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High Frequency of Germline TP53 Mutations in a Prospective Adult-Onset Sarcoma Cohort  [PDF]
Gillian Mitchell, Mandy L. Ballinger, Stephen Wong, Chelsee Hewitt, Paul James, Mary-Anne Young, Arcadi Cipponi, Tiffany Pang, David L. Goode, Alex Dobrovic, David M. Thomas, on behalf of the International Sarcoma Kindred Study
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0069026
Abstract: Sarcomas are a key feature of Li-Fraumeni and related syndromes (LFS/LFL), associated with germline TP53 mutations. Current penetrance estimates for TP53 mutations are subject to significant ascertainment bias. The International Sarcoma Kindred Study is a clinic-based, prospective cohort of adult-onset sarcoma cases, without regard to family history. The entire cohort was screened for mutations in TP53 using high-resolution melting analysis and Sanger sequencing, and multiplex-ligation-dependent probe amplification and targeted massively parallel sequencing for copy number changes. Pathogenic TP53 mutations were detected in blood DNA of 20/559 sarcoma probands (3.6%); 17 were germline and 3 appeared to be somatically acquired. Of the germline carriers, one appeared to be mosaic, detectable in the tumor and blood, but not epithelial tissues. Germline mutation carriers were more likely to have multiple cancers (47% vs 15% for non-carriers, P = 3.0×10?3), and earlier cancer onset (33 vs 48 years, P = 1.19×10?3). The median survival of mutation carriers following first cancer diagnosis was not significantly different from non-carriers. Only 10/17 (59%) pedigrees met classical or Chompret criteria for LFS. In summary, germline TP53 mutations are not rare in adult patients with sarcoma, with implications for screening, surveillance, treatment and genetic counselling of carriers and family members.
Up-regulation of cell cycle arrest protein BTG2 correlates with increased overall survival in breast cancer, as detected by immunohistochemistry using tissue microarray
Elin M?llerstr?m, Anikó Kovács, Kristina L?vgren, Szilard Nemes, Ulla Delle, Anna Danielsson, Toshima Parris, Donal J Brennan, Karin Jirstr?m, Per Karlsson, Khalil Helou
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-296
Abstract: Protein expression was evaluated using immunohistochemistry in an independent breast cancer cohort of 144 samples represented on tissue microarrays. Fisher's exact test was used to analyze the differences in protein expression between dead and alive patients. We used Cox-regression multivariate analysis to assess whether the new markers predict the survival status of the patients better than the currently used markers.BTG2 expression was demonstrated in a significantly lower proportion of samples from dead patients compared to alive patients, both in overall expression (P = 0.026) and cell membrane specific expression (P = 0.013), whereas neither ADIPOR1, ADORA1 nor CD46 showed differential expression in the two survival groups. Furthermore, a multivariate analysis showed that a model containing BTG2 expression in combination with HER2 and Ki67 expression along with patient age performed better than a model containing the currently used prognostic markers (tumour size, nodal status, HER2 expression, hormone receptor status, histological grade, and patient age). Interestingly, BTG2 has previously been described as a tumour suppressor gene involved in cell cycle arrest and p53 signalling.We conclude that high-level BTG2 protein expression correlates with prolonged survival in patients with breast carcinoma.Breast cancer is the most common malignancy among women, and accounted for approximately 1.15 million new cases and 411,000 deaths worldwide in 2002 [1]. During the last decade, the survival rate for breast cancer patients has increased dramatically due to earlier detection and new treatment protocols [2]. Presently, various clinical and pathological markers including axillary lymph node status, hormone receptor status, histological grade, tumour size, patient age, HER2 expression and vascular invasion are used to predict breast cancer prognosis and provide accurate treatment [3]. However, these markers are insufficient and approximately 20 to 30% of breast cancer p
Germline polymorphisms in SIPA1 are associated with metastasis and other indicators of poor prognosis in breast cancer
Nigel PS Crawford, Argyrios Ziogas, David J Peel, James Hess, Hoda Anton-Culver, Kent W Hunter
Breast Cancer Research , 2006, DOI: 10.1186/bcr1389
Abstract: The study population (n = 300) consisted of randomly selected non-Hispanic Caucasian breast cancer patients identified from a larger population-based series. Genomic DNA was extracted from peripheral leukocytes. Three previously described SNPs within SIPA1 (one within the promoter [-313G>A] and two exonic [545C>T and 2760G>A]) were characterized using SNP-specific PCR.The variant 2760G>A and the -313G>A allele were associated with lymph node involvement (P = 0.0062 and P = 0.0083, respectively), and the variant 545C>T was associated with estrogen receptor negative tumors (P = 0.0012) and with progesterone negative tumors (P = 0.0339). Associations were identified between haplotypes defined by the three SNPs and disease progression. Haplotype 3 defined by variants -313G>A and 2760G>A was associated with positive lymph node involvement (P = 0.0051), and haplotype 4 defined by variant 545C>T was associated with estrogen receptor and