Variant curation and interpretation in hereditary cancer genes: An institutional experience in Latin America.

BACKGROUND: Variant curation refers to the application of evidence-based methods for the interpretation of genetic variants. Significant variability in this process among laboratories affects clinical practice. For admixed Hispanic/Latino populations, underrepresented in genomic databases, the interpretation of genetic variants for cancer risk is challenging. METHODS: We retrospectively evaluated 601 sequence variants detected in patients participating in the largest Institutional Hereditary Cancer Program in Colombia. VarSome and PathoMAN were used for automated curation, and ACMG/AMP and Sherloc criteria were applied for manual curation. RESULTS: Regarding the automated curation, 11% of the variants (64/601) were reclassified, 59% (354/601) had no changes in its interpretation, and the other 30% (183/601) presented conflicting interpretations. With respect to manual curation, of the 183 variants with conflicting interpretations, 17% (N = 31) were reclassified, 66% (N = 120) had no changes in their initial interpretation, and 17% (N = 32) remained with conflicting interpretation status. Overall, 91% of the VUS were downgraded and 9% were upgraded. CONCLUSIONS: Most VUS were reclassified as benign/likely benign. Since false-positive and -negative results can be obtained with automated tools, manual curation should also be used as a complement. Our results contribute to improving cancer risk assessment and management for a broad range of hereditary cancer syndromes in Hispanic/Latino populations.

Criterios para la identificación de síndromes de cáncer de mama hereditarios. Revisión de la literatura y recomendaciones para el Instituto Nacional de Cancerología - Colombia / Criteria for the identification of hereditary breast cancer syndromes. Review of the literature and recommendations for the Instituto Nacional de Cancerología - Colombia

Introducción. Los síndromes de cáncer de mama hereditario (SCMH) corresponden a un 5% a 10% de todos los casos de la enfermedad, en su mayoría explicados por mutaciones en los genes BRCA1 y BRCA2. Se han publicado múltiples guías y recomendaciones internacionales actualizadas, con el fin de dar lineamientos para seleccionar los casos con sospecha de un SCMH. Como antecedentes locales, el Instituto Nacional de Cancerología de Colombia cuenta con un "Programa institucional para la identificación y manejo de familias con sospecha de cáncer hereditario", con fines asistenciales, dentro del cual el cáncer de mama es la patología más remitida al servicio de genética (55%; 540/986). En el 21% de los casos con cáncer de mama que cumplieron criterios NCCN se diagnosticó un SCMH, la mayoría asociados a mutaciones en los genes BRCA1 y BRCA2 (12,3%) y en menor proporción a otros genes de susceptibilidad al cáncer de mama (8,6%).Objetivo. Identificar los criterios de selección más implementados para diagnosticar los casos de cáncer de mama hereditarios a través de una revisión de la literatura, y realizar un consenso Institucional sobre las indicaciones de remisión a consejería genética y solicitud de pruebas para fines diagnósticos y de tratamiento sistémico con iPARP. Materiales y métodos. Se realizó una revisión narrativa de la literatura científica publicada en los últimos 10 años, al 30 de agosto del 2021, sobre la prevalencia de mutaciones germinales en los genes BRCA1 y BRCA2, y en otros genes no BRCA, en pacientes con cáncer de mama, obteniéndose en total 146 y seleccionándose un total de 41 artículos. En el interior de las unidades funcionales de mama y tejidos blandos, genética y oncología clínica, se presentó la evidencia disponible, realizando una discusión amplia entre las tres unidades y finalmente se definieron las indicaciones para remisión a genética, para solicitar estudios genéticos y de tratamiento sistémico con iPARP.Resultados. Según lo reportado en la literatura, los principales criterios de sospecha de un SCMH deben incluir: el subtipo triple negativo, la presentación bilateral, la edad muy temprana de diagnóstico y los antecedentes familiares (AF) de cáncer de mama antes de los 50 años o cáncer de ovario a cualquier edad.Conclusiones. Se adoptan las recomendaciones de la NCCN para la remisión a consejería genética y solicitud de estudios genéticos para identificar cáncer de mama hereditario, y se establecen los criterios del estudio OlympiA para la solicitud de estudios genéticos con el fin de guiar el tratamiento sistémico con iPARP en el Instituto Nacional de Cancerología. Lo anterior permitirá que desde nuestra Institución se ofrezca adecuadamente este servicio a la población colombiana.

