Germline variants in cancer genes in high-risk non-BRCA patients from Puerto Rico.

Inherited pathogenic variants in genes that confer moderate to high risk of breast cancer may explain up to 50% of familial breast cancer. This study aimed at identifying inherited pathogenic variants in breast cancer cases from Puerto Rico that were not linked to BRCA1 or BRCA2. Forty-eight breast cancer patients that met the clinical criteria for BRCA testing but had received a negative BRCA1/2 result were recruited. Fifty-three genes previously implicated in hereditary cancer predisposition were captured using the BROCA Agilent cancer risk panel followed by massively parallel sequencing. Missense variants of uncertain clinical significance in CHEK2 were evaluated using an in vitro kinase assays to determine their impact on function. Pathogenic variants were identified in CHEK2, MUTYH, and RAD51B in four breast cancer patients, which represented 8.3% of the cohort. We identified three rare missense variants of uncertain significance in CHEK2 and two variants (p.Pro484Leu and p.Glu239Lys) showed markedly decreased kinase activity in vitro comparable to a known pathogenic variant. Interestingly, the local ancestry at the RAD51B locus in the carrier of p.Arg47* was predicted to be of African origin. In this cohort, 12.5% of the BRCA-negative breast cancer patients were found to carry a known pathogenic variant or a variant affecting protein activity. This study reveals an unmet clinical need of genetic testing that could benefit a significant proportion of at-risk Latinas. It also highlights the complexity of Hispanic populations as pathogenic factors may originate from any of the ancestral populations that make up their genetic backgrounds.

A Recurrent BRCA2 Mutation Explains the Majority of Hereditary Breast and Ovarian Cancer Syndrome Cases in Puerto Rico.

Breast cancer is the most common cause of cancer diagnosis in women and is responsible for considerable mortality among the women of Puerto Rico. However, there are few studies in Puerto Rico on the genetic factors influencing risk. To determine the contribution of pathogenic mutations in BRCA1 and BRCA2, we sequenced these genes in 302 cases from two separate medical centers, who were not selected for age of onset or family history. We identified nine cases that are carriers of pathogenic germline mutation. This represents 2.9% of unselected cases and 5.6% of women meeting National Comprehensive Cancer Network (NCCN) criteria for BRCA testing. All of the identified pathogenic mutations were in the BRCA2 gene and the most common mutation is the p.Glu1308Ter (E1308X) mutation in BRCA2 found in eight out of nine cases, representing 89% of the pathogenic carriers. The E1308X mutation has been identified in breast and ovarian cancer families in Spain, and analysis of flanking DNA polymorphisms shows that all E1308X carriers occur on the same haplotype. This is consistent with BRCA2 E1308X being a founder mutation for the Puerto Rican population. These results will contribute to better inform genetic screening and counseling of breast and ovarian cancer cases in Puerto Rico and Puerto Rican populations in mainland United States.

No Evidence for the Pathogenicity of the BRCA2 c.6937 + 594T>G Deep Intronic Variant: A Case-Control Analysis.

BACKGROUND: The role of deep intronic variants in hereditary cancer susceptibility has been largely understudied. Previously, the BRCA2 c.6937 + 594T>G variant has been shown to preferentially promote the inclusion of a 95 nucleotide cryptic exon and to introduce a premature termination codon. Our objective was to further assess the pathogenicity of the BRCA2 c.6937 + 594T>G deep intronic variant. PATIENTS AND METHODS: We examined the association between BRCA2 c.6937 + 594T>G and breast cancer (BC) risk in 464 BC cases and 497 noncancer controls from Puerto Rico. RESULTS: The overall frequency of the G allele was 2.1% in this population. There was no association between the TG/GG genotypes and BC risk in the uncorrected model and after correcting for confounders. There was only one carrier of the GG genotype. This individual did not have personal or family history of cancer and did not meet the National Comprehensive Cancer Network criteria for hereditary cancer genetic testing. CONCLUSIONS: Although previous work has demonstrated that the BRCA2 c.6937 + 594T>G variant affects splicing, this association study does not support a pathogenic role for the BRCA2 c.6937 + 594T>G intronic variant in breast and ovarian cancer syndrome susceptibility. Furthermore, it emphasizes the need to take into account multiple diverse populations in association studies for the assessment of variant pathogenicity.

Hereditary cancer syndromes in Latino populations: genetic characterization and surveillance guidelines.

