Novel germline MLH1 and MSH2 mutations in latvian Lynch syndrome families

Novel germline MLH1 and MSH2 mutations in latvian Lynch syndrome families

Background/Aims: Hereditary non-polyposis colorectal cancer or Lynch syndrome is an autosomal dominantly inherited disease with high penetrance, mostly due to mutations in the MLH1 and MSH2 genes. The aim of this study is to investigate the mutation spectrum of the MLH1 and MSH2 genes. Methodology:...

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Published in:Experimental Oncology
Date:2012
Main Authors: Berzina, D., Irmejs, A., Kalniete, D., Borosenko, V., Nakazawa-Miklasevica, M., Ribenieks, K., Trofimovics, G., Gardovskis, J., Miklasevics, E.
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Language:English
Published: Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України 2012
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Cite this:Novel germline MLH1 and MSH2 mutations in latvian Lynch syndrome families / D. Berzina, A. Irmejs, D. Kalniete, V. Borosenko, M. Nakazawa-Miklasevica, K. Ribenieks, G. Trofimovics, J. Gardovskis, E. Miklasevics // Experimental Oncology. — 2012. — Т. 34, № 1. — С. 49-52. — Бібліогр.: 24 назв. — англ.

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Digital Library of Periodicals of National Academy of Sciences of Ukraine
id nasplib_isofts_kiev_ua-123456789-138723
record_format dspace
spelling Berzina, D.
Irmejs, A.
Kalniete, D.
Borosenko, V.
Nakazawa-Miklasevica, M.
Ribenieks, K.
Trofimovics, G.
Gardovskis, J.
Miklasevics, E.
2018-06-19T12:13:18Z
2018-06-19T12:13:18Z
2012
Novel germline MLH1 and MSH2 mutations in latvian Lynch syndrome families / D. Berzina, A. Irmejs, D. Kalniete, V. Borosenko, M. Nakazawa-Miklasevica, K. Ribenieks, G. Trofimovics, J. Gardovskis, E. Miklasevics // Experimental Oncology. — 2012. — Т. 34, № 1. — С. 49-52. — Бібліогр.: 24 назв. — англ.
1812-9269
https://nasplib.isofts.kiev.ua/handle/123456789/138723
Background/Aims: Hereditary non-polyposis colorectal cancer or Lynch syndrome is an autosomal dominantly inherited disease with high penetrance, mostly due to mutations in the MLH1 and MSH2 genes. The aim of this study is to investigate the mutation spectrum of the MLH1 and MSH2 genes. Methodology: High risk colorectal cancer families were selected from overall 1053 consecutive patients. Screening of germline mutations in the MLH1 and MSH2 was performed by direct sequencing and multiplex ligation-dependent probe amplification. Results: Ten patients fulfilled the Amsterdam I/II criteria and Bethesda guidelines of the Lynch syndrome. Three novel mutations were identified in MLH1 and MSH2 genes, as well as two known mutations in the MLH1 gene. Large rearrangements in the MLH1 gene were found in two patients. Conclusions: The mutations in the MLH1 and MSH2 genes in Latvian high-risk families are highly heterogeneous. Combination of direct sequencing and MLPA is the most appropriate molecular method of detecting hereditary nonpolyposis colorectal cancer patients and family members at risk.
This study was supported by The National Research Programme “Development of new prevention, treatment, diagnostics means and practices and biomedicine technologies for improvement of public health”.
en
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
Experimental Oncology
Original contributions
Novel germline MLH1 and MSH2 mutations in latvian Lynch syndrome families
Article
published earlier
institution Digital Library of Periodicals of National Academy of Sciences of Ukraine
collection DSpace DC
title Novel germline MLH1 and MSH2 mutations in latvian Lynch syndrome families
spellingShingle Novel germline MLH1 and MSH2 mutations in latvian Lynch syndrome families
Berzina, D.
Irmejs, A.
Kalniete, D.
Borosenko, V.
Nakazawa-Miklasevica, M.
Ribenieks, K.
Trofimovics, G.
Gardovskis, J.
Miklasevics, E.
