- Open Access
- Open Peer Review
Mutation spectrum in South American Lynch syndrome families
Hereditary Cancer in Clinical Practice volume 11, Article number: 18 (2013)
Genetic counselling and testing for Lynch syndrome have recently been introduced in several South American countries, though yet not available in the public health care system.
We compiled data from publications and hereditary cancer registries to characterize the Lynch syndrome mutation spectrum in South America. In total, data from 267 families that fulfilled the Amsterdam criteria and/or the Bethesda guidelines from Argentina, Brazil, Chile, Colombia and Uruguay were included.
Disease-predisposing mutations were identified in 37% of the families and affected MLH1 in 60% and MSH2 in 40%. Half of the mutations have not previously been reported and potential founder effects were identified in Brazil and in Colombia.
The South American Lynch syndrome mutation spectrum includes multiple new mutations, identifies potential founder effects and is useful for future development of genetic testing in this continent.
Since the initial reports on disease-predisposing mutations in the mismatch-repair (MMR) genes MLH1 [MIM:120436], MSH2 [MIM:609309] and MSH6 [MIM:600678] in the early 1990’ies, a large number of studies have contributed to the establishment of the molecular map of Lynch syndrome with over 3,072 unique genetic MMR gene variants identified. These data are predominantly based on studies from North America, Europe and Asia. The mutations affect MLH1 in 42%, MSH2 in 33%, MSH6 in 18% and PMS2 in 8% . Nonsense mutations, frameshift mutations and missense mutations predominate, whereas large genomic rearrangements and splice-site variants constitute <10% of the alterations .
The South American population is ethnically mixed from American Indian and European ancestors. In Uruguay and Argentina, European ancestry predominates. In Brazil, significant African and American Indians roots apply. In Chile, Colombia, Peru and Bolivia, Spanish colonist and American Indian ancestry influence the populations [2, 3]. Mutation screening in South American families suspected of Lynch syndrome has identified disease-predisposing germline mutations in MLH1 and MSH2 in 16-45% of families that fulfill the Amsterdam criteria and/or the Bethesda guidelines [2–7]. Hereditary colorectal cancer registries have been established in Argentina, Brazil, Uruguay and Chile with the aim to collect and share data on the MMR gene mutation spectrum, identify potential founder mutations, interpret the role of unclassified genetic variants and to study cancer risks in the South American Lynch syndrome population. We used published data and unpublished register data to describe the mutation spectrum in South American Lynch syndrome families.
All patients provided an informed consent for inclusion into the South American registers during genetic counseling sessions and is in compliance with the Helsinki Declaration.
Families that fulfilled the Amsterdam criteria [8, 9] and/or the Bethesda guidelines  were selected from the hereditary cancer registries at the Hospital Italiano (Buenos Aires, Argentina), the Hospital de las Fuerzas Armadas (Montevideo, Uruguay), the Clinica Los Condes (Santiago, Chile), the Barretos Cancer Hospital (Barretos, Brazil) and from two databases in Colombia and in Southeastern Brazil (Figure 1, Table 1) [2, 3, 5, 11]. Patients were informed about their inclusion into the registries, which generally contained data on family history, age at onset and results of genetic testing.
Methods to assess MMR status, e.g. microsatellite instability analysis and MMR protein staining, varied between the countries and were excluded from the present study since these data were incomplete. Molecular diagnosis was generally based on direct sequencing of MLH1 and MSH2. Chilean and Brazilian families were also analyzed for large genomic rearrangements using the multiplex ligation-dependent probe amplification (MLPA) method (performed using the SALSA kit P003, MRC-Holland, Amsterdam, Netherlands).
Mutation nomenclature was in accordance with the Human Genome Variation Society (HGVS) guidelines . Mutations in the MLH1 or MSH2 genes were considered deleterious if they: a) were classified as pathogenic in LOVD database; b) introduced a premature stop codon in the protein sequence (nonsense or frameshift mutation); c) occurred at donor or acceptor splice sites; or d) represented whole-exon deletions or duplications. All identified mutations were correlated to the MMR Gene Unclassified Variants Database (http://www.mmruv.info), the Mismatch Repair Genes Variant Database (http://www.med.mun.ca/mmrvariants/), the French MMR network (http://www.umd.be/MMR.html) and the International Society for Gastrointestinal Hereditary Tumors (InSIGHT) (http://www.insight-group.org).
Variants of uncertain significance
To establish the pathogenicity of variants of uncertain significance, web-based programs, i.e. Polyphen, MAPP-MMR, SIFT, P-mut and PON-MMR were applied to predict the effect of an amino acid substitution based on protein structural change and/or evolutionary conservation [13–17].
The statistical analyses were performed using the statistical software package IBM SPSS Statistics 20 (SPSS, Chicago, IL, USA).
