High-resolution functional mapping of RAD51C by saturation genome editing.

Pathogenic variants in RAD51C confer an elevated risk of breast and ovarian cancer, while individuals homozygous for specific RAD51C alleles may develop Fanconi anemia. Using saturation genome editing (SGE), we functionally assess 9,188 unique variants, including >99.5% of all possible coding sequence single-nucleotide alterations. By computing changes in variant abundance and Gaussian mixture modeling (GMM), we functionally classify 3,094 variants to be disruptive and use clinical truth sets to reveal an accuracy/concordance of variant classification >99.9%. Cell fitness was the primary assay readout allowing us to observe a phenomenon where specific missense variants exhibit distinct depletion kinetics potentially suggesting that they represent hypomorphic alleles. We further explored our exhaustive functional map, revealing critical residues on the RAD51C structure and resolving variants found in cancer-segregating kindred. Furthermore, through interrogation of UK Biobank and a large multi-center ovarian cancer cohort, we find significant associations between SGE-depleted variants and cancer diagnoses.

Case report: Turcot syndrome type 2 in a developing country within the Caribbean.

Medulloblastoma is the most common malignant pediatric brain tumor and has been linked to known cancer predisposition syndromes. We report a case of medulloblastoma of a 12-year-old Indo-Trinidadian female with a strong family history of colorectal carcinoma. In collaboration with the SickKids-Caribbean Initiative (SCI), her tumor was confirmed to be a WHO grade 4 medulloblastoma - Wnt subtype. Genetic testing further confirmed the presence of a pathogenic APC gene variant [c.3183_3187del (p.Gln1062*)] which led to a diagnosis of Turcot syndrome type 2. The index patient received multimodal therapy which included surgery, radiation and chemotherapy and is currently post end-of-treatment and in remission. This case report aims to highlight the complexity of diseases and the need for expertise in identifying them in low-and-middle income countries, the need for access to specialized testing and the benefits of collaborating between low-and-middle income and high-income countries when managing complex oncology patients.

The history of families at-risk for hereditary breast and ovarian cancer: what are the impacts of genetic counseling and testing?

Introduction: Cancer Genetic Counseling (CGC) and genetic testing (GT) assume a paramount role for hereditary cancer predisposition syndrome families. We assessed the effects of CGC and GT on women affected by cancer who are at risk for hereditary breast and ovarian cancer predisposition syndrome (HBOC). Methods: This study encompasses four time points: before the CGC session, after the CGC session when blood is drawn for GT, after disclosure of GT results, and six months following disclosure of GT results. The impacts of CGC and GT were assessed using psychosocial questionnaires. Additionally, a pedigree, genogram, and ecomap were constructed through a semistructured interview. Results: A total of sixty women were included in the study. Most participants considered their perception of cancer risk to be equivalent to that of the general population, even among those with pathogenic variants. An increased perception of breast and ovarian cancer risks was associated with a heightened inclination toward religious engagement as a coping mechanism. Patients carrying variants of uncertain significance expressed greater concerns about developing another cancer compared to those who had BRCA1 and BRCA2 wild type or pathogenic variants. Qualitative analysis of the genograms and ecomaps demonstrated that the CGC/GT processes facilitate communication within families. The genogram analyses revealed the impact of CGC and GT processes on families at risk for hereditary cancer. Changes in some family relationships were observed, and an improvement in communication was noted following the GT process. Discussion: These findings can assist healthcare professionals considering a personalized approaches in clinical practice.

Germline mutations in pediatric cancer cohort with mixed-ancestry Mexicans.

BACKGROUND: Childhood cancer is one of the primary causes of disease-related death in 5- to 14-year-old children and currently no prevention strategies exist to reduce the incidence of this disease. Childhood cancer has a larger hereditary component compared with cancer in adults. Few genetic studies have been conducted on children with cancer. Additionally, Latin American populations are underrepresented in genomic studies compared with other populations. Therefore, the aim of this study is to analyze germline mutations in a group of mixed-ancestry Mexican pediatric patients with solid and hematological cancers. METHODS: We analyzed genetic variants from 40 Mexican childhood cancer patients and their relatives. DNA from saliva or blood samples was used for whole-exome sequencing. All variants were identified following GATK best practices. RESULTS: We found that six patients (15%) were carriers of germline mutations in CDKN2A, CHEK2, DICER1, FANCA, MSH6, MUTYH, NF1, and SBDS cancer predisposition genes, and additional new variants predicted to be deleterious by in silico algorithms. A population genetics analysis detected five components consistent with the demographic models assumed for modern mixed-ancestry Mexicans. CONCLUSIONS: This report identifies potential genetic risk factors and provides a better understanding of the underlying mechanisms of childhood cancer in this population.