Original contributions
title_short Novel germline MLH1 and MSH2 mutations in latvian Lynch syndrome families
title_full Novel germline MLH1 and MSH2 mutations in latvian Lynch syndrome families
title_fullStr Novel germline MLH1 and MSH2 mutations in latvian Lynch syndrome families
title_full_unstemmed Novel germline MLH1 and MSH2 mutations in latvian Lynch syndrome families
title_sort novel germline mlh1 and msh2 mutations in latvian lynch syndrome families
author Berzina, D.
Irmejs, A.
Kalniete, D.
Borosenko, V.
Nakazawa-Miklasevica, M.
Ribenieks, K.
Trofimovics, G.
Gardovskis, J.
Miklasevics, E.
author_facet Berzina, D.
Irmejs, A.
Kalniete, D.
Borosenko, V.
Nakazawa-Miklasevica, M.
Ribenieks, K.
Trofimovics, G.
Gardovskis, J.
Miklasevics, E.
topic Original contributions
topic_facet Original contributions
publishDate 2012
language English
container_title Experimental Oncology
publisher Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
format Article
description Background/Aims: Hereditary non-polyposis colorectal cancer or Lynch syndrome is an autosomal dominantly inherited disease with high penetrance, mostly due to mutations in the MLH1 and MSH2 genes. The aim of this study is to investigate the mutation spectrum of the MLH1 and MSH2 genes. Methodology: High risk colorectal cancer families were selected from overall 1053 consecutive patients. Screening of germline mutations in the MLH1 and MSH2 was performed by direct sequencing and multiplex ligation-dependent probe amplification. Results: Ten patients fulfilled the Amsterdam I/II criteria and Bethesda guidelines of the Lynch syndrome. Three novel mutations were identified in MLH1 and MSH2 genes, as well as two known mutations in the MLH1 gene. Large rearrangements in the MLH1 gene were found in two patients. Conclusions: The mutations in the MLH1 and MSH2 genes in Latvian high-risk families are highly heterogeneous. Combination of direct sequencing and MLPA is the most appropriate molecular method of detecting hereditary nonpolyposis colorectal cancer patients and family members at risk.
issn 1812-9269
url https://nasplib.isofts.kiev.ua/handle/123456789/138723
citation_txt Novel germline MLH1 and MSH2 mutations in latvian Lynch syndrome families / D. Berzina, A. Irmejs, D. Kalniete, V. Borosenko, M. Nakazawa-Miklasevica, K. Ribenieks, G. Trofimovics, J. Gardovskis, E. Miklasevics // Experimental Oncology. — 2012. — Т. 34, № 1. — С. 49-52. — Бібліогр.: 24 назв. — англ.
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fulltext Experimental Oncology ��� ������ ���� ��arc����� ������ ���� ��arc�� ��arc�� �� NOVEL GERMLINE MLH1 AND MSH2 MUTATIONS IN LATVIAN LYNCH SYNDROME FAMILIES D. Bērziņa1,2,*, A. Irmejs1,2, D. Kalniete1,2, V. Borošenko1,2, M. Nakazawa-Miklaševiča1, K. Rībenieks1,2, G. Trofimovičs1,2, J. Gardovskis1,2, E. Miklaševičs1,2 1Hereditary Cancer Institute, Riga Stradins University, Dzirciema iela 16, Riga, Latvia, LV-1007 2Pauls Stradins Clinical University Hospital, Pilsonu iela 13, Riga, Latvia, LV-1002 Background/Aims: Hereditary non-polyposis colorectal cancer or Lynch syndrome is an autosomal dominantly inherited disease with high penetrance, mostly due to mutations in the MLH1 and MSH2 genes. The aim of this study is to investigate the mutation spectrum of the MLH1 and MSH2 genes. Methodology: High risk colorectal cancer families were selected from overall 1053 consecu- tive patients. Screening of germline mutations in the MLH1 and MSH2 was performed by direct sequencing and multiplex ligation- dependent probe amplification. Results: Ten patients fulfilled the Amsterdam I/II criteria and Bethesda guidelines of the Lynch syndrome. Three novel