Publications by authors named "Carlos Sarroca"

10 Publications

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A snapshot of current genetic testing practice in Lynch syndrome: The results of a representative survey of 33 Latin American existing centres/registries.

Eur J Cancer 2019 09 20;119:112-121. Epub 2019 Aug 20.

Hospital de Especialidades Eugenio Espejo, Subproceso de Anatomía Patológica, Área de Genética Clínica, Quito, Ecuador.

We aimed to assess the current genetics practice to manage patients with Lynch syndrome (LS) across Latin America. A Latin American LS survey was sent out to 52 centres/registries, comprising a total of 12 countries from the region. Overall, 33 centres completed the survey, of which the oldest LS registry was established in 1992 in Sao Paulo (Brazil), and the youngest this year in San Jose (Costa Rica). In total, 87% (26/30) of the participating centres/registries belonging to the nine countries are performing genetic testing. Overall, 1352 suspected families were sequenced. Pathogenic variants were identified in 34% of the families, with slightly differing distribution of variants between females and males. Path_MLH1 variants were identified in 39% of females and 50% of males (p = 0.023), while path_MSH2 were identified in 37% of females and males, followed by path_PMS2 in 11% of females and 8% of males, path_MSH6 in 13% of females and 3% of males (p < 0.001) and path_EPCAM in 0.3% of females and 2% of males. In Latin America, 9 of 12 (75%) participating countries had implemented healthcare for LS. LS screening is inconsistently applied within Latin America healthcare systems because of structural differences in the healthcare systems between the countries.
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http://dx.doi.org/10.1016/j.ejca.2019.07.017DOI Listing
September 2019

From colorectal cancer pattern to the characterization of individuals at risk: Picture for genetic research in Latin America.

Int J Cancer 2019 07 5;145(2):318-326. Epub 2018 Dec 5.

AC Camargo Cancer Center, Sao Paulo, Brazil.

Colorectal cancer (CRC) is one of the most common cancers in Latin America and the Caribbean, with the highest rates reported for Uruguay, Brazil and Argentina. We provide a global snapshot of the CRC patterns, how screening is performed, and compared/contrasted to the genetic profile of Lynch syndrome (LS) in the region. From the literature, we find that only nine (20%) of the Latin America and the Caribbean countries have developed guidelines for early detection of CRC, and also with a low adherence. We describe a genetic profile of LS, including a total of 2,685 suspected families, where confirmed LS ranged from 8% in Uruguay and Argentina to 60% in Peru. Among confirmed LS, path_MLH1 variants were most commonly identified in Peru (82%), Mexico (80%), Chile (60%), and path_MSH2/EPCAM variants were most frequently identified in Colombia (80%) and Argentina (47%). Path_MSH6 and path_PMS2 variants were less common, but they showed important presence in Brazil (15%) and Chile (10%), respectively. Important differences exist at identifying LS families in Latin American countries, where the spectrum of path_MLH1 and path_MSH2 variants are those most frequently identified. Our findings have an impact on the evaluation of the patients and their relatives at risk for LS, derived from the gene affected. Although the awareness of hereditary cancer and genetic testing has improved in the last decade, it is remains deficient, with 39%-80% of the families not being identified for LS among those who actually met both the clinical criteria for LS and showed MMR deficiency.
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http://dx.doi.org/10.1002/ijc.31920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587543PMC
July 2019

Evaluation of MLH1 variants of unclear significance.

Genes Chromosomes Cancer 2018 Jul 30;57(7):350-358. Epub 2018 Apr 30.

Biomedizinisches Forschungslabor, Medizinische Klinik 1, Universitätsklinik Frankfurt, Frankfurt, Germany.

Inactivating mutations in the MLH1 gene cause the cancer predisposition Lynch syndrome, but for small coding genetic variants it is mostly unclear if they are inactivating or not. Nine such MLH1 variants have been identified in South American colorectal cancer (CRC) patients (p.Tyr97Asp, p.His112Gln, p.Pro141Ala, p.Arg265Pro, p.Asn338Ser, p.Ile501del, p.Arg575Lys, p.Lys618del, p.Leu676Pro), and evidence of pathogenicity or neutrality was not available for the majority of these variants. We therefore performed biochemical laboratory testing of the variant proteins and compared the results to protein in silico predictions on structure and conservation. Additionally, we collected all available clinical information of the families to come to a conclusion concerning their pathogenic potential and facilitate clinical diagnosis in the affected families. We provide evidence that four of the alterations are causative for Lynch syndrome, four are likely neutral and one shows compromised activity which can currently not be classified with respect to its pathogenic potential. The work demonstrates that biochemical testing, corroborated by congruent evolutionary and structural information, can serve to reliably classify uncertain variants when other data are insufficient.
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http://dx.doi.org/10.1002/gcc.22536DOI Listing
July 2018

A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America.

BMC Cancer 2017 Sep 5;17(1):623. Epub 2017 Sep 5.

Hospital Sirio Libanes, Sao Paulo, Brazil.

Background: Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America.

Methods: Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome.

Results: We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet.

Conclusion: The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries.
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http://dx.doi.org/10.1186/s12885-017-3599-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5586063PMC
September 2017

Lynch syndrome in South America: past, present and future.

Fam Cancer 2016 07;15(3):437-45

Cleveland Clinic Foundation, Cleveland, OH, USA.