Adolescent and Young Adult Understanding of Their Childhood Cancer Predisposition Diagnosis: A Qualitative Study.

We characterized germline genetic test result understanding in adolescents and young adults (AYAs) (n = 21) with cancer 1-3.9 years post-disclosure using semistructured qualitative interviews. Most AYAs articulated their cancer risk; however, 5 did not remember results and a subset demonstrated misperceptions regarding risk or confusion regarding their medical care. These findings highlight variability in AYA understanding warranting further inquiry.

Pediatric Tumors and Developmental Anomalies: A French Nationwide Cohort Study.

OBJECTIVE: To assess the associations between congenital abnormalities and pediatric malignancies and evaluate the potential underlying molecular basis by collecting information on pediatric patients with cancer and congenital abnormalities. STUDY DESIGN: Tumeur Et Développement is a national, prospective, and retrospective multicenter study recording data of children with cancer and congenital abnormalities. When feasible, blood and tumoral samples are collected for virtual biobanking. RESULTS: From June 2013 to December 2019, 679 associations between pediatric cancers and congenital abnormalities were recorded. The most represented cancers were central nervous system tumors (n = 139; 20%), leukemia and myelodysplastic syndromes (n = 123; 18.1%), and renal tumors (n = 101; 15%). Congenital abnormalities were not related to any known genetic disorder in 66.5% of cases. In this group, the most common anomaly was intellectual disability (22.3%), followed by musculoskeletal (14.2%) and genitourinary anomalies (12.4%). Intellectual disability was mostly associated with hematologic malignancies. Embryonic tumors (neuroblastoma, Wilms tumor, and rhabdomyosarcoma) were associated with consistent abnormalities, sometimes with a close anatomical neighborhood between the abnormality and the neoplasm. CONCLUSIONS: In the first Tumeur Et Développement analysis, 3 major themes have been identified: (1) germline mutations with or without known cancer predisposition, (2) postzygotic events responsible for genomic mosaicism, (3) coincidental associations. New pathways involved in cancer development need to be investigated to improve our understanding of childhood cancers.

Impact of pri-let-7a-1 rs10739971 for Gastric Cancer Predisposition in an Amazon Region.

Gastric cancer (GC) is the fifth most common type of cancer and the fourth leading cause of cancer death. In Brazil, GC has a high incidence and mortality rates, and it is highly variable by region. The Amazon region has significant rising rates among all Brazil regions. Only very few studies have evaluated the association between genetic variants and the risk of gastric cancer in the Brazilian Amazon population. Therefore, this study aimed to investigate associations between single nucleotide polymorphisms of miRNA processing genes and the risk for GC in this population. Potentially functional single nucleotide polymorphisms from miRNA processing genes were genotyped in 159 cases and 193 healthy controls by QuantStudio Real Time PCR. According to our findings, the genotype GG of the variant rs10739971 presents a lower risk to the development of GC in comparison to the remaining genotypes (p = 0.000016; OR = 0.055; 95% CI = 0.015-0.206). This is the first study to report the association of pri-let-7a-1 rs10739971 with GC in the Brazilian Amazon population, which is a highly mixed population with a unique genetic constitution that is different from other populations that are studied in the vast majority of scientific research.

Epidemiological, Clinical, and Genomic Profile in Head and Neck Cancer Patients and Their Families.

