Genetic Characterization in High-Risk Individuals from a Low-Resource City of Peru.

Background: Genetic testing for hereditary cancers is inconsistently applied within the healthcare systems in Latin America. In Peru, the prevalence and spectrum of cancer-predisposing germline variants is thus poorly characterized. Purpose: To determine the spectrum and prevalence of cancer-predisposing germline variants and variants of uncertain significance (VUS) in high-risk individuals located in a Peruvian low-resource setting city. Methods: Individuals presenting clinical criteria for hereditary cancer syndromes or being unaffected with familial history of cancer were included in the study. Samples from a total of 84 individuals were subjected to a high-throughput DNA sequencing assay that targeted a panel of 94 cancer predisposition genes. The pathogenicity of detected germline variants was classified according to the established American College of Medical Genetics and Genomics (ACMG) criteria. All pathogenic variants were validated by cycling temperature capillary electrophoresis. Results: We identified a total of eight pathogenic variants, found in 19 out of 84 individuals (23%). Pathogenic variants were identified in 24% (10/42) of unaffected individuals with family history of cancer and in 21% (9/42) of individuals with a cancer diagnosis. Pathogenic variants were identified in eight genes: RET (3), BRCA1 (3), SBDS (2), SBDS/MLH1 (4), MLH1 (4), TP53 (1), FANCD2 (1), DDB2/FANCG (1). In cancer cases, all colon cancer cases were affected by pathogenic variants in MLH1 and SBDS genes, while 20% (2/10) of the thyroid cancer cases by RET c.1900T>C variants were affected. One patient with endometrial cancer (1/3) had a double heterozygous pathogenic variant in DDB2 and FANCG genes, while one breast cancer patient (1/14) had a pathogenic variant in TP53 gene. Overall, each individual presented at least 17 VUS, totaling 1926 VUS for the full study population. Conclusion: We describe the first genetic characterization in a low-resource setting population where genetic testing is not yet implemented. We identified multiple pathogenic germline variants in clinically actionable predisposition genes, that have an impact on providing an appropriate genetic counselling and clinical management for individuals and their relatives who carry these variants. We also reported a high number of VUS, which may indicate variants specific for this population and may require a determination of their clinical significance.

Challenges to Bringing Personalized Medicine to a Low-Resource Setting in Peru.

We provide an overview of the challenges that low-resource setting cities are facing, including a lack of global implementation of cancer screening programs, accurate data and statistics that may aid the health authorities and guide future public health activities, as well as reorient strategies, interventions and budgets to promote lifestyles that help prevent disease. Current cancer care does not fully reflect ethnic, cultural, environmental and resource differences. Herein, we described a snapshot of the cancer mortality and morbidity from a hospital that cares a rural and low-income population from Peru, called Chimbote (316,966 inhabitants) and showed the limitation of access to oncological care and genetic services. The city is located in the region of Ancash, which is a department of Northern Peru. Of note, we identified a greater proportion of cancer cases than previously described, with a young age of onset and differential profile of the most frequent cancers. With the emergence of increasingly effective interventions, it becomes paramount that populations living in resource-limited settings have access to cancer services and participate in genetics and genomic research.

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

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.

Update on Hereditary Colorectal Cancer.

In the past two decades, significant advances have been made in our understanding of colorectal (CRC) tumors with DNA mismatch (MMR) repair deficiency. The knowledge from molecular and genetic alterations in a variety of clinical conditions has refined the disease terminology and classification. Hereditary non-polyposis colorectal cancer (HNPCC) encompasses a spectrum of conditions that have significant phenotypic overlapping that makes clinical diagnosis a challenging task. Distinguishing among the HNPCC disorders is clinically important, as the approach to surveillance for patients and their at-risk family members differs according to risks for colonic and extracolonic cancer associated with each syndrome. Prospective and next-generation studies will provide valuable clinical information regarding the natural history of disease that will help differentiate the Lynch syndrome mimics and guide diagnosis and management for heterogeneous conditions currently grouped under the category of familial CRC. The review is intended to present and discuss the molecular nature of various conditions related to MMR deficiency and discusses the tools and strategies that have been used in detecting these conditions.

