Oral and maxillofacial considerations in Gardner's syndrome: a report of two cases.

Gardner's syndrome (GS) is a genetic disorder characterised by intestinal polyps, multiple osteomas, and soft-tissue tumours. Dentists play an important role in the syndrome diagnosis considering that craniomaxillofacial osteomas are a major criteria for Gardner's syndrome diagnosis. This study aimed to describe the main stomatological manifestation of GS and the importance of dentists in its diagnosis. Two patients presenting GS were evaluated. The first one had two osteomas in the mandible and GS was suspected. The colonoscopy confirmed the presence of polyposis and a prophylactic proctocolectomy was performed. The other patient had a late-stage diagnosis of GS and developed a rectum adenocarcinoma. The presence of craniomaxillofacial osteomas are a hallmark of the disease. Early-stage GS diagnosis may enable early diagnosis and preventive strategies in carriers. Other dental abnormalities, such as supernumerary teeth, hypercementosis and odontomas, can also be observed.

(18)F-FDG PET-CT for Surveillance of Brazilian Patients with Li-Fraumeni Syndrome.

PURPOSE: To evaluate the effectiveness of (18)F-Fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG-PET/CT) for detecting early cancer in carriers of germline TP53 mutation, the genetic defect underlying Li-Fraumeni and related syndromes, which predisposes to many forms of cancer throughout life. PATIENTS AND METHODS: A total of 30 adult patients from six families with germline TP53 mutations were recruited. These patients did not have a diagnosis of cancer in the 24 months preceding the study. Anomalous concentrations from whole-body (18)F-FDG-PET/CT were assessed by two independent experts. Suspicious lesions were excised and subjected to pathological examination. RESULTS: A total of 6/30 patients showed abnormal (18)F-FDG-concentration. Confirmation studies revealed three cases of cancer, including one lung cancer, one ovarian cancer, and one disseminated breast cancer. Three patients had non-malignant lesions (one Bartholin's cyst and two cases of reactive lymph nodes). CONCLUSION: (18)F-FDG-PET/CT is effective in detecting cancer in subjects who are asymptomatic according to current screening guidelines. These results further suggest that (18)F-FDG-PET/CT is an appropriate method for surveillance of cancer risk in TP53 mutation carriers.

Genome-wide DNA methylation profile of leukocytes from melanoma patients with and without CDKN2A mutations.

Melanoma is a highly aggressive cancer, accounting for up to 75% of skin cancer deaths. A small proportion of melanoma cases can be ascribed to the presence of highly penetrant germline mutations, and approximately 40% of hereditary melanoma cases are caused by CDKN2A mutations. The current study sought to investigate whether the presence of germline CDKN2A mutations or the occurrence of cutaneous melanoma would result in constitutive genome-wide DNA methylation changes. The leukocyte methylomes of two groups of melanoma patients (those with germline CDKN2A mutations and those without CDKN2A mutations) were analyzed together with the profile of a control group of individuals. A pattern of DNA hypomethylation was detected in the CDKN2A-negative patients relative to both CDKN2A-mutated patients and controls. Additionally, we delineated a panel of 90 CpG sites that were differentially methylated in CDKN2A-mutated patients relative to controls. Although we identified a possible constitutive epigenetic signature in CDKN2A-mutated patients, the occurrence of reported SNPs at the detected CpG sites complicated the data interpretation. Thus, further studies are required to elucidate the impact of these findings on melanoma predisposition and their possible effect on the penetrance of CDKN2A mutations.

Germline CDKN2A mutations in Brazilian patients of hereditary cutaneous melanoma.

