Age of onset in familial breast cancer as background data for medical surveillance.
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ABSTRACT:
SUBMITTER: Brandt A
PROVIDER: S-EPMC2813740 | biostudies-other | 2010 Jan
REPOSITORIES: biostudies-other
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Project description:BackgroundFamilial clustering of age at onset would have implications for both personalized screening and aetiology, but has not been studied for breast cancer.MethodsWe prospectively studied a cohort of 23 145 sisters to explore whether their breast cancer risk changed near the age at diagnosis of a previously affected older sister. Using an age-time-dependent variable in a Cox regression model, we estimated hazard ratios for breast cancer when participants were near their sister's diagnosis age, relative to similarly aged women whose sister was diagnosed at a very different age. To rule out a correlation driven by young-onset familial cancer, we separately investigated women who had enrolled at age 50 or older.ResultsOf the 23 145 women, 1412 developed breast cancer during follow-up (median 9.5 years). The estimated hazard ratio was 1.80 (95% confidence interval: 1.18, 2.74) at their sister's age at diagnosis, suggesting a substantial increase in risk compared with women of the same age but whose sister was diagnosed at a very different age. Restriction to women who enrolled at or after age 50 produced similar results.ConclusionsThis familial clustering suggests that there may be important genetic and/or early environmental risk factors that influence the timing of breast cancer, even when onset is late in life. Personalized screening might need to account for the age at which a sister was earlier diagnosed with breast cancer.
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Project description:Identifying genes that modify the age at onset (AAO) of Alzheimer disease and targeting them pharmacologically represent a potential treatment strategy. In this exploratory study, we sequenced the complete genomes of six individuals with familial Alzheimer disease due to the autosomal dominant mutation p.Glu280Ala in PSEN1 (MIM# 104311; NM_000021.3:c.839A>C). The disease and its AAO are highly heritable, motivating our search for genetic variants that modulate AAO. The median AAO of dementia in carriers of the mutant allele is 49 years. Extreme phenotypic outliers for AAO in this genetically isolated population with limited environmental variance are likely to harbor onset modifying genetic variants. A narrow distribution of AAO in this kindred suggests large effect sizes of genetic determinants of AAO in these outliers. Identity by descent (IBD) analysis and a combination of bioinformatics filters have suggested several candidate variants for AAO modifiers. Future work and replication studies on these variants may provide mechanistic insights into the etiopathology of Alzheimer disease.
| S-EPMC3496074 | biostudies-literature
Project description:IntroductionGenetic factors predisposing individuals to cancer remain elusive in the majority of patients with a familial or clinical history suggestive of hereditary breast cancer. Germline DNA copy number variation (CNV) has recently been implicated in predisposition to cancers such as neuroblastomas as well as prostate and colorectal cancer. We evaluated the role of germline CNVs in breast cancer susceptibility, in particular those with low population frequencies (rare CNVs), which are more likely to cause disease."MethodsUsing whole-genome comparative genomic hybridization on microarrays, we screened a cohort of women fulfilling criteria for hereditary breast cancer who did not carry BRCA1/BRCA2 mutations.ResultsThe median numbers of total and rare CNVs per genome were not different between controls and patients. A total of 26 rare germline CNVs were identified in 68 cancer patients, however, a proportion that was significantly different (P = 0.0311) from the control group (23 rare CNVs in 100 individuals). Several of the genes affected by CNV in patients and controls had already been implicated in cancer.ConclusionsThis study is the first to explore the contribution of germline CNVs to BRCA1/2-negative familial and early-onset breast cancer. The data suggest that rare CNVs may contribute to cancer predisposition in this small cohort of patients, and this trend needs to be confirmed in larger population samples.
| S-EPMC3496142 | biostudies-literature
Project description:BackgroundThe aim of this study was to identify BRCA1 and BRCA2 mutations in the Estonian population. We analyzed genetic data and questionnaire from 64 early-onset (< 45 y) breast cancer patients, 47 familial cases (patients with breast or ovarian cancer and a case of these cancers in the family), and 33 predictive cases (patients without breast or ovarian cancer, with a family history of such diseases) from Estonia for mutations in the BRCA1 gene. A sub-set of familial cases and predictive cases were also analyzed for mutations in the BRCA2 gene.MethodsFor mutation detection, we used the Polymerase Chain Reaction-Single Stranded Conformation Polymorphism Heteroduplex Analysis (PCR-SSCP-HD), followed by direct DNA sequencing.ResultsWe identified three clinically important mutations in the BRCA1 gene, including seven occurrences of the c.5382insC mutation, three of c.4154delA, and one instance of c.3881_3882delGA. We also detected six polymorphisms: c.2430T>C, c.3232A>G, c.4158A>G, c.4427T>C, c.4956A>G, and c.5002T>C. Four sequence alterations were detected in introns: c.560+64delT, c.560+ [36-38delCTT, 52-63del12], c.666-58delT, and c.5396+60insGTATTCCACTCC. In the BRCA2 gene, two clinically important mutations were found: c.9610C>T and c.6631delTTAAATG. Additionally, two alterations (c.7049G>T and c.7069+80delTTAG) with unknown clinical significance were detected.ConclusionsIn our dataset, the overall frequency of clinically important BRCA1 mutations in early-onset patients, familial cases, and predictive testing was 7.6% (144 cases, 11 mutation carriers). Pathogenic mutations were identified in 4 of the 64 early-onset breast cancer cases (6.3%). In familial cases, clinically important mutations in the BRCA1 gene were found in 6 of the 47 individuals analyzed (12.8%). In predictive cases, 1 clinically important mutation was detected in 33 individuals studied (3%). The occurrence of clinically important mutations in BRCA2 in familial cases of breast cancer was 2 of the 16 individuals analyzed (12.5%).
