Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. METHODS: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. FINDINGS: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. INTERPRETATION: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. FUNDING: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

Autosomal Recessive Adolescent Syndromic Nephronophthisis Caused by a Novel Compound Heterozygous Pathogenic Variant.

BACKGROUND Nephronophthisis, an autosomal recessive ciliopathy involving mutations in primary cilium genes, is characterized by chronic tubulointerstitial nephritis and a defective urine concentrating capacity. It accounts for about 5% of renal failure in children and adolescents and usually progresses to end-stage renal disease before the age of 30 years. Nephronophthisis is associated with extrarenal manifestations, including retinitis pigmentosa in Senior-Loken syndrome (SLS), and liver fibrosis in 10-20% of cases. While some presenting patterns could be characteristic, patients may have atypical presentation, making diagnosis difficult. Tubulointerstitial fibrosis is the predominant feature on histology and as such, diagnosis depends mostly on genetic testing. Despite advances in renal genomics over the years with a better understanding of primary cilia and ciliary theory, about 40% of nephronophthisis cases go undiagnosed. As the underlying genetic etiologies are not fully understood, morphologic pathologic findings are non-specific, and treatment options are limited to dialysis and transplantation. CASE REPORT We describe a unique case of a patient with adolescent nephronophthisis who presented with advanced chronic kidney disease and severe pancytopenia, who progressed to end-stage renal disease at the age of 19, and was found to have syndromic nephronophthisis with compound heterozygous inheritance. CONCLUSIONS This report highlights the atypical presentation patterns that can be seen in syndromic nephronophthisis, the importance of genetic diagnosis when there is a high index of suspicion, and the need to further study genetic variants to better understand and diagnose the disease and to develop targeted therapy.

Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes.

Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes.

Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency.

Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.

Association of metabolic syndrome with glioblastoma: a retrospective cohort study and review.

BACKGROUND: Metabolic syndrome is identified as a risk factor for the development of several systemic cancers, but its frequency among patients with glioblastoma and its association with clinical outcomes have yet to be determined. The aim of this study was to investigate metabolic syndrome as a risk factor for and affecting survival in glioblastoma patients. METHODS: A retrospective cohort study, consisting of patients with diagnoses at a single institution between 2007 and 2013, was conducted. Clinical records were reviewed, and clinical and laboratory data pertaining to 5 metabolic criteria were extrapolated. Overall survival was determined by time from initial surgical diagnosis to date of death or last follow-up. RESULTS: The frequency of metabolic syndrome among patients diagnosed with glioblastoma was slightly greater than the frequency of metabolic syndrome among the general population. Within a subset of patients (n = 91) receiving the full schedule of concurrent radiation and temozolomide and adjuvant temozolomide, median overall survival was significantly shorter for patients with metabolic syndrome compared with those without. In addition, the presence of all 5 elements of the metabolic syndrome resulted in significantly decreased median survival in these patients. CONCLUSIONS: We identified the metabolic syndrome at a slightly higher frequency in patients with diagnosed glioblastoma compared with the general population. In addition, metabolic syndrome with each of its individual components is associated with an overall worse prognosis in patients receiving the standard schedule of radiation and temozolomide after adjustment for age.

A rare mutation in hypophosphatasia: a case report of adult form and review of the literature.

Hypophosphatasia is a rare inborn error of metabolism characterized by low serum alkaline phosphatase activity due to loss-of-function mutations in the gene encoding the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Extracellular accumulation of TNSALP substrates leads to dento-osseous and arthritic complications featuring tooth loss, rickets or osteomalacia, and calcific arthopathies. Mild hypophosphatasia usually has autosomal dominant inheritance, severe cases are either autosomal recessive or due to a dominant negative effect. Clinical manifestations of hypophosphatasia are extremely variable, ranging from life threatening to asymptomatic clinical presentations. The clinical presentation of the adult-onset hypophosphatasia is highly variable. Fractures, joint complications of chondrocalcinosis, calcifying polyarthritis and multiple pains may reveal minor forms of the disease in adults. It is important to recognize the disease to provide the best supportive treatment and to prevent the use of anti-resorption drugs in these patients. Bone-targeted enzyme-replacement therapy (asfotase alfa) was approved in 2015 to treat pediatric-onset hypophosphatasia. We present a case of a 41-year-old male diagnosed with adult form of hypophosphatasia with a rare ALPL mutation that has been previously described only once and review the literature on the adult form of the disease and its genetic mechanism.