mutations were identified in MLH1 and MSH2 genes, as well as two known mutations in the MLH1 gene. Large rearrangements in the MLH1 gene were found in two patients. Conclusions: The mutations in the MLH1 and MSH2 genes in Latvian high-risk families are highly heterogeneous. Combination of direct sequencing and MLPA is the most appropriate mo- lecular method of detecting hereditary nonpolyposis colorectal cancer patients and family members at risk. Key Words: Lynch syndrome, mismatch repair genes, germline mutations, MLH1, MSH2. Approximately ���% of colorectal cancer cases belong to t�e �ereditary nonpolyposis colorectal can- cer �HNPCC� or Lync� syndrome. HNPCC is an auto- somal dominantly in�erited disease wit� �ig� pene- trance due to germline mutations in mismatc� repair genes. T�e increased overall mutation rate is associ- ated wit� an elevated risk of developing early onset colorectal cancer as well as extracolonic tumors� suc� as endometrial and ovary cancer in women� stomac�� small bowel� pancreas� and ot�ers [�]. Overall sur- vival is better in patients wit� HNPCC compared to pa- tients wit� sporadic cancer [�]. About 7�% of HNPCC cases �ave developed due to t�e mutations distrib- uted equally t�roug� t�e exons in t�e MLH1 and MSH2 genes [�� �]� and only some mutations �ave a proven founder effect [�]. HNPCC as a clinical syn- drome is diagnosed according to t�e Amsterdam criteria and Bet�esda guidelines and allow t�e identi- fication of �ig� risk families [�]. Family members wit� a confirmed mutation or at �ig� risk� if t�e mutation is unknown but diagnosis is clinically proven� s�ould take a screening colonoscopy every ��� years begin- ning at age ����� [�]. Endometrial sampling and transvaginal ultrasonograp�y in women from HNPCC families is also considered to be useful starting at age ����� [�� �]� as t�e risk of developing endometrial cancer for a woman in a HNPCC family is ���6�% [6]. Still� due to HNPCC most endometrial cancer cases are diagnosed symptomatically� not by transvaginal ultrasound or biopsy. Transvaginal ultrasound can be more �elpful in t�e case of ovarian cancer as t�e risk of developing it is about 6���% [6]. T�erefore� it is important to screen patients and t�eir relatives for mismatc� repair gene mutations in order to confirm t�e diagnosis of HNPCC and begin prevention mea- sures for reducing t�e probability of developing cancer. T�is allows more accurate identification of patients from HNPCC families. In previous studies� it was con- cluded t�at t�e use of t�e Amsterdam criteria for HNPCC patient diagnosis in Latvia is limited and muta- tion spectrum differs from ot�er neig�boring countries [7� 8]. T�is study continues t�e researc� of mismatc� repair gene mutations in t�e case of HNPCC. T�e aim of t�is study is to investigate t�e mutation spectrum of MLH1 and MSH2 in �ig� risk families and to accumulate information necessary for future diagnosis and consulting �ig� risk patients and t�eir family members. PATIENTS AND METHODS Patients wit� colorectal cancer corresponding to t�e Amsterdam criteria or Bet�esda guidelines were selected from ���� consecutive colorectal cancer pa- tients at t�e Pauls Stradins Clinical University Hospital or counseled at t�e Hereditary Cancer cabinet during ���������. Approval of Riga Stradins University �edi- cal et�ics committee was obtained and all patients w�o participated in t�is study signed an informed consent form. Patients or t�eir relatives w�o participated in pre- vious studies [7� �] were excluded. DNA was extracted from w�ole blood by t�e QIAgen FlexiGene DNA Kit. All DNA samples were subjected to w�ole sequencing of MLH1 and MSH2 as