progesterone receptor negative status (P = 0.0053 and P = 0.0199, respectively).Our findings imply that SIPA1 germline polymorphisms are associated with aggressive disease behavior in the cohort examined. If these results hold true in other populations, then knowledge of SIPA1 SNP genotypes could potentially enhance current staging protocols.Breast cancer is a major public health concern among Western female populations. In 2004 breast cancer was the most common form of malignancy diagnosed in females in the USA and the second leading cause of cancer mortality in women [1]. The great majority of these deaths are related to complications caused by metastatic disease, and in spite of therapeutic advances metastatic breast cancer is currently incurable [2]. It has been estimated that 24–30% of women with node-negative disease and at least 50–60% of those with node-positive disease at diagnosis will relapse [3]. Furthermore, approximately 6–10% of breast cancer patients present with clinical evidence of metastasis, and the median survival of th
Dorsomorphin Promotes Survival and Germline Competence of Zebrafish Spermatogonial Stem Cells in Culture  [PDF]
Ten-Tsao Wong, Paul Collodi
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0071332
Abstract: Zebrafish spermatogonial cell cultures were established from Tg(piwil1:neo);Tg(piwil1:DsRed) transgenic fish using a zebrafish ovarian feeder cell line (OFC3) that was engineered to express zebrafish Lif, Fgf2 and Gdnf. Primary cultures, initiated from testes, were treated with G418 to eliminate the somatic cells and select for the piwil1:neo expressing spermatogonia. Addition of dorsomorphin, a Bmp type I receptor inhibitor, prolonged spermatogonial stem cell (SSC) survival in culture and enhanced germline transmission of the SSCs following transplantation into recipient larvae. In contrast, dorsomorphin inhibited the growth and survival of zebrafish female germline stem cells (FGSCs) in culture. In the presence of dorsomorphin, the spermatogonia continued to express the germ-cell markers dazl, dnd, nanos3, vasa and piwil1 and the spermatogonial markers plzf and sox17 for at least six weeks in culture. Transplantation experiments revealed that 6 week-old spermatogonial cell cultures maintained in the presence of dorsomorphin were able to successfully colonize the gonad in 18% of recipient larvae and produce functional gametes in the resulting adult chimeric fish. Germline transmission was not successful when the spermatogonia were cultured 6 weeks in the absence of dorsomorphin before transplantation. The results indicate that Bmp signaling is detrimental to SSCs but required for the survival of zebrafish FGSCs in culture. Manipulation of Bmp signaling could provide a strategy to optimize culture conditions of germline stem cells from other species.
Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients
Daphne SC Lee, Sook-Yee Yoon, Lai Looi, Peter Kang, In Kang, Kavitta Sivanandan, Hany Ariffin, Meow Thong, Kin Chin, Nur Mohd Taib, Cheng-Har Yip, Soo-Hwang Teo
Breast Cancer Research , 2012, DOI: 10.1186/bcr3172
Abstract: A total of 100 patients with early-onset breast cancer (≤ 35 years) treated at University Malaya Medical Centre between 2003 and 2009, were analyzed for germline mutations in BRCA1, BRCA2 and TP53 by full DNA sequencing. Of the mutations identified, we examined their likely pathogenicity on the basis of prevalence in a case-control cohort, co-segregation analyses and loss of heterozygosity (LOH) in tumor tissues.We identified 11 BRCA1 (11%) and 6 BRCA2 (6%) germline carriers among early-onset breast cancer patients. Of the 83 BRCA-negative patients, we identified four exonic variants and three intronic variants in TP53. Of these, two exonic variants are clinically relevant (E346X and p. G334_R335dup6) and two novel missense mutations (A138V and E285K) are likely to be clinically relevant, on the basis of co-segregation and loss of heterozygosity (LOH). Notably, E285K was found in two unrelated individuals and haplotype analyses suggest a founder effect. Two of the three intronic variants are likely benign based on their prevalence in a control population. Clinically relevant TP53 germline mutations were identified in three of the four patients (75%) with a family history of at least two LFS-linked cancers (breast, bone or soft tissue sarcoma, brain tumors or adrenocortical cancer); 1 of the 17 patients (6%) with a family history of breast cancer only, and 1 of the 62 patients (< 2%) with no family history of breast or LFS-linked cancers.Our study reports germline BRCA1, BRCA2 and TP53 mutations are found in early-onset breast cancer patients at 11%, 6% and 5% respectively, suggesting that TP53 mutation screening should be considered for these patients. However, we find that even in low resource Asian settings where family history is poorly reported, germline TP53 mutations are found predominantly among breast cancer patients with a family history of LFS-linked cancers.To date, germline mutations in at least 10 genes linked to DNA repair have been shown to be associa
Mammographic density as a predictor of breast cancer survival: the Multiethnic Cohort
Gertraud Maskarinec, Ian S Pagano, Melissa A Little, Shannon M Conroy, Song-Yi Park, Laurence N Kolonel
Breast Cancer Research , 2013, DOI: 10.1186/bcr3378
