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Karin Álvarez

Universidad de Los Andes, Chile

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Francisco López-Köstner

Universidad de Los Andes, Chile

Mev Dominguez–Valentin

Oslo University Hospital

Carlos Vaccaro

Hospital Italiano de Buenos Aires

Florencia Neffa

Hospital Central de las Fuerzas Armadas

Pål Møller

Oslo University Hospital

Adriana Della Valle

Hospital Central de las Fuerzas Armadas

Paulina Orellana

Adolfo Ibáñez University

Pablo Kalfayan

Instituto Nacional del Cáncer

Pilar Carvallo

Pontificia Universidad Católica de Chile

Tamara Alejandra Piñero

Hospital Italiano de Buenos Aires

Cooperative Institutions

Clínica Las Condes

University of Chile

Pontificia Universidad Católica de Chile

Inserm

University of Melbourne

Istituti di Ricovero e Cura a Carattere Scientifico

Bambino Gesù Children's Hospital

Hospital Sírio-Libanês

Cancer Genetics (United States)

Rambam Health Care Campus

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Immune System, Microbiota, and Microbial Metabolites: The Unresolved Triad in Colorectal Cancer Microenvironment

Frontiers in Immunology (2021)

Michelle Hanus Daniela Parada-Venegas Glauben Landskron Ana María Wielandt Claudia Hurtado

Colorectal cancer (CRC) is one of the most common cancers worldwide. As with other cancers, CRC is a multifactorial disease due to the combined effect of genetic and environmental factors. Most cases are sporadic, but a small proportion is hereditary, estimated at around 5-10%. In both, the tumor interacts with heterogeneous cell populations, such as endothelial, stromal, and immune cells, secreting different signals (cytokines, chemokines or growth factors) to generate a favorable tumor microenvironment for cancer cell invasion and metastasis. There is ample evidence that inflammatory processes have a role in carcinogenesis and tumor progression in CCR. Different profiles of cell activation of the tumor microenvironment can promote pro or anti-tumor pathways; hence they are studied as a key target for the control of cancer progression. Additionally, the intestinal mucosa is in close contact with a microorganism community, including bacteria, bacteriophages, viruses, archaea, and fungi composing the gut microbiota. Aberrant composition of this microbiota, together with alteration in the diet‐derived microbial metabolites content (such as butyrate and polyamines) and environmental compounds has been related to CRC. Some bacteria, such as pks+ Escherichia coli or Fusobacterium nucleatum , are involved in colorectal carcinogenesis through different pathomechanisms including the induction of genetic mutations in epithelial cells and modulation of tumor microenvironment. Epithelial and immune cells from intestinal mucosa have Pattern-recognition receptors and G-protein coupled receptors (receptor of butyrate), suggesting that their activation can be regulated by intestinal microbiota and metabolites. In this review, we discuss how dynamics in the gut microbiota, their metabolites, and tumor microenvironment interplays in sporadic and hereditary CRC, modulating tumor progression.

Fusobacterium nucleatum

Tumor progression

10.3389/fimmu.2021.612826

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Citations (118)

A comprehensive characterization of the spectrum of MUTYH germline pathogenic variants in Latin America

Familial Cancer (2024)

Patricia Esperón Florencia Neffa Walter Pavicic Florencia Spirandelli Karin Álvarez

MUTYH

Human genetics

Broad spectrum

10.1007/s10689-024-00382-3

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No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study

Journal of Clinical Medicine (2021)

Mev Dominguez–Valentin John‐Paul Plazzer Julian R. Sampson Christoph Engel Stefan Aretz

Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown.To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes.Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity.Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately.Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

Lynch Syndrome

MSH2

Penetrance

MLH1

MSH6

10.3390/jcm10132856

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Citations (16)

Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report

European Journal of Cancer (2021)

Toni T. Seppälä Mev Dominguez–Valentin Emma J. Crosbie Christoph Engel Stefan Aretz

PurposeThis study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.MethodsThe Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30–69 years.ResultsOverall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.ConclusionUptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene- and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syndrome to improve outcomes.

Lynch Syndrome

MSH6

MLH1

PMS2

10.1016/j.ejca.2021.02.022

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EGFR pathway subgroups in Chilean colorectal cancer patients, detected by mutational and expression profiles, associated to different clinicopathological features

Tumor Biology (2017)

Karin Álvarez Paulina Orellana Cynthia Villarroel Luis Contreras Hiroshi Kawachi

Colorectal cancer is a multistep process affecting several signaling pathways including EGFR (epidermal growth factor receptor), a therapeutic target for metastatic disease. Our aim was to characterize the mutational and expression profiles of the EGFR pathway in colorectal tumors and to integrate these results according to five previously defined groups. We screened seven genes for mutations ( KRAS-BRAF-PIK3CA-PIK3R1-AKT1-MAP2K1-PTEN) and six proteins (EGFR-p110α-p85α-PTEN-phosphoAKT-phosphoMEK1) by immunohistochemistry, PTEN deletion, and MSI. At least one mutated gene was observed in 68% of tumors ( KRAS 45%, PIK3CA 21%, BRAF 14%, and PTEN 7%). PTEN deletion was observed in 10.7% of tumors and 19.6% were MSI-High. In all, 54% of tumors showed a high EGFR expression, 48% p110α, 4.4% phosphoAKT, and 22% phosphoMEK1; and 43% showed low PTEN expression and 22% p85α. In total, five groups of tumors were defined based on MSI, BRAF, and KRAS mutations. Three groups gather mainly early-stage tumors, whereas a fourth group is mostly conformed by advanced tumors. We described here that 71.4% of tumors from one group have a mutated PI3K/PTEN pathway, in comparison to other groups having 32%, 27%, and 25%. In addition, the five groups are differentiated by molecular features such as EGFR, p85α, p110α, and PTEN, showing variable expression among tumor groups. In conclusion, alterations on the EGFR pathway were found in a high percentage of colorectal cancer patients. Using the integration of diverse molecular markers, we ratified previous classification in an ethnic group having relevant genetic differences and living in a different environmental background, adding complementary molecular targets related to therapy.