In total, 110 families harbored MMR gene variants, of which 99 were classified as Lynch syndrome predisposing and 11 were regarded as variants of uncertain significance. Mutations in MLH1 and MSH2 were identified in 37% (range 27-65% in the different countries/registries) of the families that fulfilled the Amsterdam criteria and/or Bethesda guidelines (Table 1). When the Amsterdam criteria were considered, the mutation detection rate was 55% (81/147), whereas 15% families that fulfilled the Bethesda guidelines had disease-predisposing mutations. The mean age at diagnosis was 35–44 years for colorectal cancer and 41–49 years for endometrial cancer in the different registries (Table 1). Pedigree information was available from 54 families and showed that among the Lynch syndrome-associated tumors, 65% were colorectal cancers (of which 43% were located in the right side of the colon), 22% endometrial cancers and 13% constituted other Lynch syndrome-associated cancer types.
Of the 99 disease-predisposing MMR gene mutations, 60% affected MLH1 and 40% affected MSH2 (Table 2). Frameshift and nonsense mutations were the most common alterations (36% and 31%, respectively), followed by splice site mutations (13%), missense mutations (12%) and large deletions (8%) (Figure 2a). Though the mutations were spread over the genes, hot-spot regions included exons 16 and 18 in MLH1 (13% of the mutations each) and exon 13 in MSH2 (24% of the mutations each) (Figure 2b).
In total, 10 mutations identified in at least two South American families were classified as recurrent. Among these, the MSH2 c.2152C > T identified in Brazil represents an internationally hot-spot. Three founder mutations were identified in five South American families. The MLH1 c.545 + 3A > G and the MSH2 c.942 + 3A > T have been identified as founder mutations in Italy and in Newfoundland and were also identified in Brazilian families . The MLH1 c.1039-8T_1558 + 896Tdup has been suggested to represent a founder mutation in Colombia [2, 11]. Mutations that were unique and herein first reported in more than one family included the MLH1 c.1853delAinsTTCTT in Brazil, the MLH1 c.1856delG in Colombia and the MSH2 c.25252_2526delAG in Brazil (Table 2) (Figure 3).
In total, 11 variants of unclassified significance were identified in individuals from Argentina, Uruguay, Chile, Brazil and Colombia (Table 3) [2, 3]. In silico analysis suggested that the MLH1 c.289 T > G, the MLH1 c.794G > C and the MLH1 c.1918C > T were likely disease-predisposing (Table 3).
In South America, disease-predisposing mutations linked to Lynch syndrome have been identified in 99 families, which corresponds to 37% of the families that fulfilled the Amsterdam criteria and/or Bethesda guidelines and underwent genetic testing. The mutation rate is high compared to prevalence rates of 28% for MLH1 and 18% for MSH2 in the Asian population, 31% and 20% in a multi-ethnic American population and 26% and 19% in European/Australian populations . The mutation spectrum is predominated by MLH1 (60%) and MSH2 (40%) mutations [3, 19–22], but the seemingly larger contribution than the 42% and 33% reported in the InSIGHT database could reflect failure to test for MSH6 and PMS2 mutations in most South American studies . Referral bias in populations that have more recently been screened for mutations represents a potential limitation, but the strong contribution from MLH1 and MSH2 could also reflect population structure [2, 4, 5, 7]. Frameshift mutations and nonsense mutations were the most common types of mutations, which are in agreement with findings from other populations [1, 23–26], with hotspots in exons 16 and 18 of MLH1 and in exon 13 of MSH2 (Figure 2b). Exon 16 and 18 in MLH1 has been identified as a genetic hot spot also in other populations with 26% of the MLH1 mutations reported herein [3, 18]. The frequent mutations in MSH2 exon 13 may be linked to the c.2152C>, which was first identified in Portuguese Lynch syndrome families. This alteration accounted for 35% (6/17) of the MSH2 mutations in the Brazilian population, which is in line with the Portuguese migration to Brazil [3, 27].
Founder mutations have been identified in several populations where they significantly contribute to disease predisposition and thereby allow for directed genetic testing . Two of the mutations identified in South American Lynch syndrome families have been suggested to constitute potential founder mutations in other populations, e.g. the Italian MLH1 c.545 + 3A > G and the Newfoundland MSH2 c.942 + 3A > T . The Spanish founder mutations MLH1 c.306 + 5G > A and c.1865 T > A and MSH2 c.2635-3 T > C; c2635-5C > T; c.2063 T > G were, however, not observed in South American Lynch syndrome families [27–30]. In Colombia, the MSH2 c.1039-8T_1558 + 896Tdup was suggested to represent a founder mutation [2, 11]. The Colombian population has a mixed ancestry with a strong influence from Spanish colonists and thereby genetically differs from previously studied populations [2, 6].