| S-EPMC2867795 | biostudies-literature
Project description:The lower breast cancer incidence in Asian populations compared with Western populations has been speculated to be caused by environmental and genetic variation. Early-onset breast cancer occupies a considerable proportion of breast cancers in Asian populations, but the reason for this is unclear. We aimed to examine miRNA expression profiles in different age-onset groups and pathological subtypes in Asian breast cancer.At the first stage, 10 samples (tumor: n = 6, normal tissue: n = 4) were analyzed with an Agilent microRNA 470 probe microarray. Candidate miRNAs with expression levels that were significantly altered in breast cancer samples or selected from a literature review were further validated by quantitative real-time PCR (qPCR) of 145 breast cancer samples at the second stage of the process. Correlations between clinicopathological parameters of breast cancer patients from different age groups and candidate miRNA expression were elucidated.In the present study, the tumor subtypes were significantly different in each age group, and an onset age below 40 had poor disease-free and overall survival rates. For all breast cancer patients, miR-335 and miR-145 were down-regulated, and miR-21, miR-200a, miR-200c, and miR-141 were up-regulated. In very young patients (age < 35 y/o), the expression of 3 and 8 specific miRNAs were up- and down-regulated, respectively. In young patients (36-40 y/o), 3 and 3 specific miRNAs were up- and down-regulated, respectively. miR-532-5p was up-regulated in triple-negative breast cancer.Differential miRNA expressions between normal and tumor tissues were observed in different age groups and tumor subtypes. Evolutionarily conserved miRNA clusters, which initiate malignancy transformation, were up-regulated in the breast cancers of very young patients. None of the significantly altered miRNAs were observed in postmenopausal patients.
| S-EPMC5764434 | biostudies-literature
Project description:BackgroundSurveillance of univariate syndromic data as a means of potential indicator of developing public health conditions has been used extensively. This paper aims to improve the performance of detecting outbreaks by using a background forecasting algorithm based on the adaptive recursive least squares method combined with a novel treatment of the Day of the Week effect.MethodsPrevious work by the first author has suggested that univariate recursive least squares analysis of syndromic data can be used to characterize the background upon which a prediction and detection component of a biosurvellance system may be built. An adaptive implementation is used to deal with data non-stationarity. In this paper we develop and implement the RLS method for background estimation of univariate data. The distinctly dissimilar distribution of data for different days of the week, however, can affect filter implementations adversely, and so a novel procedure based on linear transformations of the sorted values of the daily counts is introduced. Seven-days ahead daily predicted counts are used as background estimates. A signal injection procedure is used to examine the integrated algorithm's ability to detect synthetic anomalies in real syndromic time series. We compare the method to a baseline CDC forecasting algorithm known as the W2 method.ResultsWe present detection results in the form of Receiver Operating Characteristic curve values for four different injected signal to noise ratios using 16 sets of syndromic data. We find improvements in the false alarm probabilities when compared to the baseline W2 background forecasts.ConclusionThe current paper introduces a prediction approach for city-level biosurveillance data streams such as time series of outpatient clinic visits and sales of over-the-counter remedies. This approach uses RLS filters modified by a correction for the weekly patterns often seen in these data series, and a threshold detection algorithm from the residuals of the RLS forecasts. We compare the detection performance of this algorithm to the W2 method recently implemented at CDC. The modified RLS method gives consistently better sensitivity at multiple background alert rates, and we recommend that it should be considered for routine application in bio-surveillance systems.
| S-EPMC2639573 | biostudies-literature
Project description:ObjectivesBeing either young or old at the time of breast cancer diagnosis has been suggested as an indicator of a poor prognosis. We studied the effect of age at breast cancer onset in relation to survival, focusing in particular on biological subtypes and reproductive anamnesis.Design, setting and participantsPatients with early breast cancer (n=594) treated in a Finnish University Hospital during 2003-2013 were prospectively collected and followed in median 102 months.ResultsPatients with luminal A-like breast cancer were older than the patients with luminal B-like (HER2-positive) (p=0.045) or patients with the HER2-positive (non-luminal) subtype (p=0.029). Patients ≥70 years received substantially less adjuvant chemotherapy (p=1.5×10-9) and radiotherapy (p=5.9×10-7) than younger women. Nevertheless, the estimated 10-year breast cancer-specific rates of survival were 84.2%, 92.9% and 87.0% in age groups <41 years, 41-69 years and ≥70 years, respectively, with no statistical difference (p=0.115). Survival rates were also comparable between the three age groups when assessed separately in different biological subtypes, and for patients with metastatic breast cancer there was similarly no difference between the age groups. Later menarche (p=5.7×10-8) and high parity (p=0.000078) correlated with increased age at breast cancer diagnosis, but, according to the patients' oestrogen receptor (ER) status, only among ER-positive patients.ConclusionsDespite the suggested undertreatment of older patients, we report excellent long-term outcomes in all age groups in this prospective cohort. Later endogenous endocrine exposure may cause delay in breast cancer onset, but the exact biology behind this phenomenon is so far unclear.