Inherited cancer predisposition genes are described as risk factors in head and neck cancer (HNC) families. To explore the clinical and epidemiological data and their association with a family history of cancer, we recruited 74 patients and 164 relatives affected by cancer. The germline copy number alterations were evaluated in 18 patients using array comparative genomic hybridization. Two or more first-degree relatives with HNC, tobacco-associated tumor sites (lung, esophagus, and pancreas), or other related tumors (breast, colon, kidney, bladder, cervix, stomach carcinomas, and melanoma) were reported in 74 families. Ten index patients had no exposure to any known risk factors. Family members presented tumors of 19 topographies (30 head and neck, 26 breast, 21 colon). In first-degree relatives, siblings were frequently affected by cancer (n = 58, 13 had HNC). Breast cancer (n = 21), HNC (n = 19), and uterine carcinoma (n = 15) were commonly found in first-degree relatives and HNC in second-degree relatives (n = 11). Nineteen germline genomic imbalances were detected in 13 patients; three presented gains of WRD genes. The number of HNC patients, the degree of kinship, and the tumor types detected in each relative support the role of heredity in these families. Germline alterations may potentially contribute to cancer development.

What can we learn from more than 1,000 Brazilian patients at risk of hereditary cancer?

Background: Identifying individuals at a higher risk of developing cancer is a major concern for healthcare providers. Cancer predisposition syndromes are the underlying cause of cancer aggregation and young-onset tumors in many families. Germline genetic testing is underused due to lack of access, but Brazilian germline data associated with cancer predisposition syndromes are needed. Methods: Medical records of patients referred for genetic counseling at the Oncogenetics Department at the Hospital Sírio-Libanês (Brasília, DF, Brazil) from July 2017 to January 2021 were reviewed. The clinical features and germline findings were described. Detection rates of germline pathogenic/likely pathogenic variant (P/LPV) carriers were compared between international and Brazilian guidelines for genetic testing. Results: A total of 1,091 individuals from 985 families were included in this study. Most patients (93.5%) had a family history of cancer, including 64% with a family member under 50 with cancer. Sixty-six percent of patients (720/1091) had a personal history of cancer. Young-onset cancers (<50 years old) represented 62% of the patients affected by cancer and 17% had multiple primary cancers. The cohort included patients with 30 different cancer types. Breast cancer was the most prevalent type of cancer (52.6%). Germline testing included multigene panel (89.3%) and family variant testing (8.9%). Approximately 27% (236/879) of the tested patients harbored germline P/LPVs in cancer susceptibility genes. BRCA2, BRCA1, and TP53 were the most frequently reported genes, corresponding to 18.6%, 14.4%, and 13.5% of the positive results, respectively. Genetic testing criteria from international guidelines were more effective in identifying carriers than the Brazilian National Agency of Supplementary Health (ANS) criteria (92% vs. 72%, p<0.001). Forty-six percent of the cancer-unaffected patients who harbored a germline P/LPV (45/98) would not be eligible for genetic testing according to ANS because they did not have a family variant previously identified in a cancer-affected relative. Conclusion: The high detection rate of P/LPVs in the present study is possibly related to the genetic testing approach with multigene panels and cohort's characteristics, represented mainly by individuals with a personal or family history of young-onset cancer. Testing asymptomatic individuals with suspicious family history may also have contributed to a higher detection rate. A significant number of carriers would not have been identified using ANS criteria for genetic testing.

Whole-Exome Sequencing Identifies Pathogenic Germline Variants in Patients with Lynch-Like Syndrome.

Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, characterized by germline pathogenic variants in mismatch repair (MMR)-related genes that lead to microsatellite instability. Patients who meet the clinical criteria for LS and MMR deficiency and without any identified germline pathogenic variants are frequently considered to have Lynch-like syndrome (LLS). These patients have a higher risk of CRC and extracolonic tumors, and little is known about their underlying genetic causes. We investigated the germline spectrum of LLS patients through whole-exome sequencing (WES). A total of 20 unrelated patients with MMR deficiency who met the clinical criteria for LS and had no germline variant were subjected to germline WES. Variant classification was performed according to the American College of Medical Genetics and Genomics (ACMG) criteria. Pathogenic/likely pathogenic variants were identified in 35% of patients in known cancer genes such as MUTYH and ATM. Besides this, rare and potentially pathogenic variants were identified in the DNA repair gene POLN and other cancer-related genes such as PPARG, CTC1, DCC and ALPK1. Our study demonstrates the germline mutational status of LLS patients, a population at high risk of colorectal cancer.

