Tamara Alejandra Piñero

Hospital Italiano de Buenos Aires

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Carlos Vaccaro

Hospital Italiano de Buenos Aires

Pablo Kalfayan

Instituto Nacional del Cáncer

Mev Dominguez–Valentin

Oslo University Hospital

Pål Møller

Oslo University Hospital

Eivind Hovig

Oslo University Hospital

KÁ

Karin Álvarez

Universidad de Los Andes, Chile

Florencia Neffa

Hospital Central de las Fuerzas Armadas

John‐Paul Plazzer

The Royal Melbourne Hospital

Adriana Della Valle

Hospital Central de las Fuerzas Armadas

Patricia Esperón

Hospital Central de las Fuerzas Armadas

Cooperative Institutions

Hospital Italiano de Buenos Aires

Consejo Nacional de Investigaciones Científicas y Técnicas

Instituto Universitario Hospital Italiano

Rambam Health Care Campus

Hospital Sírio-Libanês

AC Camargo Hospital

Centre International de Recherche sur le Cancer

Ben-Gurion University of the Negev

University of Vermont

Universidade de São Paulo

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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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Citations (16)

MLH1 Ile219Val Polymorphism in Argentinean Families with Suspected Lynch Syndrome

Frontiers in Oncology (2016)

Mev Dominguez–Valentin Patrik Wernhoff Andrea R. Cajal Pablo Kalfayan Tamara Alejandra Piñero

DATA REPORT article Front. Oncol., 24 August 2016Sec. Gastrointestinal Cancers Volume 6 - 2016 | https://doi.org/10.3389/fonc.2016.00189

Lynch Syndrome

MLH1

10.3389/fonc.2016.00189

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Citations (5)

MLH1 intronic variants mapping to + 5 position of splice donor sites lead to deleterious effects on RNA splicing

Familial Cancer (2020)

Tamara Alejandra Piñero Omar Soukarieh Marion Rolain Karin Álvarez Francisco López-Köstner

MSH6

MSH2

PMS2

MLH1

Lynch Syndrome

Exon skipping

10.1007/s10689-020-00182-5

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Citations (5)

Metabolic oligosaccharide engineering of Plasmodium falciparum intraerythrocytic stages allows direct glycolipid analysis by mass spectrometry

Molecular and Biochemical Parasitology (2012)

Tamara Alejandra Piñero Valnice J. Peres Alejandro M. Katzin Alicia S. Couto

Glycoconjugate

Glycome

Glycosphingolipid

10.1016/j.molbiopara.2011.12.008

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

BMC Cancer (2017)

Bernard Rossi Edenir Inêz Palmero Francisco López-Köstner Carlos Sarroca Carlos Vaccaro

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.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.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.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.

MSH6

Lynch Syndrome

MSH2

PMS2

MLH1

Microsatellite Instability

10.1186/s12885-017-3599-4

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Citations (36)

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database

Genetics in Medicine (2019)

Mev Dominguez–Valentin Julian R. Sampson Toni T. Seppälä Sanne W. ten Broeke John‐Paul Plazzer

Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer.We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years.There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer.Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

Lynch Syndrome

MSH6

MLH1

MSH2

PMS2

10.1038/s41436-019-0596-9

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Citations (487)

Artificial Intelligence-Based Quantification and Prognostic Assessment of CD3, CD8, CD146, and PDGF-Rβ Biomarkers in Sporadic Colorectal Cancer

Communications in computer and information science (2024)

F. Lohmann Martín Isac Specterman Zabala Julieta Natalia Soarez Maximiliano D’adamo Mónica Loresi

CD146

10.1007/978-3-031-75144-8_1

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Citations (0)

Universal determination of microsatellite instability using BAT26 as a single marker in an Argentine colorectal cancer cohort

Familial Cancer (2017)

María Laura González Natalia Causada-Calo Juan Pablo Santino Mev Dominguez–Valentin Fabiana Alejandra Ferro

Microsatellite Instability

MLH1

Lynch Syndrome

10.1007/s10689-017-0052-4

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Citations (7)

Síndrome de Lynch: impacto de la caracterización de familias en base a estudios genéticos

Oncología Clínica (2018)

Carlos Vaccaro Tamara Alejandra Piñero Alberto Ignacio Herrando Romina A. Cajal Alejandra Ferro

El objetivo de este trabajo fue caracterizar demográfica y molecularmente las familias con diagnóstico de síndrome de Lynch en base a estudios genéticos. Se utilizó la base prospectiva del Registro de Epidemiología Molecular de Cáncer Colorrectal (REM-CCR) del Hospital Italiano de Buenos Aires (Clinical trials.gov NCT02781337). El criterio de inclusión fue que tuvieran hecho un estudio genético entre 1996 y 2017 (secuenciación y/o determinación de grandes rearreglos de al menos un gen reparador de error de apareamiento). Se analizaron 50 familias con los criterios de Amsterdam. En 23 (46%) se identificaron variantes patogénicas (n=19) y probablemente patogénicas (n=2). El 28.6% de las variantes patogénicas fueron originalmente descritas en esta serie, entre ellas la variante c.1911del en el exón 12 de MSH2 identificada en una familia con agregación de cáncer de mama. Fue identificada una mutación fundadora de Piamonte, Italia (c.2252_2253del). Los genes afectados incluyeron MSH2 (13 variantes)MLH1 (9 variantes) y PMS2 (1 variante). La tasa de detección de mutaciones fue del 46%. Entre las familias con mutación identificada (n=23), se detectó una edad mediana de inicio del cáncer menor (46 vs. 50 años, p=0.02) y mayor incidencia de tumores extra-colorrectales (90.5% vs. 45.8%, p <0.01), que las 27 sin mutaciones. La implementación de estudios genéticos permitió caracterizar variables demográficas en base a la identificación de mutaciones germinales asociadas al síndrome de Lynch, identificándose dos grupos diferenciados por la edad de afectación y la incidencia de tumores extracolónicos.

10.56969/oc.v23i1.63

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