Caracterización molecular de cáncer colorrectal hereditario en Perú / Molecular characterization of hereditary colorectal cancer in Peru

Investigar molecularmente la deficiencia en los genes de reparo de DNA (MMR) asociados al síndrome de Lynch. Materiales y métodos: Realizar los análisis de inmunohistoquímica e inestabilidad de microsatélites (MSI) en 5 familias con sospecha de síndrome de Lynch de acuerdo a los criterios clínicos de Amsterdam y/o Bethesda, atendidos en el Hospital Nacional Almanzor Aguinaga Asenjo de la ciudad de Chiclayo (Lambayeque-Perú) durante 2007-2010. Resultados. La falta de expresión de las proteínas MLH1/PMS2 y una alta MSI (MSI-H) fueron observados en un paciente de sexo masculino de 60 años diagnosticado con adenocarcinoma de grado I. Adicionalmente, se realizó el análisis mutacional puntual en el gen BRAF (V600E) a fin de descartar que se trate de un caso esporádico de cáncer colorrectal. La ausencia de mutación en el gen analizado asociado a los resultados moleculares del tumor, sugiere la caracterización de este paciente como sospecha de síndrome de Lynch. Conclusiones: Es el primer estudio molecular reportado en la población peruana y demuestra la importancia del análisis molecular en familias con sospecha de cáncer colorrectal hereditario a fin de ofrecer posibilidades de vigilancia y seguimiento que han demostrado reducir la morbilidad y la mortalidad del cáncer colorrectal así como contribuir a la caracterización a nivel genética y clínica de este tipo de cáncer en la población peruana...

To investigate the molecular deficiency in MMR genes associated to Lynch syndrome. Material and methods: Immunohistochemical and microsatellite instability (MSI) analysis were performed in 5 families with suspected Lynch syndrome according to the clinical criteria, Amsterdam and/or Bethesda that had been treated at the Hospital Nacional Almanzor Aguinaga Asenjo (Lambayeque-Peru) during 2007-2010. Results: The absence of expression of MLH1/PMS2 and high MSI (MSI-H) were observed in a male patient aged 60 with adenocarcinoma grade I. In addition, the point mutational analysis was performed in BRAF (V600E) to rule that it is a sporadic case of colorectal cancer. The absence of mutation in BRAF together with the molecular analysis suggests the suspicion as a Lynch syndrome. Conclusions: It is the first molecular study reported in the Peruvian population and demonstrates the importance of molecular analysis in families with suspected hereditary colorectal cancer in order to provide possibilities of surveillance and monitoring that have been shown to reduce morbidity and mortality of colorectal cancer. The present study contributes to the genetic and clinical characterization of the Lynch syndrome in the Peruvian population...

Identificación de cáncer colorrectal hereditario / Identification of heredity colorectal cancer: Lynch Syndrome

El síndrome de Lynch representa aproximadamente 4% de todos los tipos de cáncer colorrectal. Este síndrome se manifiesta en las familias de manera autosómica dominante y predispone a los individuos al desarrollo de cánceres temprano en la vida. El síndrome de Lynch es causado por mutaciones en la línea germinal de los genes que codifican las proteínas responsables de la reparación del daño al ADN, MLH1, MSH2, MSH6 y PMS2. La correcta historia familiar es en la actualidad el principal método para la identificación de pacientes con alto riesgo de presentar esta enfermedad, no obstante existen criterios clínicos ya establecidos. Es muy importante establecer medidas de vigilancia y monitoreo en los personas identificadas como portadoras de este síndrome, con la finalidad de ofrecer un programa de diagnóstico a sus familiares, ya que ayuda a reducir la morbimortalidad. El objetivo de esta revisión es describir los nuevos avances y conceptos sobre el síndrome de Lynch, su espectro tumoral, las características clínicas-patológicas, la correlación genotipo-fenotipo, los métodos de diagnóstico e identificación de mutaciones, así como resaltar su impacto en salud pública.

[Molecular characterization of hereditary colorectal cancer in Peru]. / Caracterización molecular de cáncer colorrectal hereditario en Perú.

OBJECTIVE: To investigate the molecular deficiency in MMR genes associated to Lynch syndrome. MATERIAL AND METHODS: Immunohistochemical and microsatellite instability (MSI) analysis were performed in 5 families with suspected Lynch syndrome according to the clinical criteria, Amsterdam and/or Bethesda that had been treated at the Hospital Nacional Almanzor Aguinaga Asenjo (Lambayeque-Peru) during 2007-2010. RESULTS: The absence of expression of MLH1/PMS2 and high MSI (MSI-H) were observed in a male patient aged 60 with adenocarcinoma grade I. In addition, the point mutational analysis was performed in BRAF (V600E) to rule that it is a sporadic case of colorectal cancer. The absence of mutation in BRAF together with the molecular analysis suggests the suspicion as a Lynch syndrome. CONCLUSIONS: It is the first molecular study reported in the Peruvian population and demonstrates the importance of molecular analysis in families with suspected hereditary colorectal cancer in order to provide possibilities of surveillance and monitoring that have been shown to reduce morbidity and mortality of colorectal cancer in the Peruvian population.