Hereditary cancer predisposition syndromes comprise approximately 10% of diagnosed cancers; however, familial forms are believed to account for up to 30% of some cancers. In Hispanics, the most commonly diagnosed hereditary cancers include colorectal cancer syndromes such as, Lynch Syndrome, Familial Adenomatous Polyposis, and hereditary breast and ovarian cancer syndromes. Although the incidence of hereditary cancers is low, patients diagnosed with hereditary cancer syndromes are at high-risk for developing secondary cancers. Furthermore, the productivity loss that occurs after cancer diagnosis in these high-risk patients has a negative socio-economic impact. This review summarizes the genetic basis, phenotype characteristics, and the National Comprehensive Cancer Network's screening, testing, and surveillance guidelines for the leading hereditary cancer syndromes. The aim of this review is to promote a better understanding of cancer genetics and genetic testing in Hispanic patients.

Clinical Cancer Genetics Disparities among Latinos.

The three major hereditary cancer syndromes in Latinos (Hereditary Breast and Ovarian Cancer, Familial Adenomatous Polyposis and Lynch Syndrome) have been shown to exhibit geographic disparities by country of origin suggesting admixture-based disparities. A solid infrastructure of clinical genetics geared towards diagnosis and prevention could aid in reducing the mortality of these cancer syndromes in Latinos. Currently, clinical cancer genetic services in Latin America are scarce. Moreover, limited studies have investigated the mutational spectrum of these cancer syndromes in Latinos resulting in gaps in personalized medicine affecting diagnosis, treatment and prevention. The following commentary discusses available genotype and clinical information on hereditary cancer in Latinos and highlights the limited access for cancer genetic services in Latin America including barriers to genetic testing and alternatives for providing better access to genetic services. In this review, we discuss the status of clinical genetic cancer services for both US Latinos and those Latinos living in Latin America.

Estrogen Receptor Expression Is Associated with DNA Repair Capacity in Breast Cancer.

Estrogen-receptor-positive (ER+) tumors employ complex signaling that engages in crosstalk with multiple pathways through genomic and non-genomic regulation. A greater understanding of these pathways is important for developing improved biomarkers that can better determine treatment choices, risk of recurrence and cancer progression. Deficiencies in DNA repair capacity (DRC) is a hallmark of breast cancer (BC); therefore, in this work we tested whether ER signaling influences DRC. We analyzed the association between ER positivity (% receptor activation) and DRC in 270 BC patients, then further stratified our analysis by HER2 receptor status. Our results show that among HER2 negative, the likelihood of having low DRC values among ER- women is 1.92 (95% CI: 1.03, 3.57) times the likelihood of having low DRC values among ER+ women, even adjusting for different potential confounders (p<0.05); however, a contrary pattern was observed among HER2 positives women. In conclusion, there is an association between DRC levels and ER status, and this association is modified by HER2 receptor status. Adding a DNA repair capacity test to hormone receptor testing may provide new information on defective DNA repair phenotypes, which could better stratify BC patients who have ER+ tumors. ER+/HER2- tumors are heterogeneous, incompletely defined, and clinically challenging to treat; the addition of a DRC test could better characterize and classify these patients as well as help clinicians select optimal therapies, which could improve outcomes and reduce recurrences.

Differential promoter methylation of kinesin family member 1a in plasma is associated with breast cancer and DNA repair capacity.

Methylation alterations of CpG islands, CpG island shores and first exons are key events in the formation and progression of human cancer, and an increasing number of differentially methylated regions and genes have been identified in breast cancer. Recent studies of the breast cancer methylome using deep sequencing and microarray platforms are providing a novel insight on the different roles aberrant methylation plays in molecular subtypes of breast cancer. Accumulating evidence from a subset of studies suggests that promoter methylation of tumor-suppressor genes associated with breast cancer can be quantified in circulating DNA. However, there is a paucity of studies that examine the combined presence of genetic and epigenetic alterations associated with breast cancer using blood-based assays. Dysregulation of DNA repair capacity (DRC) is a genetic risk factor for breast cancer that has been measured in lymphocytes. We isolated plasma DNA from 340 participants in a breast cancer case control project to study promoter methylation levels of five genes previously shown to be associated with breast cancer in frozen tissue and in cell line DNA: MAL, KIF1A, FKBP4, VGF and OGDHL. Methylation of at least one gene was found in 49% of the cases compared to 20% of the controls. Three of the four genes had receiver characteristic operator curve values of ≥ 0.50: MAL (0.64), KIF1A (0.51) and OGDHL (0.53). KIF1A promoter methylation was associated with breast cancer and inversely associated with DRC. This is the first evidence of a significant association between genetic and epigenetic alterations in breast cancer using blood-based tests. The potential diagnostic utility of these biomarkers and their relevance for breast cancer risk prediction should be examined in larger cohorts.

The association of DNA Repair with breast cancer risk in women. A comparative observational study.