Approximately 10 % of all cutaneous melanoma cases occur in a familial context. The major susceptibility gene for familial melanoma is CDKN2A. In Latin America, genetic studies investigating melanoma predisposition are scarce. The aim of this work was to investigate germline CDKN2A point mutations and genomic rearrangements in a cohort of 59 Brazilian melanoma-prone patients. Screening of CDKN2A alterations was performed by sequencing and multiplex ligation probe amplification. Germline CDKN2A mutations affecting p16(INK4a) were detected in 8 unrelated probands (13.6 %), including 7 familial cases and one patient with multiple melanomas; 4 out of 8 mutation carriers met the criteria for familial melanoma and had multiple primary lesions. Although this study adds to the literature on melanoma susceptibility in Latin America, it is limited by the small size of the cohort. Our findings suggest that stringent inclusion criteria led to a substantially increased rate of CDKN2A mutation detection. This consideration should be taken into account when referring patients for genetic screening in a setting of limited budget, such as in developing countries.

Mutational spectrum of the APC and MUTYH genes and genotype-phenotype correlations in Brazilian FAP, AFAP, and MAP patients.

BACKGROUND: Patients with multiple colorectal adenomas are currently screened for germline mutations in two genes, APC and MUTYH. APC-mutated patients present classic or attenuated familial adenomatous polyposis (FAP/AFAP), while patients carrying biallelic MUTYH mutations exhibit MUTYH-associated polyposis (MAP). The spectrum of mutations as well as the genotype-phenotype correlations in polyposis syndromes present clinical impact and can be population specific, making important to obtain genetic and clinical data from different populations. METHODS: DNA sequencing of the complete coding region of the APC and MUTYH genes was performed in 23 unrelated Brazilian polyposis patients. In addition, mutation-negative patients were screened for large genomic rearrangements by multiplex ligation-dependent probe amplification, array-comparative genomic hybridization, and duplex quantitative PCR. Biallelic MUTYH mutations were confirmed by allele-specific PCR. Clinical data of the index cases and their affected relatives were used to assess genotype-phenotype correlations. RESULTS: Pathogenic mutations were identified in 20 of the 23 probands (87%): 14 in the APC gene and six in the MUTYH gene; six of them (30%) were described for the first time in this series. Genotype-phenotype correlations revealed divergent results compared with those described in other studies, particularly regarding the extent of polyposis and the occurrence of desmoid tumors in families with mutations before codon 1444 (6/8 families with desmoid). CONCLUSIONS: This first comprehensive investigation of the APC and MUTYH mutation spectrum in Brazilian polyposis patients showed a high detection rate and identified novel pathogenic mutations. Notably, a significant number of APC-positive families were not consistent with the predicted genotype-phenotype correlations from other populations.

Integration of genomics in cancer care.

PURPOSE: The article aims to introduce nurses to how genetics-genomics is currently integrated into cancer care from prevention to treatment and influencing oncology nursing practice. ORGANIZING CONSTRUCT: An overview of genetics-genomics is described as it relates to cancer etiology, hereditary cancer syndromes, epigenetics factors, and management of care considerations. METHODS: Peer-reviewed literature and expert professional guidelines were reviewed to address concepts of genetics-genomics in cancer care. FINDINGS: Cancer is now known to be heterogeneous at the molecular level, with genetic and genomic factors underlying the etiology of all cancers. Understanding how these factors contribute to the development and treatment of both sporadic and hereditary cancers is important in cancer risk assessment, prevention, diagnosis, treatment, and long-term management and surveillance. CONCLUSIONS: Rapidly developing advances in genetics-genomics are changing all aspects of cancer care, with implications for nursing practice. CLINICAL RELEVANCE: Nurses can educate cancer patients and their families about genetic-genomic advances and advocate for use of evidence-based genetic-genomic practice guidelines to reduce cancer risk and improve outcomes in cancer management.

Highly prevalent TP53 mutation predisposing to many cancers in the Brazilian population: a case for newborn screening?