A rare mutation in hypophosphatasia: a case report of adult form and review of the literature

SUMMARY Hypophosphatasia is a rare inborn error of metabolism characterized by low serum alkaline phosphatase activity due to loss-of-function mutations in the gene encoding the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Extracellular accumulation of TNSALP substrates leads to dento-osseous and arthritic complications featuring tooth loss, rickets or osteomalacia, and calcific arthopathies. Mild hypophosphatasia usually has autosomal dominant inheritance, severe cases are either autosomal recessive or due to a dominant negative effect. Clinical manifestations of hypophosphatasia are extremely variable, ranging from life threatening to asymptomatic clinical presentations. The clinical presentation of the adult-onset hypophosphatasia is highly variable. Fractures, joint complications of chondrocalcinosis, calcifying polyarthritis and multiple pains may reveal minor forms of the disease in adults. It is important to recognize the disease to provide the best supportive treatment and to prevent the use of anti-resorption drugs in these patients. Bone-targeted enzyme-replacement therapy (asfotase alfa) was approved in 2015 to treat pediatric-onset hypophosphatasia. We present a case of a 41-year-old male diagnosed with adult form of hypophosphatasia with a rare ALPL mutation that has been previously described only once and review the literature on the adult form of the disease and its genetic mechanism.

Personalized Medicine: Monogenic Diabetes.

Personalized medicine in diabetes is a topic which has gained significant momentum in recent years (Raz et al. 2013). A rapid rise in the number and combinations of diabetes therapies coupled with an unprecedented rise in diabetes prevalence rates has necessitated diabetes guidelines which emphasize the need for personalized patient-centered care (ADA 2014). There are many questions regarding the role genetics may be able to play in guiding therapy. Recent pharmacogenetic research has revealed polymorphisms that may impact patient response to metformin (Dong et al 2011) and glucagon-like-polypeptide-1 therapies (Smushkin et al. 2012). This may hold promise for helping identify patients who will better respond to specific agents and in the longer-term may help ensure a smooth journey along the therapeutic pathway. Monogenic or "single-gene" diabetes comprises nearly 2% of all cases of type 2 diabetes and provides a model for individualizing care. This review will discuss the diagnosis and treatment of this condition.

Cholesterol and family history: when genetics matters.

Familial hypercholesterolemia (FH) is an inherited, autosomal codominant disease that increases the risk for cardiovascular mortality by 100 fold. Patients usually have LDL levels above 300 mg/dl. Although signs such as tendon xanthomas, xanthelasmas and corneal arcus may suggest the diagnosis, genetic testing is the'most accurate way of diagnosing FH. Genetic testing has been shown to be a cost-efficient method to screen individuals and their relatives for FH. Establishing an accurate diagnosis is important: high potency statins are first-choice agents, the treatment goal is at least a 50% reduction in LDL cholesterol, and LDL apheresis may be indicated.

Description of the first case of adenomyomatosis of the gallbladder in an infant.

We report here the case of the youngest patient with adenomyomatosis of the gallbladder in a female infant diagnosed at 4 months of age. This diagnosis was made based on characteristic ultrasonography findings in a patient that was undergoing routine surveillance for a suspected clinical diagnosis of Beckwith-Wiedemann syndrome. The patient remains asymptomatic and currently no surgical interventions have been needed. We review the pathophysiology and ultrasonographic findings of this rare condition and present a comparison with the only other four pediatric cases of adenomyomatosis of the gallbladder.

Molecular subtypes of glioblastoma are relevant to lower grade glioma.