In conclusion, disease-predisposing mutations in MLH1 and MSH2 have been identified in a relatively large proportion of the South American families suspected of Lynch syndrome that have been tested. Genetic hot-spot regions, internationally recognized founder mutations and potential South American founder mutation have been recognized, which is of relevance for genetic counseling and testing that are increasingly available in South America.
Plazzer JP, Sijmons RH, Woods MO, Peltomaki P, Thompson B, DenDunnen JT, Macrae F: The InSiGHT database: utilizing 100 years of insights into Lynch Syndrome. Fam Cancer 2013, 12: 175–180. 10.1007/s10689-013-9616-0
Giraldo A, Gomez A, Salguero G, Garcia H, Aristizabal F, Gutierrez O, Angel LA, Padron J, Martinez C, Martinez H, et al.: MLH1 and MSH2 mutations in Colombian families with hereditary nonpolyposis colorectal cancer (Lynch syndrome)–description of four novel mutations. Fam Cancer 2005, 4: 285–290. 10.1007/s10689-005-4523-7
Valentin MD, da Silva FC, dos Santos EM, Lisboa BG, de Oliveira LP, Ferreira Fde O, Gomy I, Nakagawa WT, Aguiar Junior S, Redal M, et al.: Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals. Fam Cancer 2011, 10: 641–647. 10.1007/s10689-011-9461-y
Sarroca C, Valle AD, Fresco R, Renkonen E, Peltomaki P, Lynch H: Frequency of hereditary non-polyposis colorectal cancer among Uruguayan patients with colorectal cancer. Clin Gen 2005, 68: 80–87. 10.1111/j.1399-0004.2005.00458.x
Rossi BM, Lopes A, Oliveira Ferreira F, Nakagawa WT, Napoli Ferreira CC, Casali Da Rocha JC, Simpson CC, Simpson AJ: hMLH1 and hMSH2 gene mutation in Brazilian families with suspected hereditary nonpolyposis colorectal cancer. Ann Surg Oncol 2002, 9: 555–561.
Alvarez K, Hurtado C, Hevia MA, Wielandt AM, de la Fuente M, Church J, Carvallo P, Lopez-Kostner F: Spectrum of MLH1 and MSH2 mutations in Chilean families with suspected Lynch syndrome. Dis Colon Rectum 2010, 53: 450–459. 10.1007/DCR.0b013e3181d0c114
Vaccaro CA, Bonadeo F, Roverano AV, Peltomaki P, Bala S, Renkonen E, Redal MA, Mocetti E, Mullen E, Ojea-Quintana G, et al.: Hereditary nonpolyposis colorectal cancer (Lynch Syndrome) in Argentina: report from a referral hospital register. Dis Colon Rectum 2007, 50: 1604–1611. 10.1007/s10350-007-9037-y
Vasen HF, Mecklin JP, Khan PM, Lynch HT: The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 1991, 34: 424–425. 10.1007/BF02053699
Vasen HF, Watson P, Mecklin JP, Lynch HT: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999, 116: 1453–1456. 10.1016/S0016-5085(99)70510-X
Rodriguez-Bigas MA, Boland CR, Hamilton SR, et al.: A national cancer institute workshop on hereditary nonpolyposis colorectal cancer syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 1997, 89: 1758–1762. 10.1093/jnci/89.23.1758
Alonso-Espinaco V, Giraldez MD, Trujillo C, van der Klift H, Munoz J, Balaguer F, Ocana T, Madrigal I, Jones AM, Echeverry MM, et al.: Novel MLH1 duplication identified in Colombian families with Lynch syndrome. Genet Med 2011, 13: 155–160. 10.1097/GIM.0b013e318202e10b
denDunnen JT, Antonarakis SE: Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 2000, 15: 7–12. 10.1002/(SICI)1098-1004(200001)15:1<7::AID-HUMU4>3.0.CO;2-N
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR: A method and server for predicting damaging missense mutations. Nat Methods 2010, 7: 248–249. 10.1038/nmeth0410-248
Chao EC, Velasquez JL, Witherspoon MS, Rozek LS, Peel D, Ng P, Gruber SB, Watson P, Rennert G, Anton-Culver H, et al.: Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). Hum Mutat 2008, 29: 852–860. 10.1002/humu.20735
Kumar P, Henikoff S, Ng PC: Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009, 4: 1073–1081. 10.1038/nprot.2009.86
Ferrer-Costa C, Orozco M, de la Cruz X: Sequence-based prediction of pathological mutations. Proteins 2004, 57: 811–819. 10.1002/prot.20252
Ali H, Olatubosun A, Vihinen M: Classification of mismatch repair gene missense variants with PON-MMR. Hum Mutat 2012, 33: 642–650. 10.1002/humu.22038