The unusually high population frequency of a germline TP53 mutation (R337H) predisposing to early cancer has led to mass newborn testing for this mutation in the State of Paraná, southern Brazil. Newborn screening for inherited cancer risk is complex and controversial. In this paper, we discuss the justifications for this screening by considering the medical and scientific evidence for this mutation. R337H has been identified in Brazilian families with Li-Fraumeni or related syndromes predisposing to cancers in childhood (ie, brain, renal, and adrenocortical carcinomas), adolescence (ie, soft tissue and bone sarcomas), and young adulthood (ie, breast cancer). R337H has also been detected in children with adrenocortical carcinoma without a documented family history of cancer. The mutation is estimated to occur in about 0.3% of the population in southern Brazil and is associated with increased cancer risk throughout life. Cancer patterns in families positive for R337H suggest strong genetic modifying effects, making it difficult to predict individual risk. Because protocols for cancer-risk management in Li-Fraumeni or related syndromes are debatable, extreme care should prevail in predictive testing of children for R337H. A detailed assessment of the risks, benefits, and costs is needed to ensure that medical, social, and ethical justifications for newborn screening are met.

Detection of R337H, a germline TP53 mutation predisposing to multiple cancers, in asymptomatic women participating in a breast cancer screening program in Southern Brazil.

Germline TP53 mutations predispose to a rare familial cancer syndrome, the Li-Fraumeni Syndrome (LFS), characterized by the early onset of multiple cancers including childhood adrenocortical carcinomas, sarcomas and brain tumors, and breast and colon cancer in young adults. An identical germline mutation at codon 337 in TP53 (R337H) has been shown to be causally related to an increased risk of multiple cancers in unrelated subjects with familial cancer risk in Southern Brazil. Here we have assessed the prevalence of R337H in 750 healthy women participating in a community-based breast cancer screening program in the area of Porto Alegre. The mutant was detected in two participants (0.3%) who were fourth-degree relatives and reported a familial history of cancer at multiple sites that did not match classical criteria for LFS and its variants. Testing in additional family members detected the mutation in three subjects, one of whom developed breast cancer at the age of 36. These findings indicate that R337H may be a low penetrance mutant which predisposes to multiple cancers and occurs in the population of Southern Brazil at a frequency 10-20 times higher than other TP53 mutants commonly associated with LFS.

The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families.

A TP53 germline mutation, R337H, has been previously described in children from southern Brazil with adrenocortical tumours but no documented familial history of other cancers. Here, we have screened for TP53 mutation 45 Brazilian unrelated individuals with family histories fulfilling the clinical definitions of Li-Fraumeni (LFS) or Li-Fraumeni-like (LFL) syndromes. Mutations were found in 13 patients (28.9%), including six (46.1%) R337H mutations, and four novel germline mutations (V173M, V197M, G244D and IVS6+1G>T). Families with the R337H mutation presented a wide spectrum of tumours, including breast cancers (30.4%), brain cancers (10.7%), soft tissue sarcomas (10.7%) and adrenocortical carcinomas (8.9%). Testing of 53 Brazilian subjects with no cancer history showed that R337H was not a common polymorphism in that population. Moreover, loss of heterozygocity with retention of the R337H allele was observed in a breast adenocarcinoma, supporting a role for this mutation in breast tumorigenesis. These results show that the TP53 R337H germline mutation predisposes to a larger spectrum of tumours, similar to the one reported for other TP53 mutations.

Diagnóstico molecular da síndrome de Li-Fraumeni em famílias brasileiras / Molecular diagnosis of Li-Fraumeni syndrome in Brazillian families

A Síndrome de Li-Fraumeni (SLF) é uma síndrome rara de predisposição ao. câncer associada a mutações no gene TP53. É transmitida de forma autossômica dominante, predispondo indivíduos afetados ao risco aumentado de desenvolvimento de tumores em idade jovem. Os objetivos deste trabalho são caracterizar mutações germinativas n o gene TP53 em famílias brasileiras com diagnóstico clínico de SLF e. de sua variante Li-Fraumeni like (LFL), avaliar o papel das mutações na síndrome e estabelecer correlações genótipo-fenótipo. Foram incluídas 45 famílias brasileiras que preencheram os critérios clínicos da síndrome. A metodologia incluiu a. amplificação dos dez éxons codificantes do gene TP53 por PCR no DNA genômico e rastreamento de alterações por DHPLC, seguido de seqüenciamento das regiões. suspeitas. Foram encontradas 13 mutações germinativas (29.5%), sendo 12 mutações missense e uma em sítio de splicing. A troca Arg337His (R337H), descrita. anteriormente como relacionada exclusivamente a carcinomas adrenocorticais infantis, foi verificada em seis famílias com LFL. Foram detectadas três mutações novas, Val173Met, Val197Met e Gly244Asp, duas mutações já descritas, Arg213Gly e Gly245Ser, em famílias não relacionadas, e uma mutação em sítio doador de splicing do íntron 6. Verificou-se baixa prevalência de mutações em famílias SLF (11%). A mutação R337H ocorreu em freqüência elevada (46,1%) nas famílias SLF brasileiras, predispondo ao amplo espectro tumoral. Tumores adrenocorticais foram 2,3 vezes mais freqüentes em famílias com a mutação R337H se comparado a. famílias com outras mutações, sugerindo efeito tecido-específico. Esta é a primeira descrição da prevalência de mutações no gene TP53 nas SLF e LFL na América. Latina, representando 4,6% das mutações descritas na literatura