BACKGROUND: Previous studies have found a link between a low DNA repair capacity (DRC) level and increased cancer risk. Our aim was to assess the statistical association of DRC level and breast cancer (BC) using a case-control epidemiological study in a Hispanic community. METHODS: We conducted a comparative observational study to assess the validity of DRC in detecting BC in 824 women throughout Puerto Rico. Over a 6-year period, we compared 285 women newly diagnosed with BC to 539 without BC. DRC levels were measured in lymphocytes by means of a host-cell reactivation assay. We assessed the sensitivity, specificity, and association using the receiver operating characteristic curve analysis. Multiple logistic regression-adjusted odds ratios were estimated with 95% confidence level to measure the strength of the association of DRC and BC after adjusting for all confounders simultaneously. RESULTS: Compared to women without cancer, women with BC showed an average decrease of 60% in their DRC levels (p < 0.001). Validity of the association of DRC as a measure of BC risk showed a sensitivity of 83.2% and specificity of 77.6% (p < 0.0001). CONCLUSIONS: Our results support the usefulness of DRC level as a measure of BC risk. Additional studies in other populations are needed to further verify its usefulness.

Triple negative breast cancer: a retrospective study of Hispanics residing in Puerto Rico.

OBJECTIVE: Triple-negative breast cancer (TNBC) demonstrates unique clinicopathological characteristics and survival outcomes. Several studies have documented important disparities in Hispanic women compared to other racial/ethnic groups; nevertheless, data on this entity in a population based Latin country are very limited. Our goal was to assess demographic and clinicopathological characteristics in essentially a pure population of Puerto Rican females with TNBC residing in Puerto Rico, as well as to determine their overall survival and progression-free survival in order to compare with published data. METHODS: By searching the electronic medical records data base, 54 patients were identified as TNBC. The median follow-up period was 25 months (range, 2-78). Univariate analysis of pretreatment risk factors was conducted. RESULTS: The median age at diagnosis was 55 years. Of 54 cases, 51 had stage I-III presentation. T1/T2 tumors were found in 88.9% and absence of nodal involvement in 68.5%. Prognostic factors for progression free survival (PFS) that were statistically significant were lymph node involvement (p = 0.02), tumor size > 2 cm (p = 0.037) and stage IV (p = 0.00002). The 5-year overall survival and PFS were 81% and 80%, respectively. CONCLUSION: RESULTS are very similar to published data on females from North America and Europe. Differences in clinical outcome and stage at diagnosis in Hispanic women with TNBC are more likely explained by socioeconomic status and adequate access to care, rather than biological/genetic differences. The association of triple-negative breast cancer with poor prognosis deserves re-evaluation given that patients with negative node involvement and no metastasis appear to be highly

Identification of the prevalent BRCA1 and BRCA2 mutations in the female population of Puerto Rico.

Mutations in the breast cancer 1, early onset (BRCA1) and breast cancer 2 (BRCA2) genes are responsible for the majority of hereditary breast cancers. Knowledge of the incidence and prevalence of BRCA mutations in a specific population or ethnic group is necessary to provide accurate genetic counseling for breast cancer patients and their families; however, these data have not been gathered in the population of Puerto Rico. We conducted a retrospective study of female breast cancer patients undergoing genetic testing for BRCA mutations in the highest-volume breast surgery practices in San Juan, Puerto Rico. Data collection includes three-generation family cancer history and results from complete BRCA sequencing. A total of six different deleterious mutations were observed, including one mutation in BRCA1 and five mutations in BRCA2. Three recurrent mutations (BRCA1 del exon1-2, BRCA2 4150G>T, and BRCA2 6027del4) account for over 70% of all the BRCA mutations observed in this study population. This study examines for the first time the characteristics of hereditary breast cancer in Puerto Rico and assesses the accuracy of existing genetic risk assessment tools in that population. This data is expected to contribute to providing accurate and efficient tools for the clinical management of hereditary breast cancer in Puerto Rico.

Granuloma piogénico recidivante de lesiones múltiples / Recurrent pyogenic granuloma with multiple lesions

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Función paratiroidea en el autotrasplante paratiroideo subcutáneo preesternal en el hiperparatiroidismo secundario / Parathyroid function in presternal subcutaneous parathyroid autotransplantation in secondary hyperparathyroidism

Introducción. Se ha estudiado la función del tejido paratiroideo trasplantado subcutáneamente. Pacientes y método. Se ha estudiado a 13 pacientes sobre una población en diálisis total de 187 (6,95 por ciento) pacientes. Se realizó paratiroidectomía total y autotrasplante subcutáneo preesternal. Resultados. Descendió el valor de hormona paratiroidea a las 24 h en todos los casos. Se observan concentraciones valorables de hormona paratiroidea a partir de la quinta semana postransplante en todos los casos. Conclusiones. El trasplante paratiroideo subcutáneo preesternal es una alternativa válida y funcional en el tratamiento del hiperparatiroidismo secundario (AU)

Evaluation of Breast Imaging Reporting and Data System Category 3 mammograms and the use of stereotactic vacuum-assisted breast biopsy in a nonacademic community practice.

