Gene expression profiles in pairs of synchronous and metachronous bilateral breast tumors and primaries and their local recurrences
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE27531 | GEO | 2018/02/13
REPOSITORIES: GEO
Similar Datasets
Project description:Bilaterality of breast cancer is an indicator of constitutional cancer susceptibility, however, the molecular causes underlying this predisposition in the majority of cases is not known. We hypothesize that epigenetic misregulation of cancer related genes could partially account for this predisposition. We have performed methylation microarray analysis of peripheral blood DNA from 14 women with bilateral breast cancer compared to 14 unaffected matched controls throughout 17 candidate breast cancer susceptibility genes including BRCA1, BRCA2, CHEK2, ATM, ESR1, SFN, CDKN2A, TP53, GSTP1, CDH1, CDH13, HIC1, PGR, SFRP1, MLH1, RARB and HSD17B4. We show that the majority of methylation variability is associated with intragenic repetitive elements. Detailed validation of the tiled region around ATM was performed by bisulfite modification and pyrosequencing of the same samples and in a second set of peripheral blood DNA from 190 bilateral breast cancer patients compared to 190 controls. We show significant hypermethylation of one intragenic repetitive element in breast cancer cases compared to controls (p=0.0017) with the highest quartile of methylation associated with a three-fold increased risk of breast cancer (OR = 3.20, 95% C.I.=1.78-5.86, p=0.000083). Increased methylation of this locus is associated with lower steady state ATM mRNA level and correlates with age of cancer patients but not controls, suggesting a combined age-phenotype related association. This research demonstrates the potential for gene-body epigenetic misregulation of ATM and other cancer related genes in peripheral blood DNA that may be useful as a novel marker to estimate breast cancer risk. Keywords: Differential Methylation Hybridisation
2009-01-29 | GSE14603 | GEO
Project description:Introduction Warthin tumor is described as papillary cystadenoma lymphomatosum and is the second most common tumor of the parotid glands. Bilateral synchronous incidence is rare, occurring in 7 to 10% of the cases. It is more common in males between 60 and 70 years of age and is closely related to smoking. There is slow growth and the condition is a delimited nodule of regular outlines; it has low rates of malignant progression and recurrence. Objective Report a case of synchronous bilateral Warthin tumor occurring in an elderly patient, and review incidence and peculiarities of this tumor. Case Report A 78-year-old man who used to smoke had a history of mild pain in the topography of right parotid three weeks ago. Patient with hypertension, diabetes and a longtime smoker (smoking a pack per day for 32 years) noticed a progressive bulging in the right parotid region for about 2.5 years ago, and noticed another progressive bulging (althought in the left parotid region), for about one year ago. Patient denied fever, redness, skin lesions and pain during this period until last three weeks, when he sought medical attention for a mild pain in the right facial region. The patient underwent cervical magnetic resonance imaging that showed tumor lesions in both parotids. Fine needle aspiration revealed a typical lesion of epithelial oxyphilic cells associated with reactive lymphoid proliferation, suggesting Warthin tumor. The patient underwent two superficial parotidectomies, and the histopathologic result from both tumors of parotid glands showed papillary cystadenoma lymphomatosum. Conclusion The occurrence of synchronous bilateral Warthin tumor is extremely rare, and anamnesis and physical examination, as well as some complementary examinations, are important means for diagnostic evaluation. Confirmation of the diagnosis can only be obtained through a histopathologic study. A superficial or total parotidectomy is the recommended treatment for the disease.