BACKGROUND: Gliomas are the most common primary malignant brain tumors in adults with great heterogeneity in histopathology and clinical course. The intent was to evaluate the relevance of known glioblastoma (GBM) expression and methylation based subtypes to grade II and III gliomas (ie. lower grade gliomas). METHODS: Gene expression array, single nucleotide polymorphism (SNP) array and clinical data were obtained for 228 GBMs and 176 grade II/II gliomas (GII/III) from the publically available Rembrandt dataset. Two additional datasets with IDH1 mutation status were utilized as validation datasets (one publicly available dataset and one newly generated dataset from MD Anderson). Unsupervised clustering was performed and compared to gene expression subtypes assigned using the Verhaak et al 840-gene classifier. The glioma-CpG Island Methylator Phenotype (G-CIMP) was assigned using prediction models by Fine et al. RESULTS: Unsupervised clustering by gene expression aligned with the Verhaak 840-gene subtype group assignments. GII/IIIs were preferentially assigned to the proneural subtype with IDH1 mutation and G-CIMP. GBMs were evenly distributed among the four subtypes. Proneural, IDH1 mutant, G-CIMP GII/III s had significantly better survival than other molecular subtypes. Only 6% of GBMs were proneural and had either IDH1 mutation or G-CIMP but these tumors had significantly better survival than other GBMs. Copy number changes in chromosomes 1p and 19q were associated with GII/IIIs, while these changes in CDKN2A, PTEN and EGFR were more commonly associated with GBMs. CONCLUSIONS: GBM gene-expression and methylation based subtypes are relevant for GII/III s and associate with overall survival differences. A better understanding of the association between these subtypes and GII/IIIs could further knowledge regarding prognosis and mechanisms of glioma progression.

Methylation markers of malignant potential in meningiomas.

OBJECT: Although most meningiomas are benign, about 20% are atypical (Grade II or III) and have increased mortality and morbidity. Identifying tumors with greater malignant potential can have significant clinical value. This validated genome-wide methylation study comparing Grade I with Grade II and III meningiomas aims to discover genes that are aberrantly methylated in atypical meningiomas. METHODS: Patients with newly diagnosed meningioma were identified as part of the Ohio Brain Tumor Study. The Infinium HumanMethylation27 BeadChip (Illumina, Inc.) was used to interrogate 27,578 CpG sites in 14,000 genes per sample for a discovery set of 33 samples (3 atypical). To verify the results, the Infinium HumanMethylation450 BeadChip (Illumina, Inc.) was used to interrogate 450,000 cytosines at CpG loci throughout the genome for a verification set containing 7 replicates (3 atypical), as well as 12 independent samples (6 atypical). A nonparametric Wilcoxon exact test was used to test for difference in methylation between benign and atypical meningiomas in both sets. Heat maps were generated for each set. Methylation results were validated for the 2 probes with the largest difference in methylation intensity by performing Western blot analysis on a set of 20 (10 atypical) samples, including 11 replicates. RESULTS: The discovery array identified 95 probes with differential methylation between benign and atypical meningiomas, creating 2 distinguishable groups corresponding to tumor grade when visually examined on a heat map. The validation array evaluated 87 different probes and showed that 9 probes were differentially methylated. On heat map examination the results of this array also suggested the existence of 2 major groups that corresponded to histological grade. IGF2BP1 and PDCD1, 2 proteins that can increase the malignant potential of tumors, were the 2 probes with the largest difference in intensity, and for both of these the atypical meningiomas had a decreased median production of protein, though this was not statistically significant (p = 0.970 for IGF2BP1 and p = 1 for PDCD1). CONCLUSIONS: A genome-wide methylation analysis of benign and atypical meningiomas identified 9 genes that were reliably differentially methylated, with the strongest difference in IGF2BP1 and PDCD1. The mechanism why increased methylation of these sites is associated with an aggressive phenotype is not evident. Future research may investigate this mechanism, as well as the utility of IGF2BP1 as a marker for pathogenicity in otherwise benign-appearing meningiomas.