de- scribed earlier [��� ��]. �utations were confirmed by sequencing bot� DNA strands on an independent PCR product. Samples wit� no mutation detected by sequencing were subjected to t�e multiplex ligation-dependent probe amplification ��LPA� analysis. �LPA and sequencing reactions were per- formed using t�e SALSA �LPA P��� �LH�/�SH� kit ��RC-Holland� t�e Net�erlands�. �LPA reactions were analyzed using t�e Applied Biosystems genetic Received: December 22, 2011. *Correspondence: E-mail: dace.berzina@rsu.lv Abbreviations used: HNPCC – hereditary non-polyposis colorectal cancer, MLPA – multiplex ligation-dependent probe amplification, FAP – family adenomatous polyposis. Exp Oncol ���� ��� �� ����� �� Experimental Oncology ��� ������ ���� ��arc�� analyzer ABI����. T�e following databases were used for mutation analysis: INSIGHT-group database ��ttp://www.insig�t-group.org/mutations/� and NCBI SNP database ��ttp://www.ncbi.nlm.ni�.gov/snp/�. Table. Patients and their families data (CRC — colorectal cancer, Ut — uterine cancer, Ov — ovarian cancer, Li — liver cancer, Pro — prostate cancer, CSU — cancer site unknown, d — died) Patient, age at CRC diagnosis Pedigree Diagno- sis accor- ding to Gene status D321, 41 y I:1 I:2 Ut 46 CRC 66 d 66 Ut 48 CRC 65 CRC 43 d 43 CRC 32 d 34 CRC 37 CRC 41 II:5 II:3 II:4 II:1 II:2 III:2III:1 IV:1 III:3III:4 III:5 III:6 Amster- dam cri- teria I MLH1 wt MSH2 wt J236, 58 y I:1 I:2 Ut 40 d 72 CRC 58 CRC 36 II:3 II:1 II:2 III:2III:1 Amster- dam cri- teria II MLH1 1340delTGinsC L447fsM490X MSH2 wt C321, 47 y I:1 I:2 Ut 48 d 50 Ov 45 d 60 CSU 59 d 60 CSU 46 d 48 CRC 47 II:5 II:6 II:7II:3 II:4II:1 II:2 IV:1 IV:2 Amster- dam cri- teria II MLH1 wt MSH2 288delGTinsA R96fsL173X C450, 67 y I:1 I:2 CRC 51 d 53 CRC 69 d 69 CRC 67 II:5II:3 II:4II:1 II:2 III:2III:1 IV:1 III:3 III:4III:5 Ov 65 d 65 Ut 48 d 50 Amster- dam cri- teria II MLH1 wt MSH2 wt Patient, age at CRC diagnosis Pedigree Diagno- sis accor- ding to Gene status C152, 60 y I:1 I:2 Li 82 d 84 Li 75 d 76 CRC 37 d 47 CRC 60 II:1 II:2 III:2III:1 III:3 III:4 Amster- dam cri- teria II MLH1 1546C>T Q516X MSH2 wt D500, 65 y I:1 I:2 Ut 70 d 84 Ut 40 d 45 CRC 65 II:3 II:1 II:2 III:1 Amster- dam cri- teria II MLH1 6th exon dupli- cation MSH2 wt A538, 50 y I:1 I:2 CRC 73 d 73 Pro 65 d 65 CRC 50 II:3 II:4II:1II:2 III:1 III:2 Bethesda criteria MLH1 12th exon deletion MSH2 wt E430, 43 y I:1 I:2 CRC 45 d 60 CRC 43 II:3 II:1 II:2 III:1 Bethesda criteria MLH1 37G>T E13X MSH2 wt D583, 48 y I:1 I:2 Ut 40 d 46 CRC 48 II:3 II:4 II:1 II:2 III:1 Bethesda criteria MLH1 1959G>T MSH2 wt E595, 60 y I:1 I:2 CRC 46 d 47 CRC 60 II:1 Bethesda criteria MLH1 wt MSH2 wt Experimental Oncology ��� ������ ���� ��arc����� ������ ���� ��arc�� ��arc�� �� RESULTS Amsterdam I criteria define HNPCC families ac- cording to family colorectal cancer �istory and t�e age of onset; at least two successive generations and t�ree patients s�ould be involved� at least one of w�ic� is a first degree relative to t�e ot�er two� one of t�e cancers s�ould be diagnosed before age �� and fam- ily adenomatous polyposis �FAP� s�ould be excluded. Amsterdam II criteria also include cancers t�at are as- sociated wit� t�e HNPCC� suc� as endometrial� small intestine� stomac�� and ot�ers. Bet�esda guidelines are used to test colorectal cancers for microsatellite in- stability� and it is proven� t�at t�ese are more applicable for detecting patients w�o s�ould undergo genetic testing [�]. In t�is study� t�e main criteria used from t�e Bet�esda guidelines were t�e young age of onset �before ��� in one of t�e affected family members. Ten index patients were identified from ���� con- secutive colorectal cancer patients in Latvia by fam- ily �istory according to t�e Amsterdam I/II criteria or Bet�esda guidelines. Among t�em � patient fulfilled t�e Amsterdam I criteria ��.