| S-EPMC4297016 | biostudies-other
Project description:BackgroundSynchronous tumors can be independent primary tumors or a primary-metastatic (clonal) pair, which may have clinical implications. Mutational profiling of tumor DNA is increasingly common in the clinic. We investigated whether mutational profiling can distinguish independent from clonal tumors in breast and other cancers, using a carefully defined test based on the Clonal Likelihood Score (CLS = 100 x # shared high confidence (HC) mutations/ # total HC mutations).MethodsStatistical properties of a formal test using the CLS were investigated. A high CLS is evidence in favor of clonality; the test is implemented as a one-sided binomial test of proportions. Test parameters were empirically determined using 16,422 independent breast tumor pairs and 15 primary-metastatic tumor pairs from 10 cancer types using The Cancer Genome Atlas.ResultsWe validated performance of the test with its established parameters, using five published data sets comprising 15,758 known independent tumor pairs (maximum CLS = 4.1%, minimum p-value = 0.48) and 283 known tumor clonal pairs (minimum CLS 13%, maximum p-value <0.01), across renal cell, testicular, and colorectal cancer. The CLS test correctly classified all validation samples but one, which it appears may have been incorrectly classified in the published data. As proof-of-concept we then applied the CLS test to two new cases of invasive synchronous bilateral breast cancer at our institution, each with one hormone receptor positive (ER+/PR+/HER2-) lobular and one triple negative ductal carcinoma. High confidence mutations were identified by exome sequencing and results were validated using deep targeted sequencing. The first tumor pair had CLS of 81% (p-value < 10-15), supporting clonality. In the second pair, no common mutations of 184 variants were validated (p-value >0.99), supporting independence. A plausible molecular mechanism for the shift from hormone receptor positive to triple negative was identified in the clonal pair.ConclusionWe have developed the statistical properties of a carefully defined Clonal Likelihood Score test from mutational profiling of tumor DNA. Under identified conditions, the test appears to reliably distinguish between synchronous tumors of clonal and of independent origin in several cancer types. This approach may have scientific and clinical utility.
| S-EPMC4640562 | biostudies-literature
Project description:BackgroundEvidence suggests that patients with synchronous bilateral breast cancer (SBBC), diagnosed within 4 months, have an inferior prognosis compared to unilateral breast cancer (UBC) patients. Using data from nationwide Danish clinical databases, this cohort study investigated whether the inferior prognosis could be explained by SBBC patients having a more aggressive disease, or whether the prognosis could be explained by the fact that they have two simultaneous cancers.MethodsPatients were diagnosed from 1999-2015. The main outcome was excess mortality, subtracting background population mortality from observed mortality. Differences between SBBC and UBC patients were evaluated by rate ratios (RR) and estimated by Poisson regression.ResultsIn total, 1214 SBBC and 59 177 UBC patients were included. SBBC patients had a significantly higher excess mortality than UBC patients after adjustment for age and period (RR = 1.73; 95% CI:1.44-2.08; p < 0.01) and after adjusting for characteristics of the worst tumour as traditionally done (RR = 1.31; 95% CI:1.08-1.57; p = 0.01). However, adjusting for characteristics of both tumours, using a more advanced competing risks model, no difference was observed (RR = 1.01; 95% CI:0.83-1.22; p = 0.93).ConclusionsOur study does not support that the inferior prognosis in SBBC patients is due to having more aggressive tumours per se, but rather the combined effect of having two simultaneous cancers.
| S-EPMC6461871 | biostudies-literature
Project description:BACKGROUND:Today, no objective criteria exist to differentiate between individual primary tumors and intra- or intermammary dissemination respectively, in patients diagnosed with two or more synchronous breast cancers. To elucidate whether these tumors most likely arise through clonal expansion, or whether they represent individual primary tumors is of tumor biological interest and may have clinical implications. In this respect, high resolution genomic profiling may provide a more reliable approach than conventional histopathological and tumor biological factors. METHODS:32 K tiling microarray-based comparative genomic hybridization (aCGH) was used to explore the genomic similarities among synchronous unilateral and bilateral invasive breast cancer tumor pairs, and was compared with histopathological and tumor biological parameters. RESULTS:Based on global copy number profiles and unsupervised hierarchical clustering, five of ten (p = 1.9 x 10-5) unilateral tumor pairs displayed similar genomic profiles within the pair, while only one of eight bilateral tumor pairs (p = 0.29) displayed pair-wise genomic similarities. DNA index, histological type and presence of vessel invasion correlated with the genomic analyses. CONCLUSION:Synchronous unilateral tumor pairs are often genomically similar, while synchronous bilateral tumors most often represent individual primary tumors. However, two independent unilateral primary tumors can develop synchronously and contralateral tumor spread can occur. The presence of an intraductal component is not informative when establishing the independence of two tumors, while vessel invasion, the presence of which was found in clustering tumor pairs but not in tumor pairs that did not cluster together, supports the clustering outcome. Our data suggest that genomically similar unilateral tumor pairs may represent a more aggressive disease that requires the addition of more severe treatment modalities, and underscores the importance of evaluating the clonality of multiple tumors for optimal patient management. In summary, our findings demonstrate the importance of evaluating the properties of both tumors in order to determine the most optimal patient management.