Li D, Hu F, Wang F, Cui B, Dong X, Zhang W, Lin C, Li X, Wang D, Zhao Y: Prevalence of pathological germline mutations of hMLH1 and hMSH2 genes in colorectal cancer. PloS One 2013, 8: e51240. 10.1371/journal.pone.0051240
Dominguez MV, Bastos EP, Santos EM, Oliveira LP, Ferreira FO, Carraro DM, Rossi BM: Two new MLH1 germline mutations in Brazilian Lynch syndrome families. Int J Colorectal Dis 2008, 23: 1263–1264. 10.1007/s00384-008-0515-z
da Silva FC, de Oliveira LP, Santos EM, Nakagawa WT, Aguiar Junior S, Valentin MD, Rossi BM, de Oliveira Ferreira F: Frequency of extracolonic tumors in Brazilian families with Lynch syndrome: analysis of a hereditary colorectal cancer institutional registry. Fam Cancer 2010, 9: 563–570. 10.1007/s10689-010-9373-2
Monteiro Santos EM, Valentin MD, Carneiro F, de Oliveira LP, de Oliveira FF, Junior SA, Nakagawa WT, Gomy I, de FariaFerraz VE, da Silva Junior WA, et al.: Predictive models for mutations in mismatch repair genes: implication for genetic counseling in developing countries. BMC Cancer 2012, 12: 64. 10.1186/1471-2407-12-64
Valentin MD, Da Silva FC, Santos EM, Da Silva SD, De Oliveira FF, Aguiar Junior S, Gomy I, Vaccaro C, Redal MA, Della Valle A, et al.: Evaluation of MLH1 I219V polymorphism in unrelated South American individuals suspected of having Lynch syndrome. Anticancer Res 2012, 32: 4347–4351.
Peltomaki P, Vasen HF, The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer: Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. Gastroenterology 1997, 113: 1146–1158. 10.1053/gast.1997.v113.pm9322509
Apessos A, Mihalatos M, Danielidis I, Kallimanis G, Agnantis NJ, Triantafillidis JK, Fountzilas G, Kosmidis PA, Razis E, Georgoulias VA, Nasioulas G: hMSH2 is the most commonly mutated MMR gene in a cohort of Greek HNPCC patients. Br J Cancer 2005, 92: 396–404.
Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, et al.: The consensus coding sequences of human breast and colorectal cancers. Science 2006, 314: 268–274. 10.1126/science.1133427
Nilbert M, Wikman FP, Hansen TV, Krarup HB, Orntoft TF, Nielsen FC, Sunde L, Gerdes AM, Cruger D, Timshel S, et al.: Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population. Fam Cancer 2009, 8: 75–83. 10.1007/s10689-008-9199-3
Isidro G, Veiga I, Matos P, Almeida S, Bizarro S, Marshall B, Baptista M, Leite J, Regateiro F, Soares J, et al.: Four novel MSH2 /MLH1 gene mutations in portuguese HNPCC families. Hum Mutat 2000, 15: 116.
Borras E, Pineda M, Blanco I, Jewett EM, Wang F, Teule A, Caldes T, Urioste M, Martinez-Bouzas C, Brunet J, et al.: MLH1 founder mutations with moderate penetrance in Spanish Lynch syndrome families. Cancer Res 2010, 70: 7379–7391. 10.1158/0008-5472.CAN-10-0570
Menendez M, Castellvi-Bel S, Pineda M, de Cid R, Munoz J, Gonzalez S, Teule A, Balaguer F, Ramon y Cajal T, Rene JM, et al.: Founder effect of a pathogenic MSH2 mutation identified in Spanish families with Lynch syndrome. Clin Gen 2010, 78: 186–190. 10.1111/j.1399-0004.2009.01346.x
Medina-Arana V, Barrios Y, Fernandez-Peralta A, Herrera M, Chinea N, Lorenzo N, Jimenez A, Martin-Lopez JV, Gonzalez-Hermoso F, Salido E, Gonzalez-Aguilera JJ: New founding mutation in MSH2 associated with hereditary nonpolyposis colorectal cancer syndrome on the Island of Tenerife. Cancer Lett 2006, 244: 268–273. 10.1016/j.canlet.2005.12.033
The authors declare that they have no competing interests.
MDV, MN, BMR participated in the conception and design of the study. All authors participated in the acquisition of data, or analysis, interpretation of data and have been involved in drafting the manuscript. All authors read and approved the final manuscript.
About this article
Cite this article
Dominguez-Valentin, M., Nilbert, M., Wernhoff, P. et al. Mutation spectrum in South American Lynch syndrome families. Hered Cancer Clin Pract 11, 18 (2013). https://doi.org/10.1186/1897-4287-11-18
- Lynch syndrome
- South America