectively) is characteristic of tumor DNA compared to normal DNA and promotes carcinogenesis in multiple ways including genomic instability. Long interspersed element (LINE), an abundant class of retrotransposons, provides a surrogate marker for global hypomethylation. We developed methylation-specific multiplex ligation-dependent probe amplification assays to study LINE-1 methylation in cases of colorectal, gastric, and endometrial cancer (N = 276), stratified by patient category [sporadic; Lynch syndrome (LS); familial colorectal cancer type X (FCCX)] and microsatellite instability status. Within each patient group, LINE-1 showed lower methylation in tumor DNA relative to paired normal DNA and hypomethylation was statistically significant in most cases. Interestingly, normal colorectal mucosa samples from different patient groups displayed differences in LINE-1 methylation that mirrored differences between the respective tumor tissues, with a decreasing trend for LINE-1 methylation from patients with sporadic colorectal cancer to LS to FCCX. Despite the fact that the degree of LINE-1 methylation is generally tissue specific, normal colorectal mucosa, gastric mucosa, and endometrium from LS patients showed similar levels of LINE-1 methylation. Our results suggest that the degree of LINE-1 methylation may constitute a "field defect" that may predispose normal tissues for cancer development.
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http://dx.doi.org/10.1007/s00109-011-0854-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383956PMC
July 2012

Distinct genetic and epigenetic signatures of colorectal cancers according to ethnic origin.

Cancer Epidemiol Biomarkers Prev 2012 Jan 25;21(1):202-11. Epub 2011 Oct 25.

Department of Medical Genetics, University of Helsinki, Helsinki, Finland.

Background: The outcome of colorectal cancer varies depending on ethnic origin. Egyptian colorectal carcinoma is surprisingly young-age disease with high proportion of rectal and advanced stage cancers.

Methods: We characterized 69 sporadic Egyptian colorectal cancers for promoter methylation at 24 tumor suppressor genes, microsatellite instability, and expression of mismatch repair, p53, and β-catenin proteins. Data were compared with 80 Western colorectal carcinoma of sporadic and familial origin from Finland.

Results: Egyptian colorectal carcinomas showed significantly higher methylation of the microsatellite stable (MSS) tumors as reflected by the average number of methylated genes per case (P = 0.00002) and tumor suppressor gene methylator phenotype (TSGMP), defined here as methylation of ≥ 5 genes, (P = 0.0001) compared with the sporadic Western cancers. The TSGMP was associated with advanced stage in the Egyptian cancers (P = 0.0016). Four genes were differentially methylated between Egyptian and Western cases, of which the association of CDKN2B/p15 methylation with Egyptian origin was outstanding (P = 4.83 E-10). Egyptian carcinoma also showed significantly lower frequency of nuclear β-catenin localization than the sporadic Western cancers (P = 0.00006) but similar to that of the familial Western subset designated as familial colorectal cancer type X.

Conclusions: We show novel pathway in colon carcinogenesis marked by high methylation of MSS cancers, remarkable CDKN2B/p15 methylation, and low frequency of Wnt signaling activation.

Impact: Our findings highlight the possible effect of environmental exposures in carcinogenesis through DNA methylation and should have applications in prevention, molecular diagnosis, prognosis, and treatment.
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http://dx.doi.org/10.1158/1055-9965.EPI-11-0662DOI Listing
January 2012

Molecular analysis of endometrial tumorigenesis: importance of complex hyperplasia regardless of atypia.

Clin Cancer Res 2009 Sep 1;15(18):5772-83. Epub 2009 Sep 1.

Department of Medical Genetics, University of Helsinki, Helsinki, Finland.

Purpose: Endometrial carcinoma (EC) is common in the population and the most frequent extracolonic malignancy in hereditary nonpolyposis colorectal carcinoma (HNPCC)/Lynch syndrome. We characterized precursor lesions of endometrioid EC to identify markers of malignant transformation and tumor progression.

Experimental Design: Serial specimens of normal endometrium, simple hyperplasia, complex hyperplasia without atypia, complex hyperplasia with atypia, and endometrial carcinoma obtained during a 10-year surveillance of DNA mismatch repair (MMR) gene mutation carriers (together 110 samples) were molecularly profiled and compared with a sporadic reference series of endometrial specimens taken for nonmalignant reasons (62 samples).

Results: Among MMR gene mutation carriers, decreased MMR protein expression was present in 7% in normal endometrium, 40% in simple hyperplasia, 100% in complex hyperplasia without atypia, 92% in complex hyperplasia with atypia, and 100% in endometrial carcinoma. Microsatellite instability frequencies were lower (6%, 17%, 67%, 38%, and 64%, respectively). Among 24 tumor suppressor genes, the number of methylated loci increased from normal endometrium to simple hyperplasia to complex hyperplasia (complex hyperplasia without atypia/complex hyperplasia with atypia) in both Lynch syndrome and reference series. The most frequently methylated genes were CDH13, RASSF1A, and GSTP1. In MMR gene mutation carriers, MMR and methylation defects appeared up to 12 years before endometrial carcinoma.

Conclusions: Molecular changes in endometrial tissue are detectable several years before endometrial carcinoma in genetically predisposed individuals. Abnormal MMR and methylation classify normal endometrium and simple hyperplasia into one category and complex hyperplasia without atypia, complex hyperplasia with atypia, and endometrial carcinoma into another, suggesting that, contrary to a traditional view, complex hyperplasia without atypia and complex hyperplasia with atypia are equally important as precursor lesions of endometrial carcinoma.
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http://dx.doi.org/10.1158/1078-0432.CCR-09-0506DOI Listing
September 2009
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