ntroduction: Hereditary breast and ovarian cancer syndromes (HBOC) represents 5% to 10% of all breast cancer cases, and BRCA1andBRCA2 explain most of these syndromes. Multiple guidelines and updated recommendations have been published to define which patients should be selected for genetic testing based on a clinical suspicion of a HBOC syndrome. For context, the Instituto Nacional de Cancerología from Colombia developed an "Institutional Program for the identification and management of families with suspected hereditary cancer" for healthcare purposes, within which breast cancer is the most referred pathology to the genetics service (55%; 540/986). Inherited cancer was diagnosed in 21% of the patients with breast cancer who met NCCN criteria; most of these were associated with BRCA1 and BRCA2 mutations (12.3%) and to a lesser extent to other breast cancer susceptibility genes (8.6%).Objective: To identify the most implemented selection criteria to diagnose inherited breast cancer cases, through a review of the literature, and to achieve an institutional consensus on the indications for referral to genetic counseling and genetic testing for diagnostic and systemic treatment with PARPi.Materials and methods: A narrative review of the scientific literature published in the last 10 years as of August 30, 2021 on the prevalence of germline mutations in the BRCA1 and BRCA2 genes, and in other non-BRCA genes, in patients with breast cancer was carried out. Overall, 146 articles were first identified but only 41 were selected. Within the functional units of breast and soft tissue, genetics and clinical oncology, the available evidence was presented and a broad discussion was carried out; finally the indications for referral to genetic counseling, for genetic testing and for systemic treatment with PARPi were defined.Results: As reported in the literature, clinical criteria for HBOC syndrome should include: triple negative subtype, bilateral presentation, very early age of diagnosis and family history (FH) of breast cancer before 50 years of age or ovarian cancer at any age. Conclusions: The NCCN recommendations for referral to genetic counseling and ordering genetic testing to diagnose HBOC cases are adopted at the Instituto Nacional de Cancerología from Colombia, as well as the OlympiA study criteria for ordering genetic testing to guide systemic PARPi therapy. This will allow our Institution to adequately offer this service to the Colombian population.

SDHB exon 1 deletion: A recurrent germline mutation in Colombian patients with pheochromocytomas and paragangliomas.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) (known as PPGL in combination) are rare neuroendocrine tumors of the adrenal medulla and extra-adrenal ganglia. About 40% of the patients with PPGL have a hereditary predisposition. Here we present a case-series of 19 unrelated Colombian patients with a clinical diagnosis of PPGL tumors that underwent germline genetic testing as part of the Hereditary Cancer Program developed at the Instituto Nacional de Cancerología, Colombia (INC-C), the largest reference cancer center in the country. Ten of 19 patients (52.63%) were identified as carriers of a pathogenic/likely pathogenic (P/LP) germline variant in a known susceptibility gene. The majority of the P/LP variants were in the SDHB gene (9/10): one corresponded to a nonsense variant c.268C>T (p.Arg90*) and eight cases were found to be carriers of a recurrent CNV consisting of a large deletion of one copy of exon 1, explaining 42% (8/19) of all the affected cases. Only one additional case was found to be a carrier of a missense mutation in the VHL gene: c.355T>C (p.Phe119Leu). Our study highlights the major role of SDHB in Colombian patients with a clinical diagnosis of PGL/PCC tumors and supports the recommendation of including the analysis of large deletions/duplications of the SDHB gene as part of the genetic counselling to improve the detection rate of hereditary cases and their clinical care.

Mutational analysis of BRCA1 and BRCA2 genes in women with familial breast cancer from different regions of Colombia.