A variable age of onset segregation model for linkage analysis, with correction for ascertainment, applied to glioma.

BACKGROUND: We propose a 2-step model-based approach, with correction for ascertainment, to linkage analysis of a binary trait with variable age of onset and apply it to a set of multiplex pedigrees segregating for adult glioma. METHODS: First, we fit segregation models by formulating the likelihood for a person to have a bivariate phenotype, affection status and age of onset, along with other covariates, and from these we estimate population trait allele frequencies and penetrance parameters as a function of age (N = 281 multiplex glioma pedigrees). Second, the best fitting models are used as trait models in multipoint linkage analysis (N = 74 informative multiplex glioma pedigrees). To correct for ascertainment, a prevalence constraint is used in the likelihood of the segregation models for all 281 pedigrees. Then the trait allele frequencies are reestimated for the pedigree founders of the subset of 74 pedigrees chosen for linkage analysis. RESULTS: Using the best-fitting segregation models in model-based multipoint linkage analysis, we identified 2 separate peaks on chromosome 17; the first agreed with a region identified by Shete and colleagues who used model-free affected-only linkage analysis, but with a narrowed peak: and the second agreed with a second region they found but had a larger maximum log of the odds (LOD). CONCLUSIONS: Our approach was able to narrow the linkage peak previously published for glioma. IMPACT: We provide a practical solution to model-based linkage analysis for disease affection status with variable age of onset for the kinds of pedigree data often collected for linkage analysis.

A nomogram for individualized estimation of survival among patients with brain metastasis.

PURPOSE: An estimated 24%-45% of patients with cancer develop brain metastases. Individualized estimation of survival for patients with brain metastasis could be useful for counseling patients on clinical outcomes and prognosis. METHODS: De-identified data for 2367 patients with brain metastasis from 7 Radiation Therapy Oncology Group randomized trials were used to develop and internally validate a prognostic nomogram for estimation of survival among patients with brain metastasis. The prognostic accuracy for survival from 3 statistical approaches (Cox proportional hazards regression, recursive partitioning analysis [RPA], and random survival forests) was calculated using the concordance index. A nomogram for 12-month, 6-month, and median survival was generated using the most parsimonious model. RESULTS: The majority of patients had lung cancer, controlled primary disease, no surgery, Karnofsky performance score (KPS) ≥ 70, and multiple brain metastases and were in RPA class II or had a Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) score of 1.25-2.5. The overall median survival was 136 days (95% confidence interval, 126-144 days). We built the nomogram using the model that included primary site and histology, status of primary disease, metastatic spread, age, KPS, and number of brain lesions. The potential use of individualized survival estimation is demonstrated by showing the heterogeneous distribution of the individual 12-month survival in each RPA class or DS-GPA score group. CONCLUSION: Our nomogram provides individualized estimates of survival, compared with current RPA and DS-GPA group estimates. This tool could be useful for counseling patients with respect to clinical outcomes and prognosis.

Variation in age at cancer diagnosis in familial versus nonfamilial Barrett's esophagus.

BACKGROUND: Genetic influences may be discerned in families that have multiple affected members and may manifest as an earlier age of cancer diagnosis. In this study, we determine whether cancers develop at an earlier age in multiplex Familial Barrett's Esophagus (FBE) kindreds, defined by 3 or more members affected by Barrett's esophagus (BE) or esophageal adenocarcinoma (EAC). METHODS: Information on BE/EAC risk factors and family history was collected from probands at eight tertiary care academic hospitals. Age of cancer diagnosis and other risk factors were compared between nonfamilial (no affected relatives), duplex (two affected relatives), and multiplex (three or more affected relatives) FBE kindreds. RESULTS: The study included 830 nonfamilial, 274 duplex, and 41 multiplex FBE kindreds with 274, 133, and 43 EAC and 566, 288, and 103 BE cases, respectively. Multivariable mixed models adjusting for familial correlations showed that multiplex kindreds were associated with a younger age of cancer diagnosis (P = 0.0186). Median age of cancer diagnosis was significantly younger in multiplex compared with duplex and nonfamilial kindreds (57 vs. 62 vs. 63 years, respectively, P = 0.0448). Mean body mass index was significantly lower in multiplex kindreds (P = 0.0033), as was smoking (P < 0.0001), and reported regurgitation (P = 0.0014). CONCLUSIONS: Members of multiplex FBE kindreds develop EAC at an earlier age compared with nonfamilial EAC cases. Multiplex kindreds do not have a higher proportion of common risk factors for EAC, suggesting that this aggregation might be related to a genetic factor. IMPACT: These findings indicate that efforts to identify susceptibility genes for BE and EAC will need to focus on multiplex kindreds.