BACKGROUND: Breast Imaging Reporting and Data System (BI-RADS) Category 3 represents 'probably benign' mammographic abnormalities requiring close follow-up, but biopsies sometimes are performed on Category 3 abnormalities. Controversy exists as to when these biopsies are justified. The goals of the current study were to evaluate the use of stereotactic vacuum-assisted breast biopsy (SVABB) for BI-RADS 3 lesions in a nonacademic community hospital-based practice, to evaluate the false- negative rate of Category 3 mammograms, and to determine whether any specific lesions misinterpreted as BI-RADS 3 abnormalities might commonly be associated with malignant disease. METHODS: From August 2000 to December 2002, the authors performed 947 SVABB procedures on 911 patients. They focused on 156 SVABBs of BI-RADS 3 abnormalities. RESULTS: Of 634 SVABB procedures requested by outside sources, 114 (18%) were performed for BI-RADS 3 abnormalities, compared with 42 (13%) of 313 SVABB procedures that were performed based on mammographic findings at the authors' practice (P = 0.075). After SVABB, 7 of 156 patients with BI-RADS 3 lesions were diagnosed with breast carcinoma and 1 was diagnosed with atypical ductal hyperplasia. Therefore, the false-negative rate of BI-RADS 3 mammograms was 4.5% (i.e., 7 of 156 patients). Patients with linear microcalcifications had the highest rate of cancer (4 of 14 [29%]) compared with patients without microcalcifications (1 of 64 [1.5%]) and patients with nonlinear microcalcifications (2 of 69 [2.9%]). CONCLUSIONS: The use of SVABB for BI-RADS 3 lesions reflected uncertainty regarding the potential for a diagnosis of malignant disease rather than the financial incentive of performing a biopsy. SVABB was not necessary for patients with BI-RADS 3 lesions without microcalcifications or for patients with nonlinear microcalcifications. Lesions with linear (casting or branching) microcalcifications should not be considered BI-RADS 3 abnormalities.

Nutrition in advanced digestive cancer.

PURPOSE OF REVIEW: The provision of nutrition to patients with advanced digestive cancer, especially those with obstruction, has been an issue discussed by physicians, administrators and patients themselves. There is no real consensus about this topic, perhaps because of the fact that this discussion involves medical, emotional, ethical, economical and legal considerations that are not easily encompassed by any single decision. On the other hand, the quality of life or survival of these patients must be thoroughly evaluated because one of the basic tenets of medicine has always been 'primum non nocere' ('above all, do not harm'). Quality of life itself is a complicated concept because it has no specific definition and varies with each individual and depends upon his/her actual living reality, past experiences, future hopes, dreams and even ambitions. RECENT FINDINGS: Recent studies have presented controversial results when evaluating the benefits of providing nutritional therapy to patients with advanced digestive cancer with obstruction. Therefore, decision-making should be addressed on an individual basis, but at the same time should be based on defined protocols within each institution. A key factor to be considered is communication among all those involved in the process; most important is the role of the patient and his/her family, who should be able to communicate their feelings, concerns and ethical principles. SUMMARY: Nutritional therapy in advanced digestive cancer is an instrument that should be evaluated as an extra tool that may offer improved quality of life to those with obstruction, despite the associated increased costs. However, in this delicate matter, our decisions should not be driven by increased pressure by medical system administrators to limit financial expenditure.

Hernias de Morgagni. presentación de una serie de casos tratados en la era prelaparoscópica / Morgagni's hernias. Presentation of a series of cases treated in the prelaparoscopic era

Material y método. Revisión de hernias de Morgagni intervenidas en tres hospitales entre los años 1980 y 2000.Resultados. Se recogieron 28 casos, y la proporción varones/mujeres era de 12/16. La edad media fue para los varones de 45 ñ 13,2 (rango: 7-83) y para las mujeres de 51 ñ 16,4 (rango: 18-85) años. Los hallazgos fueron casuales en 13 casos y sintomáticos en 15 ocasiones: cuadros digestivos inespecíficos (n = 8), respiratorios (n = 5) y cardíacos (n = 2). Siete casos fueron intervenidos por vía torácica. En 19 ocasiones el abordaje fue abdominal y en dos, mediante laparoscopia. Se han observado 6 recidivas (21,4 por ciento).Conclusiones. Las hernias de Morgagni son poco frecuentes. Existe riesgo elevado de recidiva tras el tratamiento tradicional. La mayoría se trataron de forma electiva y por abordaje abdominal. (AU)