TP53 Pathogenic Variants in Early-Onset Breast Cancer Patients Fulfilling Hereditary Breast and Ovary Cancer and Li-Fraumeni-like Syndromes.

TP53 gene mutation is the most common genetic alteration in human malignant tumors and is mainly responsible for Li-Fraumeni syndrome. Among the several cancers related to this syndrome, breast cancer (BC) is the most common. The TP53 p.R337H germline pathogenic variant is highly prevalent in Brazil's South and Southeast regions, accounting for 0.3% of the general population. We investigated the prevalence of TP53 germline pathogenic variants in a cohort of 83 BC patients from the Midwest Brazilian region. All patients met the clinical criteria for hereditary breast and ovarian cancer syndrome (HBOC) and were negative for BRCA1 and BRCA2 mutations. Moreover, 40 index patients fulfilled HBOC and the Li-Fraumeni-like (LFL) syndromes criteria. The samples were tested using next generation sequencing for TP53. Three patients harbored TP53 missense pathogenic variants (p.Arg248Gln, p.Arg337His, and p.Arg337Cys), confirmed by Sanger sequencing. One (1.2%) patient showed a large TP53 deletion (exons 2-11), which was also confirmed. The p.R337H variant was detected in only one patient. In conclusion, four (4.8%) early-onset breast cancer patients fulfilling the HBOC and LFL syndromes presented TP53 pathogenic variants, confirming the relevance of genetic tests in this group of patients. In contrast to other Brazilian regions, TP53 p.R337H variant appeared with low prevalence.

Unraveling the Genetic Architecture of Hepatoblastoma Risk: Birth Defects and Increased Burden of Germline Damaging Variants in Gastrointestinal/Renal Cancer Predisposition and DNA Repair Genes.

The ultrarare hepatoblastoma (HB) is the most common pediatric liver cancer. HB risk is related to a few rare syndromes, and the molecular bases remain elusive for most cases. We investigated the burden of rare damaging germline variants in 30 Brazilian patients with HB and the presence of additional clinical signs. A high frequency of prematurity (20%) and birth defects (37%), especially craniofacial (17%, including craniosynostosis) and kidney (7%) anomalies, was observed. Putative pathogenic or likely pathogenic monoallelic germline variants mapped to 10 cancer predisposition genes (CPGs: APC, CHEK2, DROSHA, ERCC5, FAH, MSH2, MUTYH, RPS19, TGFBR2 and VHL) were detected in 33% of the patients, only 40% of them with a family history of cancer. These findings showed a predominance of CPGs with a known link to gastrointestinal/colorectal and renal cancer risk. A remarkable feature was an enrichment of rare damaging variants affecting different classes of DNA repair genes, particularly those known as Fanconi anemia genes. Moreover, several potentially deleterious variants mapped to genes impacting liver functions were disclosed. To our knowledge, this is the largest assessment of rare germline variants in HB patients to date, contributing to elucidate the genetic architecture of HB risk.

Germline Variants in Cancer Genes from Young Breast Cancer Mexican Patients.

Breast cancer (BC) is one of the most frequent cancer types in women worldwide. About 7% is diagnosed in young women (YBC) less than 40 years old. In Mexico, however, YBC reaches 15% suggesting a higher genetic susceptibility. There have been some reports of germline variants in YBC across the world. However, there is only one report from a Mexican population, which is not restricted by age and limited to a panel of 143 genes resulting in 15% of patients carrying putatively pathogenic variants. Nevertheless, expanding the analysis to whole exome involves using more complex tools to determine which genes and variants could be pathogenic. We used germline whole exome sequencing combined with the PeCanPie tool to analyze exome variants in 115 YBC patients. Our results showed that we were able to identify 49 high likely pathogenic variants involving 40 genes on 34% of patients. We noted many genes already reported in BC and YBC worldwide, such as BRCA1, BRCA2, ATM, CHEK2, PALB2, and POLQ, but also others not commonly reported in YBC in Latin America, such as CLTCL1, DDX3X, ERCC6, FANCE, and NFKBIE. We show further supporting and controversial evidence for some of these genes. We conclude that exome sequencing combined with robust annotation tools and further analysis, can identify more genes and more patients affected by germline mutations in cancer.