Abstract: Female MEC participants, aged ≥ 50 years at cohort entry, diagnosed with primary invasive breast cancer, and enrolled in a mammographic density case-control study were part of this analysis. At cohort entry, anthropometric and demographic information was collected by questionnaire. Tumor characteristics and vital status were available through linkage with the Hawaii Tumor Registry. Multiple digitized prediagnostic mammograms were assessed for mammographic density using a computer-assisted method. Cox proportional hazards regression was applied to examine the effect of mammographic density on breast cancer survival while adjusting for relevant covariates.Of the 607 cases, 125 were diagnosed as in situ, 380 as localized, and 100 as regional/distant stage. After a mean follow-up time of 12.9 years, 27 deaths from breast cancer and 100 deaths from other causes had occurred; 71 second breast cancer primaries were diagnosed. In an overall model, mammographic density was not associated with breast cancer-specific survival (HR = 0.95 per 10%; 95%CI: 0.79-1.15), but the interaction with radiotherapy was highly significant (p = 0.006). In stratified models, percent density was associated with a reduced risk of dying from breast cancer (HR = 0.77; 95%CI: 0.60-0.99; p = 0.04) in women who had received radiation, but with an elevated risk (HR = 1.46; 95% CI: 1.00-2.14; p = 0.05) in patients who had not received radiation. High breast density predicted a borderline increase in risk for a second primary (HR = 1.72; 95% CI: 0.88-2.55; p = 0.15).Assessing mammographic density in women with breast cancer may identify women with a poorer prognosis and provide them with radiotherapy to improve outcomes.Mammographic density - the distribution of fat, connective, and epithelial tissue in the breast - has been used as a biomarker because a high percentage of dense parenchyma on mammographic images confers a four- to six-fold risk for breast cancer [1], but its relation to breast cancer su
Introduction to the studies of cohort in epidemiología and to the analysis of survival
Francisco J Díaz Ceballos
MedUNAB , 2005,
Abstract: The cohort design is a major methodological tool in epidemiologicaland medical research. This article introducesthe basic concepts and statistical methods supporting thisdesign. After describing the fundamental ideas of prospectiveand retrospective cohort designs and of fi xed and variablecohort designs, this article focuses on the basic tools used invariable cohort designs. These tools are part of the so calledsurvival analysis. The concepts of censoring, life table, survivalfunction, the Kaplan-Meier estimator and the cumulativehazard function are then described. Statistical methods forcomparing two survival functions such as the Cochran-Mantel-Haenszel and log-rank tests and the log-rank stratifi edtest are also explained. Finally, the alternative person-yearsmethod is introduced. The concepts and methods are illustratedwith a retrospective cohort study of the age of onsetof daily smoking in patients with schizophrenia
Discovery Analysis of TCGA Data Reveals Association between Germline Genotype and Survival in Ovarian Cancer Patients  [PDF]
Rosemary Braun, Richard Finney, Chunhua Yan, Qing-Rong Chen, Ying Hu, Michael Edmonson, Daoud Meerzaman, Kenneth Buetow
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0055037
Abstract: Background Ovarian cancer remains a significant public health burden, with the highest mortality rate of all the gynecological cancers. This is attributable to the late stage at which the majority of ovarian cancers are diagnosed, coupled with the low and variable response of advanced tumors to standard chemotherapies. To date, clinically useful predictors of treatment response remain lacking. Identifying the genetic determinants of ovarian cancer survival and treatment response is crucial to the development of prognostic biomarkers and personalized therapies that may improve outcomes for the late-stage patients who comprise the majority of cases. Methods To identify constitutional genetic variations contributing to ovarian cancer mortality, we systematically investigated associations between germline polymorphisms and ovarian cancer survival using data from The Cancer Genome Atlas Project (TCGA). Using stage-stratified Cox proportional hazards regression, we examined 650,000 SNP loci for association with survival. We additionally examined whether the association of significant SNPs with survival was modified by somatic alterations. Results Germline polymorphisms at rs4934282 (AGAP11/C10orf116) and rs1857623 (DNAH14) were associated with stage-adjusted survival ( = 1.12e-07 and 1.80e-07, FDR = 1.2e-04 and 2.4e-04, respectively). A third SNP, rs4869 (C10orf116), was additionally identified as significant in the exome sequencing data; it is in near-perfect LD with rs4934282. The associations with survival remained significant when somatic alterations. Conclusions Discovery analysis of TCGA data reveals germline genetic variations that may play a role in ovarian cancer survival even among late-stage cases. The significant loci are located near genes previously reported as having a possible relationship to platinum and taxol response. Because the variant alleles at the significant loci are common (frequencies for rs4934282 A/C alleles = 0.54/0.46, respectively; rs1857623 A/G alleles = 0.55/0.45, respectively) and germline variants can be assayed noninvasively, our findings provide potential targets for further exploration as prognostic biomarkers and individualized therapies.