After decades of unawareness about Lynch syndrome, the medical community in South America is increasingly interested and informed. The visits and support of mentors like H. T. Lynch had been crucial to this awakening. Several countries have at least one registry with skilled personnel in genetic counseling and research. However, this only represents a very restricted resource for the region. According to the GETH, there are 27 hereditary cancer care centers in South America (21 in Brazil, 3 in Argentina, 1 in Uruguay, 1 in Chile and 1 in Peru). These registries differ in fundamental aspects of function, capabilities and funding, but are able to conduct high quality clinical, research and educational activities due to the dedication and personal effort of their members, and organizational support. More support from the governments as well as the participation of the community would boost the initiatives of people leading these groups. Meantime, the collaboration among the South American registries and the involvement of registries and leaders from developed countries will allow to maximize the efficiency in caring for affected patients and their families. The aim of this article is to describe how the knowledge of LS began to be spread in South America, how the first registries were organized and to summarize the current state of progress. In addition, we will provide an update of the clinical and molecular findings in the region.
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http://dx.doi.org/10.1007/s10689-016-9903-7DOI Listing
July 2016

Mutation spectrum in South American Lynch syndrome families.

Hered Cancer Clin Pract 2013 Dec 18;11(1):18. Epub 2013 Dec 18.

The Danish HNPCC Register, Clinical Research Centre, Hvidovre Hospital, Copenhagen University, Hvidovre, Denmark.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1186/1897-4287-11-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904200PMC
December 2013

Evaluation of MLH1 I219V polymorphism in unrelated South American individuals suspected of having Lynch syndrome.

Anticancer Res 2012 Oct;32(10):4347-51

Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.

Background: Some single-nucleotide polymorphisms are associated with higher risk of colorectal cancer development and are suggested to explain part of the genetic contribution to Lynch syndrome.

Aim: To evaluate the mutL homolog 1 (MLH1) I219V polymorphism in 124 unrelated South American individuals suspected of having Lynch syndrome, based on frequency, association with pathogenic MLH1 and mutS homolog 2 (MSH2) mutation and clinical features.

Materials And Methods: DNA was obtained from peripheral blood and polymerase chain reaction (PCR) was performed, followed by direct sequencing.

Results: The Val allelic of the I219V polymorphism was found in 51.61% (64/124) of the individuals, with an allelic frequency of 0.3. MLH1 or MHS2 pathogenic mutations were found in 32.81% (21/64) and in 23.33% (14/60) of Val-carriers and non-carriers, respectively.

Conclusion: The Val-carrying genotype was frequent in the studied population; however, it does not appear to exert any modifier effect on MLH1 or MSH2 pathogenic mutations and the development of colorectal cancer.
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October 2012

Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals.

Fam Cancer 2011 Dec;10(4):641-7

Laboratory of Genomics and Molecular Biology, Centro Internacional de Pesquisa e Ensino, A.C.Camargo Hospital, São Paulo, Brazil.

Lynch syndrome (LS) is an autosomal dominant syndrome that predisposes individuals to development of cancers early in life. These cancers are mainly the following: colorectal, endometrial, ovarian, small intestine, stomach and urinary tract cancers. LS is caused by germline mutations in DNA mismatch repair genes (MMR), mostly MLH1 and MSH2, which are responsible for more than 85% of known germline mutations. To search for germline mutations in MLH1 and MSH2 genes in 123 unrelated South American suspected LS patients (Bethesda or Amsterdam Criteria) DNA was obtained from peripheral blood, and PCR was performed followed by direct sequencing in both directions of all exons and intron-exon junctions regions of the MLH1 and MSH2 genes. MLH1 or MSH2 pathogenic mutations were found in 28.45% (34/123) of the individuals, where 25/57 (43.85%) fulfilled Amsterdam I, II and 9/66 (13.63%) the Bethesda criteria. The mutations found in both genes were as follows: nonsense (35.3%), frameshift (26.47%), splicing (23.52%), and missense (9%). Thirteen alterations (35.14%) were described for the first time. The data reported in this study add new information about MLH1 and MSH2 gene mutations and contribute to better characterize LS in Brazil, Uruguay and Argentina. The high rate of novel mutations demonstrates the importance of defining MLH1 and MSH2 mutations in distinct LS populations.
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http://dx.doi.org/10.1007/s10689-011-9461-yDOI Listing
December 2011

Three new mutations in hereditary nonpolyposis colorectal cancer (Lynch syndrome II) in Uruguay.

Cancer Genet Cytogenet 2003 Apr;142(1):13-20

Uruguayan Collaborative Group: Survey of Hereditary Oncologic Disorders, Hospital Central de las Fuerzas Armadas, 11600 Montevideo, Uruguay.

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common hereditary form of colorectal cancer (CRC). Our purpose is to describe three extended HNPCC families, each of which manifests novel germline mutations in Uruguay, a small country that is a study model for cancer investigation given its high cancer incidence and mortality rate. This is a study of three extended HNPCC families in which extensive genealogic information, medical history, and pathology findings are critically reviewed. DNA testing was performed for evidence of HNPCC mutations. The findings reveal three novel germline mutations, namely MLH1, with a deletion resulting in a frameshift and a premature stop codon (codon 228) in one of the families; in the second family, MSH2 exon 1, codon 61 at nucleotide 181, which results in immediate stop of translation; and in the third family, a mutation in MSH2 at exon 3: the amino acid at nucleotide 530, codon 117, causing a frameshift and a premature stop codon eight base pairs later. We conclude that it is important to study HNPCC mismatch repair genes because of emerging evidence for genotypic and phenotypic heterogeneity, which will harbor the potential to eventually translate this knowledge into specific screening and management protocols. Future projections for such mutations could even contribute to the emergence of molecular-based designer drugs developed through advances in genomics, proteomics, high-throughput screening, and bioinformatics, which would be effective therapeutically for these high-cancer risk patients.
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http://dx.doi.org/10.1016/s0165-4608(02)00766-5DOI Listing
April 2003