�%�� � fulfilled t�e Amster- dam II criteria ��.�7%� and � fulfilled t�e Bet�esda guidelines ��.�8%�. �edical and family �istories are summarized in t�e Table. Seven patients out of �� were found to �arbor mutations in t�e MLH1 or MSH2 genes including large rearrangements. Four out of � patients meeting t�e Amsterdam II criteria were �arboring mutations. T�ree out of � patients meeting t�e Bet�esda guidelines were �arboring mutations. No mutation was detected in t�e only patient meeting t�e Amsterdam I criteria. DNA sequencing revealed MLH1 and MSH2 muta- tions in five index patients. Four of t�ose mutations including two nonsense mutations �MLH1, �7G>T and ���6C>T� and two frames�ift mutations �MLH1� ����delTGinsC and MSH2� �88delGTinsA� are clinical- ly significant� as t�ey result in a truncated protein. One nonsense mutation in t�e first exon of t�e MLH1 gene �7G>T �E��X� was discovered in patient E���. Patient C��� carried t�e nonsense mutation ���6C>T �Q��6X� in t�e MLH1 exon �6. Patient C��� �ad a mutation in t�e MSH2 exon � �88delGTinsA w�ic� leads to a prema- ture stop codon at t�e amino acid position �7�. �uta- tion in t�e MLH1 exon �� ����delTGinsC� discovered in patient J��6� truncates protein� leading to premature stop at codon ���. Patient J��6’s family members were available for analysis: �is son was diagnosed wit� colorectal cancer at age �6� and daug�ter ��� years old at present� is not diagnosed wit� any cancer. Bot� siblings carry t�e ����delTGinsC mutation in t�e MLH1 gene. In patient D�8�� t�e MLH1 gene mutation ���� G>T was found in exon �7. �LPA analysis revealed two large rearrangements. In patients A��8 and D���� large rearrangements of t�e MLH1 gene were found using �LPA. Patient A��8 �ad t�e deletion of exon ��. Patient D��� �as t�e duplication of exon 6. None of all t�e mutations t�at were found in t�is study coincided wit� t�e previously reported mutations in Latvia [7� �]. DISCUSSION About ���� new colorectal cancer cases are diagnosed in Latvia every year and approximately ��� of t�em at t�e Pauls Stradins Clinical University Hospital. Less t�an �% are FAP cases [��]. As con- cluded before� t�e HNPCC rate from consecutive colorectal cancer patients in Latvia is about �% [7] and about �� primary diagnosed HNPCC patients can be expected in Latvia per year. T�e HNPCC is es- timated at about �.��% wit�in t�e population of Latvia [��]. In ot�er studies� �ereditary colorectal cancer is estimated at ���% from all t�e colorectal cancer cases [��� ��] and �.��% from t�e total population [�6]. It is possible t�at t�e number of HNPCC cases in Latvia is underestimated due to a lower reliability of patients’ family data or t�e lack of full informa- tion about t�e medical �istory of a family. It �as been described t�at finding �ereditary cancer families in Latvia is a common problem because of small fami- lies� as t�ere is small number of first degree relatives and not all patients cooperate wit� t�e doctors [�7]. Families wit� �ereditary cancer syndrome are more easily detected if t�e family is large. Previously in Latvia a statistically significant difference was observed be- tween t�e size of t�e family diagnosed wit� �ereditary cancer� according to defined criteria� and families wit� non-diagnostic findings. T�e mean numbers of blood relatives wit�in t�e families wit� �ereditary cancer syndromes were ��.6 and ��.�� w�ile t�e mean number of blood relatives for t�e families not diagnosed wit� �ereditary cancer syndrome was �.