A Plant Germline-Specific Integrator of Sperm Specification and Cell Cycle Progression  [PDF]
Lynette Brownfield,Said Hafidh,Michael Borg,Anna Sidorova,Toshiyuki Mori,David Twell
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000430
Abstract: The unique double fertilisation mechanism in flowering plants depends upon a pair of functional sperm cells. During male gametogenesis, each haploid microspore undergoes an asymmetric division to produce a large, non-germline vegetative cell and a single germ cell that divides once to produce the sperm cell pair. Despite the importance of sperm cells in plant reproduction, relatively little is known about the molecular mechanisms controlling germ cell proliferation and specification. Here, we investigate the role of the Arabidopsis male germline-specific Myb protein DUO POLLEN1, DUO1, as a positive regulator of male germline development. We show that DUO1 is required for correct male germ cell differentiation including the expression of key genes required for fertilisation. DUO1 is also necessary for male germ cell division, and we show that DUO1 is required for the germline expression of the G2/M regulator AtCycB1;1 and that AtCycB1:1 can partially rescue defective germ cell division in duo1. We further show that the male germline-restricted expression of DUO1 depends upon positive promoter elements and not upon a proposed repressor binding site. Thus, DUO1 is a key regulator in the production of functional sperm cells in flowering plants that has a novel integrative role linking gametic cell specification and cell cycle progression.
Molecular apocrine differentiation is a common feature of breast cancer in patients with germline PTEN mutations
Guillaume Banneau, Micka?l Guedj, Ga?tan MacGrogan, Isabelle de Mascarel, Valerie Velasco, Renaud Schiappa, Valerie Bonadona, Albert David, Catherine Dugast, Brigitte Gilbert-Dussardier, Olivier Ingster, Pierre Vabres, Frederic Caux, Aurelien de Reynies, Richard Iggo, Nicolas Sevenet, Fran?oise Bonnet, Michel Longy
Breast Cancer Research , 2010, DOI: 10.1186/bcr2626
Abstract: We first performed a microarray study of three tumors from patients with Cowden disease in the context of a transcriptomic study of 74 familial breast cancers. A subsequent histological and immunohistochemical study including 12 additional cases of Cowden disease breast carcinomas was performed to confirm the microarray data.Unsupervised clustering of the 74 familial tumors followed the intrinsic gene classification of breast cancer except for a group of five tumors that included the three Cowden tumors. The gene expression profile of the Cowden tumors shows considerable overlap with that of a breast cancer subgroup known as molecular apocrine breast carcinoma, which is suspected to have increased androgenic signaling and shows frequent ERBB2 amplification in sporadic tumors. The histological and immunohistochemical study showed that several cases had apocrine histological features and expressed GGT1, which is a potential new marker for apocrine breast carcinoma.These data suggest that activation of the ERBB2-PI3K-AKT pathway by loss of PTEN at early stages of tumorigenesis promotes the formation of breast tumors with apocrine features.The classification of breast cancer was recently enriched by the addition of gene expression microarray data for the main histopathological tumor types [1]. The most widely used transcriptomic classification, the Intrinsic Gene Set or Stanford classification, divides breast cancer into luminal A, luminal B, basal-like, normal-like and HER2 classes [2-4]. It is based on studies of sporadic tumors, and reflects mainly tumor cell type and HER2 status. Few studies have looked at the gene expression profile of breast cancers arising in patients with a familial predisposition to cancer. In those studies, the tumors arising in patients with germline BRCA1 mutations frequently had a basal-like phenotype, whereas BRCA2-related tumors had no particular type or a luminal B type [5]. Little is known about the transcriptomic profile of breast canc
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