Li-Fraumeni syndrome (OMIM #151623) (LFS) is a rare cancer predisposition syndrome associated with germline mutations in the TP53 gene (OMIM #191170). It is transmitted in an autossomal dominant pattern, which predisposes affected individuals to an increased risk of developing a variety of cancers at an earlier age. The objectives of this study were to analyze TP53 mutations in Brazilian families who received clinical diagnosis of LFS and its variant, Li-Fraumeni-like syndrome (LFL). The molecular profile of the TP53 gene was analyzed in 45 Brazilian unrelated individuals with family histories fulfilling the clinical definitions of LFS or LFL. Analysis of TP53 exons 2 to 11 by PCR in genomic DNA, screening by DHPLC and sequencing of abnormal profiles revealed mutations in 13 patients (29.5%). Twelve missense mutations were detected and one splice site mutation. Arg337His (R337H) mutations, previously described as related only to adrenocortical tumors in children, were detected in 6 families. Three novel germline mutations (Val173Met, Val197Met and Gly244Asp) and two already described mutations (Arg213Gly e Gly 245Ser) were also detected in three families. Families fulfilling the classical definiton of LFS presented a low detection rate (11%). R337H mutations were frequent in Brazilian LFS families (46,1%), predisposing to a wide tumour spectrum. Adrenocortical tumors are 2,3 times more frequent among R337H carriers if compared to other mutations, suggesting a tumorspecific effect. This is the first description of TP53 gene prevalence and mutation pattern among SLF/LFL in Latin America, representing 4.6% of all mutations described in scientific literature

TP53 Gene and Li-Fraumeni Syndrome

Cancer is a disease that strikes most families and itsdevastating effects bring suffering and instability to bothpatient and family. Clustering of cancers in certainfamilies is even more devastating, leading medicine tostudy its origin and ways to prevent it. Many cancersyndromes have been identified due to the repeatedoccurrence of specific tumors over a certain age-range.The rare cancer predisposition Li-Fraumeni syndrome(OMIM #151623; LFS) is transmitted in an autosomaldominant pattern, which predisposes affectedindividuals to an increased risk of developing a varietyof cancers at an early age, including childhood. The mostcharacteristic forms of cancers in LFS include soft-tissuesarcoma, breast cancers, brain tumors, and adrenocorticalcarcinomas. LFS is a dominantly inherited syndrome,frequently associated with germline mutations in theTP53 gene (OMIM #191170), which encodes protein p53.This protein regulates cell cycle, apoptosis, DNA repair,differentiation, senescence and development. Activationof p53 prevents DNA replication and cell proliferationwhen cells are subjected to stress that may disturb geneticor genomic integrity. Thus, TP53 acts as a major tumorsuppressor gene by exerting simultaneous control onmany components of the molecular mechanisms ofcarcinogenesis. Loss of p53 function may favor cancerdevelopment and explains predisposition in germlineTP53 mutation carriers. This review will discuss the maincharacteristics of TP53, its regulation, the consequencesof its inactivation in cancer, the germline TP53 mutationrelated to Li-Fraumeni syndrome and strategies forsurveillance.