Reviewing the occurrence of large genomic rearrangements in patients with inherited cancer predisposing syndromes: importance of a comprehensive molecular diagnosis.

INTRODUCTION: Hereditary cancer predisposition syndromes are caused by germline pathogenic or likely pathogenic variants in cancer predisposition genes (CPG). The majority of pathogenic variants in CPGs are point mutations, but large gene rearrangements (LGRs) are present in several CPGs. LGRs can be much more difficult to characterize and perhaps they may have been neglected in molecular diagnoses. AREAS COVERED: We aimed to evaluate the frequencies of germline LGRs in studies conducted in different populations worldwide through a qualitative systematic review based on an online literature research in PubMed. Two reviewers independently extracted data from published studies between 2009 and 2020. In total, 126 studies from 37 countries and 5 continents were included in the analysis. The number of studies in different continents ranged from 3 to 48 and for several countries there was an absolute lack of information. Asia and Europe represented most of the studies, and LGR frequencies varied from 3.04 to 15.06% in different continents. MLPA was one of the methods of choice in most studies (93%). EXPERT OPINION: The LGR frequencies found in this review reinforce the need for comprehensive molecular testing regardless of the population of origin and should be considered by genetic counseling providers.

Characterizing Pediatric Familial Adenomatous Polyposis in Patients Undergoing Colectomy in the United States.

OBJECTIVE: To characterize a multi-institutional cohort of pediatric patients who underwent colectomy for familial adenomatous polyposis (FAP). STUDY DESIGN: In this retrospective cohort study, diagnosis and procedure codes were used to identify patients who underwent colectomy for FAP within the Pediatric Health Information System (PHIS). The inclusion criteria were validated at 3 children's hospitals and applied to PHIS to generate a cohort of patients with FAP between 2 and 21 years who had undergone colectomy between 2009 and 2019. Demographics, clinical and surgical characteristics, and endoscopic procedure trends as identified through PHIS are described. Descriptive and comparative statistics were used to analyze data. RESULTS: Within the PHIS, 428 pediatric patients with FAP who underwent colectomy were identified. Median age at colectomy was 14 years (range 2-21 years); 264 patients (62%) received an ileal pouch anal anastomosis and 13 (3%) underwent ileorectal anastomosis. Specific anastomotic surgical procedure codes were not reported for 151 patients (35%). Endoscopic assessment at the surgical institution occurred in 40% of the cohort before colectomy and in 22% of the cohort following colectomy. CONCLUSIONS: In this cohort, colectomy took place at an earlier age than suggested in published guidelines. Ileal pouch anal anastomosis is the predominant procedure for pediatric patients with FAP who underwent colectomy in US pediatric centers. Endoscopic assessment trends before and after surgery suggest that the surgical institution plays a limited role in the care of this population.

Molecular profiling of osteosarcoma in children and adolescents from different age groups using a next-generation sequencing panel.

Osteosarcoma (OS) is a malignant bone tumor, with a peak of incidence in the second decade of life and possibly associated with the presence of germline mutations. Besides, clinicians have pointed to a second, rarer group of patients that develops OS before 10 years old. Here we access, through next-generation sequencing (NGS) strategy, the genetic alterations present in OS and blood samples from patients diagnosed before and during the second decade of life. A custom NGS panel, designed for the main alterations described in childhood and adolescence neoplasms, named Oncomine Childhood Cancer Research Assay (OCCRA©), was used. Of all 84 OS samples investigated, 42 (50%) presented some somatic variant, with TP53, MYC, CDK4, RB1 and PDGFRA genes harboring the most observed genetic variants. MYC CNVs were more frequent in tumors from patients diagnosed before 10 years old (X21= 5.18, p = 0.023). Additionally, patients diagnosed during the second decade of life presented a higher percentage of somatic and germline variants. Germline variants in TP53 and RB1 were found in 5 of the 11 (45.5%) patients analyzed. Clinical variables and tumor histopathological characteristics were also collected and correlated with our molecular findings.