10.1177/1010428317724517

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Citations (12)

P.19.6 PIK3CA somatic mutation in congenital monomelic muscular hypertrophy of the upper extremity. Case report

Neuromuscular Disorders (2013)

Claudia Castiglioni Paulina Orellana Fernando Las‐Heras Daniel Hinzpeter Paola Paolinelli

Proteus syndrome

10.1016/j.nmd.2013.06.687

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Abstract 2645: Genomic deletions and point mutations in the STK11 gene in Peutz-Jeghers Chilean families

Cancer Research (2012)

Paulina Orellana Karin Álvarez Claudio Heine Cristóbal Suazo Eliana Pinto

Abstract Background: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant hereditary disease characterized by mucocutaneous pigmentation and gastrointestinal hamartomatous polyposis. Individuals with PJS are at increased risk for development of various neoplasms. The genetic susceptibility for PJS has been associated with germline mutation in the serine/threonine kinase 11 (STK11) gene. The aim of the present study was to characterize the genotype and phenotype of Chilean PJS patients. Methods: Mutation screening of 13 patients from 8 PJS families was performed by using single strand conformation polymorphism (SSCP) analysis and DNA sequencing, covering the entire coding region and the splice-site boundaries. In addition, multiplex ligation-dependent probe amplification (MLPA) assay was used for the identification of large exonic deletions or duplications. Results: We identified seven different pathogenic mutations in STK11 gene in 7 unrelated families. Point mutations correspond to a small deletion (c.109delC) in exon 1 that generates a premature stop codon and two intronic mutations localized in splice site of intron 4 (c.597+2 T>A) and intron 6 (c.862-2 A>G). The pathogenic effect on splicing of intronic changes was demonstrated in mRNA of STK11 from lymphocytes of patients. By MLPA, we identified four large deletions ranging from one exon to the whole gene. Breakpoints were identified in two of these patients. Three point mutations (43%, 3/7) may be considered as novel. Conclusions: Different germline mutations in STK11 were detected. A combination of sensitive techniques may improve a high STK11 mutation detection frequency (88%) in PJS Chilean families. Funded by Clinica Las Condes Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2645. doi:1538-7445.AM2012-2645

STK11

Splice site mutation

10.1158/1538-7445.am2012-2645

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Novel human pathological mutations. Gene symbol: APC. Disease: adenomatous polyposis coli.

Human Genetics (2010)

Francisco López-Köstner Karin Álvarez de la Fuente M Wielandt Am Paulina Orellana

Adenomatous polyposis coli

Human genetics

Amino acid substitution

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Large deletions and splicing‐site mutations in the STK11 gene in Peutz‐Jeghers Chilean families

Clinical Genetics (2012)

Paulina Orellana Francisco López-Köstner Claudio Heine Cristóbal Suazo Eliana Pinto

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder characterized by mucocutaneous melanocytic macules, gastrointestinal hamartomatous polyposis and an increased risk of various neoplasms. Germline mutations in the serine/threonine kinase 11 (STK11) gene have been identified as a cause for PJS. The aim of this study was to characterize the genotype of Chilean PJS patients. Mutation screening of 13 patients from eight PJS families was performed using a single strand conformation polymorphism analysis, DNA sequencing and multiplex ligation-dependent probe amplification assay. The breakpoints of the genomic rearrangements were assessed by a long-range polymerase chain reaction and sequencing. The results revealed the existence of seven different pathogenic mutations in STK11 gene in seven unrelated families, including three point mutations and four large genomic deletions. Three of these point mutations (43%, 3/7) may be considered as novel. Our results showed that a germline mutation is present in STK11 in 88% of probands fulfilling the diagnostic criteria of PJS. In this study, the combination of two different experimental approaches in the screening of the STK11 in PJS, led to a higher percentage of mutation detection.

STK11

Peutz–Jeghers syndrome

10.1111/j.1399-0004.2012.01928.x

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Citations (11)

Structure and functionality in flavivirus NS-proteins: Perspectives for drug design

Antiviral Research (2009)

Michela Bollati Karin Álvarez R. Assenberg Cécile Baronti Bruno Canard

Flaviviridae are small enveloped viruses hosting a positive-sense single-stranded RNA genome. Besides yellow fever virus, a landmark case in the history of virology, members of the Flavivirus genus, such as West Nile virus and dengue virus, are increasingly gaining attention due to their re-emergence and incidence in different areas of the world. Additional environmental and demographic considerations suggest that novel or known flaviviruses will continue to emerge in the future. Nevertheless, up to few years ago flaviviruses were considered low interest candidates for drug design. At the start of the European Union VIZIER Project, in 2004, just two crystal structures of protein domains from the flaviviral replication machinery were known. Such pioneering studies, however, indicated the flaviviral replication complex as a promising target for the development of antiviral compounds. Here we review structural and functional aspects emerging from the characterization of two main components (NS3 and NS5 proteins) of the flavivirus replication complex. Most of the reviewed results were achieved within the European Union VIZIER Project, and cover topics that span from viral genomics to structural biology and inhibition mechanisms. The ultimate aim of the reported approaches is to shed light on the design and development of antiviral drug leads.

Flavivirus

Antiviral drug

Zika Virus

NS3

10.1016/j.antiviral.2009.11.009

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Citations (322)