| S-EPMC2474633 | biostudies-literature
Project description:Multiple tumours from the same patient were analysed for copy number alterations to assess tumour clonality. Seventy-four tumours corresponding to 37 patients were stratified into four groups based on the anatomic location of the multiple breast cancers (ipsilateral or bilateral) and time interval between the diagnoses (synchronous or metachronous). Ipsilateral was defined as tumours occurring in the same breast while bilateral was defined as the occurrence of tumours in both breasts. Metachronicity was defined as a time interval greater than six months between the diagnoses of the first and second tumours, while synchronicity specified that the two tumours occurred concurrently (BM: bilateral-metachronous; BS: bilateral-synchronous; IM: ipsilateral-metachronous; IS: ipsilateral-synchronous).
2019-01-03 | GSE108984 | GEO
Project description:This clinical case resulted from an ongoing trial at Vanderbilt University and abroad where ER+ breast cancer patients are administered 2-3 weeks of aromatase inhibitor therapy leading up to definitive surgical resection of the tumor. In this case, we describe a study patient presenting with bilateral primary ER+ breast tumors. Short term hormonal therapy substantially reduced proliferation in one tumor, while the second was essentially unchanged. Extensive molecular and genetic workup of the two tumors yielded divergent lesions in the two tumors; an activating KRAS mutation in the responsive tumor, and an amplification of the FGFR1 locus in the treatment-refractory tumor.
2012-07-17 | GSE39387 | GEO
Project description:This clinical case resulted from an ongoing trial at Vanderbilt University and abroad where ER+ breast cancer patients are administered 2-3 weeks of aromatase inhibitor therapy leading up to definitive surgical resection of the tumor. In this case, we describe a study patient presenting with bilateral primary ER+ breast tumors. Short term hormonal therapy substantially reduced proliferation in one tumor, while the second was essentially unchanged. Extensive molecular and genetic workup of the two tumors yielded divergent lesions in the two tumors; an activating KRAS mutation in the responsive tumor, and an amplification of the FGFR1 locus in the treatment-refractory tumor. Surgical tumor specimens from ER+ breast cancer patient 7603 who was administered letrozole for 16 days leading up to definitive surgery were utilized for RNA extraction and hybridization to Affymetrix Gene expression microarrays.
2012-07-16 | E-GEOD-39387 | biostudies-arrayexpress
Project description:Multiple tumours from the same patient were analysed for DNA methylation to assess tumour clonality. Seventy-four tumours corresponding to 37 patients were stratified into four groups based on the anatomic location of the multiple breast cancers (ipsilateral or bilateral) and time interval between the diagnoses (synchronous or metachronous). Ipsilateral was defined as tumours occurring in the same breast while bilateral was defined as the occurrence of tumours in both breasts. Metachronicity was defined as a time interval greater than six months between the diagnoses of the first and second tumours, while synchronicity specified that the two tumours occurred concurrently (BM: bilateral-metachronous; BS: bilateral-synchronous; IM: ipsilateral-metachronous; IS: ipsilateral-synchronous). A subset of 16 samples was randomly selected to represent each clinical group with four samples corresponding to two patients per group and analysed for DNA methylation using Illumina Infinium Human MethylationEPIC BeadChips.
2019-01-03 | GSE108982 | GEO
Project description:Synchronous bilateral breast cancer (sBBC) occurs after both breasts have been affected by the same germline genetics and environmental exposures. Little evidence exists regarding immune infiltration and response to treatment in sBBCs. Here we show that the impact of the subtype of breast cancer on levels of tumor infiltrating lymphocytes (TILs, n = 277) and on pathologic complete response (pCR) rates (n = 140) differed according to the concordant or discordant subtype of breast cancer of the contralateral tumor: luminal breast tumors with a discordant contralateral tumor had higher TIL levels and higher pCR rates than those with a concordant contralateral tumor. Tumor sequencing revealed that left and right tumors (n = 20) were independent regarding somatic mutations, copy number alterations and clonal phylogeny, whereas primary tumor and residual disease were closely related both from the somatic mutation and from the transcriptomic point of view. Our study indicates that tumor-intrinsic characteristics may have a role in the association of tumor immunity and pCR and demonstrates that the characteristics of the contralateral tumor are also associated with immune infiltration and response to treatment.
| S-EPMC10033420 | biostudies-literature