� [�7]. As proven by case of �ereditary breast cancer families in Latvia during population screening� t�e results of clinical screening and mutation screening do not overlap and molecular screening reveals more mutation carriers as clinical criteria [�7]. Similar results were observed in t�e case of HNPCC from patients corresponding wit� t�e Amsterdam criteria — mutations were found in some of t�e patients� and mutation screening in con- secutive patients revealed patients wit�out familial cancer �istory [�8]. In t�is study� only one patient is diagnosed according to t�e Amsterdam I criteria and t�e patient did not �arbor any mutation in t�e MLH1 and MSH2 genes. Five patients were diagnosed according to t�e Amsterdam II criteria� w�ic� also in- cluded cancers t�at were associated wit� t�e HNPCC syndrome� not only colorectal cancer. Out of t�ose five patients� four of t�em �ad mismatc� repair gene mutations. From four patients w�o corresponded wit� t�e Bet�esda guidelines� t�ree patients �ad germline mutations in mismatc� repair genes. T�ree families did not �ave any mutation in t�e MLH1 and MSH2 genes. T�e syndrome of t�ose patients could be due to t�e mutations in ot�er mismatc� repair genes or associ- ated wit� an unknown susceptibility locus or epimuta- tions [�����]. Up until now� several MLH1� MSH2 and �� Experimental Oncology ��� ������ ���� ��arc�� MSH6 gene mutations in t�e case of HNPCC �ave been found in Latvia [7� �]� but none of t�ese mutations were found in our researc�. None of t�e mutations �ad a proven founder effect in Latvian colorectal cancer patients� alt�oug� t�e mutation MLH1 ����+� A>G t�at was found in Latvia [7] is described in Polis� and Finn- is� populations [8� ��]. Information about t�e MLH1 ����G>T mutation is not consequential and t�ere is a possibility t�at t�e exact mutation does not affect mismatc� repair. T�e mutation is predicted to form alternative splice site� resulting in exon skipping [��]� alt�oug� information available in t�e INSIGHT-group database does not conclude pat�ogenesis of t�is mutation in all cases. However� t�is mutation can be considered a rare poly- morp�ism� as t�ere is no p�enotypic consequence [�8� ��]. We concluded t�at 6 mutations out of 7 were pat�ogenic� as t�ey resulted in altered protein� t�us affecting mismatc� repair and resulting in t�e devel- opment of cancer. T�e mutation MLH1 �7G>T �E��X� �as been reported in t�e INSIGHT-group database. �utations in t�e MLH1 and MSH2 genes are �ig�ly �eterogeneous in Latvia. Combination of direct se- quencing of t�e MLH1 and MSH2 genes and �LPA is t�e most appropriate molecular met�od of detecting HNPCC patients and family members at risk. ACKNOWLEDGEMENTS T�is study was supported by T�e National Researc� Programme “Development of new prevention� treat- ment� diagnostics means and practices and biomedi- cine tec�nologies for improvement of public �ealt�”. REFERENCES 1. Lynch HT, Lynch JF, Attard TA. Diagnosis and mana­ gement of hereditary colorectal cancer syndromes: Lynch syndrome as a model. CMAJ 2009; 181: 273–80. 2. Stigliano V, Assisi D, Cosimelli M, et al. Survival of he­ reditary non­polyposis colorectal cancer patients compared with sporadic colorectal cancer patients. J Exp Clin Cancer Res 2008; 27: 39. 3. Liu B, Parsons R, Papadopoulos N, et al. Analysis of mis­ match repair genes in hereditary non­polyposis colorectal cancer patients. Nature Med 1996; 2: 169–74. 4. Mangold E, Pagenstecher C, Friedl W, et al. Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1.721 german families suspected of hereditary nonpolyposis colorectal cancer. Int J Cancer 2005; 116: 692–702. 5. 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