| S-EPMC7852949 | biostudies-literature
Project description:BackgroundThe RecQ Like Helicase (RECQL) gene has previously been shown to predispose to breast cancer mainly in European populations, in particular to estrogen receptor (ER) and/or progesterone receptor (PR) positive tumor. Here, we investigated the contribution of pathogenic RECQL germline variants to hereditary breast cancer in early-onset and familial breast cancer patients from Pakistan.MethodsComprehensive RECQL variant analysis was performed in 302 BRCA1 and BRCA2 negative patients with ER and/or PR positive breast tumors using denaturing high-performance liquid chromatography followed by DNA sequencing. Novel variants were classified using Sherloc guidelines.ResultsOne novel pathogenic protein-truncating variant (p.W75*) was identified in a 37-year-old familial breast cancer patient. The pathogenic variant frequencies were 0.3% (1/302) in early-onset and familial breast cancer patients and 0.8% (1/133) in familial patients. Further, three novel variants of unknown significance, p.I141F, p.S182S, and p.C475C, were identified in familial breast cancer patients at the age of 47, 68, and 47 respectively. All variants were absent in 250 controls.ConclusionsOur data suggest that the RECQL gene plays a negligible role in breast cancer predisposition in Pakistan.
| S-EPMC7749988 | biostudies-literature
Project description:Since BRCA mutations are only responsible for 10-20% of cases of breast cancer in patients with early-onset or a family history and since next-generation sequencing technology allows the simultaneous sequencing of a large number of target genes, testing for multiple cancer-predisposing genes is now being considered, but its significance in clinical practice remains unclear. We then developed a sequencing panel containing 68 genes that had cancer risk association for patients with early-onset or familial breast cancer. A total of 133 patients were enrolled and 30 (22.6%) were found to carry germline deleterious mutations, 9 in BRCA1, 11 in BRCA2, 2 in RAD50, 2 in TP53 and one each in ATM, BRIP1, FANCI, MSH2, MUTYH, and RAD51C. Triple-negative breast cancer (TNBC) was associated with the highest mutation rate (45.5%, p = 0.025). Seven of the 9 BRCA1 mutations and the single FANCI mutation were in the TNBC group; 9 of the 11 BRCA2, 1 of the 2 RAD50 as well as BRIP1, MSH2, MUTYH, and RAD51C mutations were in the hormone receptor (HR)(+)Her2(-) group, and the other RAD50, ATM, and TP53 mutations were in the HR(+)Her2(+) group. Mutation carriers were considered as high-risk to develop malignancy and advised to receive cancer screening. Screening protocols of non-BRCA genes were based on their biologic functions; for example, patients carrying RAD51C mutation received a screening protocol similar to that for BRCA, since BRCA and RAD51C are both involved in homologous recombination. In conclusion, we consider that multiple gene sequencing in cancer risk assessment is clinically valuable.
| S-EPMC4884994 | biostudies-literature
Project description:ObjectivesFamilial amyloid polyneuropathy (FAP ATTRV30M) shows a wide variation in age-at-onset (AO) between clusters, families, and among generations. We will now explore some candidate genes involved in altered disease pathways in order to assess their role as genetic modifiers of AO, using a family-centered approach.MethodsWe analyzed 62 tagging SNPs from nine genes-NGAL,MMP-9,BGN,MEK1,MEK2,ERK1,ERK2,HSP27, and YWHAZ - in a sample of 318 V30M Portuguese patients (106 families), currently under follow-up. A generalized estimating equation analysis was used to take into account nonindependency of AO between relatives. Also, an in silico analysis was performed in order to assess the functional impact of significant variants associated with AO.ResultsWe found for the first time variants from six genes (NGAL,BGN (in the female group), MEK1,MEK2,HSP27, and YWHAZ) that were significantly associated with early- and/or late-onset. Then, we confirmed a strong synergistic interaction between NGAL and MMP-9 genes. Additionally, by an in silico analysis, we found some variants for MEK1 gene that may alter binding of the transcription factors and that influence the regulation of gene expression regarding microRNA binding sites and splicing regulatory factors.InterpretationThese findings showed that different genetic factors can modulate differently the onset of disease's symptoms and revealed new mechanisms with clinical implications in the genetic counseling and follow-up of mutation carriers and could contribute for development of potential therapeutical targets.
| S-EPMC5288465 | biostudies-literature