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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 BRCA 2. 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 CHEK 2 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.

Nucleotide Excision Repair (NER) is a critical pathway involved in breast cancer (BC). We have previously published that a low DNA repair capacity (DRC) is associated with a higher risk of BC in Puerto Rican women. Let-7b belongs to a miRNA family with tumor suppressor activity that targets oncogenes. We isolated miRNAs from plasma of 153 Puerto Rican women with and without BC. DRC was measured in lymphocytes by means of a host cell reactivation assay. These women were divided into four groups according to their DRC level: High (>3.8%) and low (<3.8%). The four groups consisted of BC patients with high (n = 35) and low (n = 43) DRC and controls with high (n = 39) and low (n = 36) DRC. Epidemiologic data were collected at initial BC diagnosis and almost five years after diagnosis. A significant difference in Let-7b expression was found in BC patients with high DRC versus the remaining groups (p < 0.001). Thus, our data reveal a possible role of Let-7b on DRC during breast carcinogenesis. Our study is innovative because it provides the first evidence that Let-7b may play role in DRC regulation (through the NER repair pathway) in BC.

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.

Among women, the most prevalent type of cancer is breast cancer, affecting 1 out of every 8 women in the United States; in Puerto Rico, 70 out of every 100,000 will develop some type of breast cancer. Therefore, a better understanding of the potential risk factors for breast cancer could lead to the development of early detection tools. A gene that has been proposed as a risk factor in several populations around the world is Apolipoprotein E (apoE). ApoE functions as a mechanism of transport for lipoproteins and cholesterol throughout the body, with 3 main isoforms present in humans (apoE2, apoE3, and apoE4). Whether or not apoE4 is a risk factor for breast cancer remains controversial. Previous studies have either included test subjects of all ages (20–80) or have focused on late-onset (after age 50) breast cancer; none has concentrated specifically on early-onset (aged 50 and younger) breast cancer. The objectives of this study was to examine (in a Puerto Rican population) the differences in the relative frequency of occurrence of apoE4 in non-breast cancer versus breast cancer patients and to examine, as well, the potential differences of same in early- versus late-onset patients. We found an increased frequency of apoE4 (odds ratio 2.15) only in early-onset breast cancer survivors, which is similar to the findings of those studies that combined or adjusted for age as well as for an association between apoE4 and decreased tumor size. ApoE is also a potential risk factor for long-term cognitive effects after chemotherapy and affects response to hormone replacement. Our data supports the theory that knowing the apoE genotype of women who are at risk of developing breast cancer may be beneficial, as such knowledge would aid in the prediction of tumor size and the development of treatment regimens.

Apoptosis involves a highly organized and programmed series of events aimed at maintaining genomic stability by eliminating defective host cells. The purpose of this study was to determine the threshold doses and environmental UV-A and UV-B exposure times necessary to produce apoptosis and necrosis in the normal cells of a human fibroblast cell line. Environmental UV-A and UV-B doses were measured over a 6 year period with a four-channel UV radiometer. The fibroblasts were irradiated once using an Oriel UV Solar Simulator with six doses of environmentally-based UV. Doses corresponded to 0, 11, 19, 23 and 45 min of average environmental UV-A and UV-B radiation at solar noon in Puerto Rico. The Annexin-V binding method was used to differentiate between normal fibroblasts and apoptotic or necrotic fibroblasts. The threshold dose from apoptosis to necrosis was found between 24–28 kJ/m2, which corresponded to 19 and 23 min of environmental UV-A and UV-B exposure. This study provides the first data that specify the environmental threshold doses of UV-A and UV-B at which human fibroblasts undergo apoptosis and necrosis. These results may provide valuable dose–response thresholds for apoptosis and necrosis for future mechanistic studies and baseline data for skin cancer prevention programs.

Elevated temperature (28-34⚬C) has been hypothesized as the primary cause of the loss of algal endosymbionts in coral reef-associated invertebrates, a phenomenon observed on a world-wide scale over the last decade. In past studies of this \"bleaching\" phenomenon, there has been an underlying assumption that temperature adversely affects the animal hosts, the algae thereby being relegated to a more passive role. Because photosynthesis is a sensitive indicator of thermal stress in plants and has a central role in the nutrition of symbiotic invertebrates, we have tested the hypothesis that elevated temperature adversely affects photosynthesis in the symbiotic dinoflagellate Symbiodinium microadriaticum. The results, based on analyses of light-mediated O2evolution and in vivo fluorescence, indicate that photosynthesis is impaired at temperatures above 30⚬C and ceases completely at 34-36⚬C. These observations are discussed in the context of possible mechanisms that may function in the disassociation of algal-invertebrate symbioses in response to elevated temperature.

Puerto Rican residents are exposed to some of the highest levels of environmental ultraviolet radiation in the world; paradoxically, the melanoma incidence in Puerto Rico is lower than that of the US mainland. The overall objective of this case-control pilot study was to test the hypotheses that (1) persons with melanoma have a significantly lower DNA repair capacity (DRC) in relation to controls matched by age, (2) decline in DRC is associated with vertical depth of melanoma invasion, and (3) DRC is associated with anatomical tumor location. Controls (n  =  124) were examined by dermatologists; cases (n  =  62) were histopathologically confirmed. The mean DRC ± 1 SE of controls was 6.46% ± 0.3. Melanoma patients (n  =  62) had a mean decrease in DRC of 3% (6.25% ± 0.5), which was not statistically different from controls (P  =  0.697). No significant differences in DRC were evident in participants with either in situ or malignant melanoma tumors; neither were such differences evident when evaluating anatomical location of tumors (ie, non-sun-exposed versus sun-exposed). DRC generally declined in participants with increased depth of melanoma tumor penetration when compared with controls and those with small in situ tumors. These findings should be examined in a larger-scale population study that includes participants with more advanced metastatic melanoma.

The population of Argentina is the result of the intermixing between several groups, including Indigenous American, European and African populations. Despite the commonly held idea that the population of Argentina is of mostly European origin, multiple studies have shown that this process of admixture had an impact in the entire Argentine population. In the present study we characterized the distribution of Indigenous American, European and African ancestry among individuals from different regions of Argentina and evaluated the level of discrepancy between self-reported grandparental origin and genetic ancestry estimates. A set of 99 autosomal ancestry informative markers (AIMs) was genotyped in a sample of 441 Argentine individuals to estimate genetic ancestry. We used non-parametric tests to evaluate statistical significance. The average ancestry for the Argentine sample overall was 65% European (95%CI: 63-68%), 31% Indigenous American (28-33%) and 4% African (3-4%). We observed statistically significant differences in European ancestry across Argentine regions [Buenos Aires province (BA) 76%, 95%CI: 73-79%; Northeast (NEA) 54%, 95%CI: 49-58%; Northwest (NWA) 33%, 95%CI: 21-41%; South 54%, 95%CI: 49-59%; p<0.0001] as well as between the capital and immediate suburbs of Buenos Aires city compared to more distant suburbs [80% (95%CI: 75-86%) versus 68% (95%CI: 58-77%), p = 0.01]. European ancestry among individuals that declared all grandparents born in Europe was 91% (95%CI: 88-94%) compared to 54% (95%CI: 51-57%) among those with no European grandparents (p<0.001). Our results demonstrate the range of variation in genetic ancestry among Argentine individuals from different regions in the country, highlighting the importance of taking this variation into account in genetic association and admixture mapping studies in this population.