Germline variants in DNA repair genes are associated with young-onset head and neck cancer.

The genetic predisposition to head and neck carcinomas (HNSCC) and how the known risk factors (papillomavirus infection, alcohol, and tobacco consumption) contribute to the early-onset disease are barely explored. Although HNSCC at early onset is rare, its frequency is increasing in recent years. Germline and somatic variants were assessed to build a comprehensive genetic influence pattern in HNSCC predisposition and patient outcome. Whole-exome sequencing was performed in 45 oral and oropharynx carcinomas paired with normal samples of young adults (≤49 years). We found FANCG, CDKN2A, and TPP germline variants previously associated with HNSCC risk. At least one germline variant in DNA repair pathway genes was detected in 67% of cases. Germline and somatic variants (including copy number variations) in FAT1 gene were identified in 9 patients (20%) and 12 tumors (30%), respectively. Somatic variants were found in HNSCC associated genes, such as TP53, CDKN2A, and PIK3CA. To date, 55 of 521 cases from the large cohort of TCGA presented < 49 years old. A comparison between the somatic alterations of TCGA-HNSCC at early onset and our dataset revealed strong similarities. Protein-protein interaction analysis between somatic and germline altered genes revealed a central role of TP53. Altogether, germline alterations in DNA repair genes potentially contribute to an increased risk of developing HNSCC at early-onset, while FAT1 could impact the prognosis.

Whole-exome sequencing of non-BRCA1/BRCA2 mutation carrier cases at high-risk for hereditary breast/ovarian cancer.

The current study aimed to identify new breast and/or ovarian cancer predisposition genes. For that, whole-exome sequencing (WES) was performed in the germline DNA of 52 non-BRCA1/BRCA2/TP53 mutation carrier women at high-risk for hereditary breast and ovarian cancer (HBOC). All variants were classified using information from population and disease specific databases, in silico prediction tools and the American College of Medical Genetics and Genomics (ACMG) criteria. Loss of heterozygosity (LOH) of tumor samples and segregation analyses were performed whenever possible. The variants identified were investigated in a second, independent cohort of 17 BC cases. Pathogenic/Likely Pathogenic variants were identified in known cancer genes such as CHEK2, MUTYH, PMS2, and RAD51C. Rare and potentially pathogenic variants were identified in DNA repair genes (FAN1, POLQ, and RAD54L) and other cancer-related genes such as DROSHA and SLC34A2. Interestingly, the variant c.149T>G in the FAN1 gene was identified in two unrelated families, and exhibited LOH in the tumor tissue of one of them. In conclusion, this is the largest Brazilian WES study involving families at high-risk for HBOC which has brought novel insights into the role of potentially new genetic risk factors for hereditary breast and ovarian cancer.

Using Co-segregation and Loss of Heterozygosity Analysis to Define the Pathogenicity of Unclassified Variants in Hereditary Breast Cancer Patients.

The use of gene panels introduces a new dilemma in the genetics field due to the high frequency of variants of uncertain significance (VUS). The objective of this study was to provide evidence that may help in the classification of these germline variants in terms of their clinical impact and association with the disease in question. A total of 52 unrelated women at-risk for HBOC and negative for BRCA1/BRCA2 pathogenic variants were evaluated through a gene panel comprising 14 breast and/or ovarian cancer susceptibility genes. Of the 453 germline variants identified, 15 variants (classes 3, 4, and 5) in the ATM, BRIP1, CHEK2, MRE11A, MUTHY, PALB2, RAD50, and RAD51C genes were evaluated via databases, co-segregation studies and loss of heterozygosity in the tumor. The co-segregation analysis allowed the establishment of an association with the presence of variants and the risk of cancer for variant c.316C>T in the BRIP1 gene. Four variants of uncertain significance showed loss of heterozygosity in the tumor (ATM c.4709T>C; CHEK2 c.1036C>T; PALB2 c.1001A>G, and RAD50 c.281T>C), which is an indication of pathogenicity. Thus, the present study provides novel evidence that favors the association of variants in moderate-risk genes with the development of hereditary breast cancer.