PURPOSE: The main risk factor for familial breast cancer is the presence of mutations in BRCA1 and BRCA2 genes. The prevalence of mutations in these genes is heterogeneous and varies according to geographical origin of studied families. In Colombia mutations in these genes have been mainly studied on patients from Andean region. Bogotá and Medellin presented its own battery of mutations. This study aims to identify mutations in BRCA1-2 genes in women with familial breast cancer from different regions of Colombia. METHODS: One hundred four families with a history of breast cancer were sampled in different regions of Colombia, and the BRCA1 gene and exon 11 of the BRCA2 gene were sequenced. To predict the possible effects of sequence alterations found in protein function, different bioinformatics tools were used. RESULTS: A total of 33 variants were found; 18 in BRCA1 and 15 in BRCA2, of which 15 are unique variants of Colombia. In silico analysis established that alterations p.Thr790Ala, p.Arg959Lys and p.Glu1345Lys in the BRCA1 gene and variants p.Leu771Phe, p.Asn818Lys, p.Val859Ser*22 and p.Lys1032Ile in the BRCA2 gene are considered likely pathogenic. Both the mutations as the variants of unknown clinical significance, in their great majority, presented a specific region distribution and they were different from those reported in previous studies. CONCLUSIONS: In this study we report the BRCA1 and BRCA2 spectrum of mutations and their distribution by regions in Colombia. Our results may help to design a diagnostic test including recurrent mutations for screening high risk to breast cancer families in Colombia.

Efecto del extracto acuoso de Piper elongatum Vahl. (matico) sobre la motilidad intestinal en ratones / Effect of aqueous extract from Piper elongatum Vahl (matico) on the intestinal motility in mice

Objetivo: evaluar el efecto del extracto acuoso de Piper elongatum Vahl. (matico) sobre la motilidad intestinal en ratones BALB/c. Métodos: estudio experimental. Se empleó el método del carbón activado. Los grupos fueron: Grupo 1 control negativo con NaCl 9.0 por ciento, Grupo 2 control positivo con loperamida 10 mg/Kg, grupos tratamiento de la planta a dosis de 125 mg/Kg (Grupo3), 250 mg/Kg (Grupo4) y 500 mg/Kg (Grupo5). Se utilizaron las pruebas estadísticas de ShapiroWilk, ANOVA y Bonferroni; se consideró p<0,05 como significativo e intervalo de confianza 95 por ciento. Resultados: el porcentaje del intestino recorrido por el carbón activado fue de 69,4±4,5; 24,9±3,0; 75,3±4,3; 71,1±4,5; 56,4±2,7 y 59,4±3,0 en los grupos del 1 al 5, respectivamente. La prueba post hoc Bonferroni no mostró diferencias entre el control negativo y los grupos tratamiento con Piper elongatum Vahl., mientras que sí existió diferencia entre el control positivo con los demás grupos y entre el grupo 3 y 5 (p<0,001). Conclusiones: el extracto acuoso de las hojas de Piper elongatum Vahl. no posee efecto sobre la motilidad intestinal a las dosis evaluadas, se requieren más estudios(AU)

Objective: to evaluate the effect of aqueous extract from Piper elongatum Vahl (matico) on the intestinal motility in BALB/c mice. Methods: experimental study that used activated carbon. The involved groups were: Group 1 with negative control with 9.0 percent NaCl; Group 2 positive control with loperamide 10mg/Kg, groups treated with the plant at doses of 125 mg/kg (Group3), 250 mg/kg (Group4) and 500 mg/Kg (Group5). ShapiroWilk, ANOVA and Bonferroni statistical tests were used; p<0.05 was considered as significant and 95 percent confidence interval. Results: the percentages of intestine explored with the active charcoal were 69,4±4,5; 24,9±3,0; 75,3±4,3; 71,1±4,5; 56,4±2,7 and 59,4±3,0 in groups 1 to 5 respectively. The ANOVA on this variable showed a p<0,001. The post hoc Bonferroni test showed no differences between the negative control and treatment groups with Piper elongatum Vahl whereas there was a difference between the positive control and the other groups and between the groups 3 and 5 (p<0.001). Conclusions: the aqueous extract from Piper elongatum Vahl has no effect on the intestinal motility at the evaluated doses, so further studies are needed(AU)