Estrés y conductas antidisciplinarias en estudiantes de una facultad de medicina de Bogotá / Stress and Misconduct in Students of a Medical School in Bogotá

Introducción: los estudiantes de medicina se someten durante su formación académica a muchos factores estresantes. A su vez, incurren en transgresiones disciplinarias con frecuencia. El tiempo transcurrido en la carrera, así como el estrés han sido propuestos como posibles factores asociados a mala conducta. Objetivo: explorar, a través de un modelo de regresión logística, la posible asociación entre estrés y variables como sexo, semestre y edad, y actitudes antidisciplinarias en estudiantes de medicina de una universidad privada de Bogotá. Materiales y métodos: estudio descriptivo de corte transversal. Se encuestaron 433 estudiantes que cursaban entre tercer y sexto año de medicina. Resultados: la frecuencia de estudiantes que está de acuerdo (61,4%) y que incurre (44,9%) con frecuencia en comportamientos antidisciplinarios es alta. El estrés (OR: 1,04; IC 95%: 1,01-1,06) y el sexo masculino (OR: 1,90; IC 95%: 1,27-2,84) predicen débilmente la posibilidad de incurrir en transgresiones, lo que indica una asociación (bondad de ajuste: p>0,9 para falta de ajuste) con significado incierto (R²=0,03). En el subgrupo de estudiantes de tercer a quinto año, el semestre que se está cursando (OR: 1,27; IC 95%: 1,11-1,45), al igual que el estrés (OR: 1,04 IC 95%: 1,01-1,07) y el sexo masculino (OR: 2,06; IC 95%: 1,32-3,21) predicen de manera igualmente débil (bondad de ajuste: p>0,38 para falta de ajuste, R²=0,053) la frecuencia de transgresiones. Conclusiones: además del estrés y el sexo, otros factores, como la subcultura estudiantil en un país del tercer mundo y la personalidad del estudiante podrían explicar la alta tendencia a no atenerse a las normas en los estudiantes de medicina encuestados.

Introduction: Medical students are subject to many stressing events during their training. Previous studies have shown that they frequently engage in misconduct. The time spent in training as well as stress have been proposed as possible risk factors that favor misconduct. Objectives: This study seeks to establish through a logistic regression model a possible association between factors such as stress, sex, time spent in training and age, and misconduct among a group of medical students in a private university in Bogotá. Materials and Methods: This was a survey-based study. The survey was completed by 433 third to sixth year medical students. Results: The frequency of students that agree with (61.4%) and admit to have engaged frequently in misconduct (44.9%) is high. Stress (OR: 1.04; 95% CI: 1.01-1.06) and male sex (OR: 1.90; 95% CI: 1.27-2.84) are weak predictors of the chance of engaging in misconduct, indicating an association (goodness-of-fit: p>0.9 for lack of fit) but with uncertain importance (R²=0.03). In a subgroup of students between third and fifth year, time spent in training (OR: 1.27; 95% CI: 1.11-1.45), stress (OR: 1.04 95% CI: 1.01-1.07) and being male (OR: 2.06; 95% CI: 1.32-3.21) also weakly predict (goodness-of-fit: p>0.38 for lack of fit, R²=0,053) the frequency of misconduct. Conclusions: Besides stress and sex, other factors, such as a particular subculture among third world students, and students’ own personality, may explain the high tendency to transgress rules among surveyed medical students.