Síndrome de Li Fraumeni: análisis clínico de un caso y revisión de la literatura / Li-Fraumeni syndrome: clinical case study and literature survey / Síndrome de Li Fraumeni: análise clínica de um caso e uma revisão da literatura

Resumen: El síndrome de Li-Fraumeni (SLF) es una enfermedad hereditaria autosómica dominante con elevada penetrancia, que se caracteriza por la aparición precoz de múltiples tumores en un individuo y una marcada agregación familiar. Aproximadamente el 70% de los pacientes que cumplen criterios clínicos para su diagnóstico son portadores de la mutación germinal del gen TP53 localizado en el cromosoma 17p13. El gen TP53 es un supresor tumoral que cumple una importante función en el control de la estabilidad genómica. Se estima que el riesgo de desarrollar cáncer es del 50 % para las mujeres a los 31 años de edad y para los hombres a los 46 años y cerca del 100 % para ambos sexos a los 70 años. El curso clínico de la enfermedad es similar que en pacientes sin SLF a excepción de la edad más temprana al diagnóstico. Presentamos el caso de una paciente de 31 años a la que se diagnostica un condrosarcoma pelviano tratado con cirugía y al momento de la recidiva, aproximadamente 8 meses después, un cáncer de mama localizado. En otro miembro de su familia se había identificado la mutación 375G>C en el gen TP53 mediante secuenciación Sanger, la cual fue detectada posteriormente en nuestra paciente. Se discuten aspectos particulares del manejo como la minimización de la exposición a la radioterapia (por reportes de tumores malignos en zonas irradiadas) y el especial manejo de la repercusión del diagnóstico a nivel de los otros integrantes de la familia.

Abstract: The Li-Fraumeni syndrome (SLF) is a highly penetrant condition with an autosomal dominant inheritance pattern, characterized by an early onset of multiple tumors in a subject and a marked familial occurrence. About 70 % of patients meeting clinical criteria for diagnosis of the disease carry the germline mutation of TP53 gene located in chromosome 17p13. TP53 is a tumor suppressor gene known for its major role in genome stability control. It has been estimated that risk of cancer development is 50 % for women at the age of 31 and for men at the age of 46 and nearly 100 % for both men and women at 70 years of age. Except at earlier ages of diagnosis, the clinical course of the disease for healthy patients and for patients suffering SLF shows similarities. We present the case of a 31-year-old patient diagnosed both with pelvic chondrosarcoma treated surgically and localized breast cancer during relapse, about 8 months later. By Sanger sequencing, mutation 375G>C had been identified in TP53 gene in another family member, and said mutation was later detected in our patient. We discuss particular aspects of treatment procedures, such as minimizing radiotherapy exposure (due to reports of malignancies in radiated areas) and the special management of diagnosis implications for other family members.

Resumo: A síndrome de Li-Fraumeni (SLF) é uma doença hereditária autorexistente dominante com pena de penetração, que caracteriza a aparição precoz de múltiplos tumores em um indivíduo e uma coletânea familiar. Aproximadamente o 70% dos pacientes com critérios clínicos para o diagnóstico em crianças portadores da mutação germinal do gen TP53 localizado no cromosoma 17p13. El gen TP53 é um tumor tumoral que cumple uma função importante no controle da estabilização genómica. Se estima que o riesgo do desengate faz dos 50% para as mulheres aos 31 anos de idade e para os 40 anos e cerca de 100% para ambos os sexos aos 70 anos. O curso clínico da doença é semelhante ao que ocorre com a SLF a exceção da doença mais tem sido diagnosticada. Presentamos o caso de um paciente de 31 años que diagnostica um paciente de pélvico com relato ao momento da recidiva, aproximadamente 8 meses depois, em um lugar de mama próximo. En otio miembro de la familia se habiocuident to the mutación 375G> C en el gen TP53 por secuenciación Sanger, a cual fue detectada em recente paciente. A discussão foi feita sobre os aspectos do tratamento com a minimização da exposição à radioterapia (por tumores malignos em zonas irradiadas) e o especial manejo da repercussão do diagnóstico a nível dos otros integrantes da familia