Publications
35 results found
Cereser B, Yiu A, Tabassum N, et al., 2023, The mutational landscape of the adult healthy parous and nulliparous human breast, Nature Communications, Vol: 14, Pages: 1-11, ISSN: 2041-1723
The accumulation of somatic mutations in healthy human tissues has been extensively characterized, but the mutational landscape of the healthy breast is still poorly understood. Our analysis of whole-genome sequencing shows that in line with other healthy organs, the healthy breast during the reproduction years accumulates mutations with age, with the rate of accumulation in the epithelium of 15.24 ± 5 mutations/year. Both epithelial and stromal compartments contain mutations in breast-specific driver genes, indicative of subsequent positive selection. Parity- and age-associated differences are evident in the mammary epithelium, partly explaining the observed difference in breast cancer risk amongst women of different childbearing age. Parity is associated with an age-dependent increase in the clone size of mutated epithelial cells, suggesting that older first-time mothers have a higher probability of accumulating oncogenic events in the epithelium compared to younger mothers or nulliparous women. In conclusion, we describe the reference genome of the healthy female human breast during reproductive years and provide evidence of how parity affects the genomic landscape of the mammary gland.
Passman AM, Haughey MJ, Carlotti E, et al., 2023, Hepatocytes undergo punctuated expansion dynamics from a periportal stem cell niche in normal human liver, JOURNAL OF HEPATOLOGY, Vol: 79, ISSN: 0168-8278
- Author Web Link
- Cite
- Citations: 1
Cereser B, Tabassum N, Belluz LDB, et al., 2021, Mutational burden of the normal breast during age and pregnancy, San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Tabassum N, Constantin TA, Cereser B, et al., 2021, A cell-cycle signature classifier for pan-cancer analysis (vol 39, pg 6041, 2020), ONCOGENE, Vol: 40, Pages: 1752-1752, ISSN: 0950-9232
Tabassum N, Cereser B, Stebbing J, 2020, A cell-cycle signature classifier for pan-cancer analysis, ONCOGENE, Vol: 39, Pages: 6041-6042, ISSN: 0950-9232
- Author Web Link
- Cite
- Citations: 8
Cereser B, Tabassum N, Belluz LDB, et al., 2020, Mutational landscapes of normal breast during age and pregnancy determine cancer risk, Biorxiv
<h4>ABSTRACT</h4> The accumulation of somatic mutations in the healthy breast throughout life and pregnancy is poorly understood 1–10 . Similarly, the mutational landscape of both epithelial and stromal components of the mammary gland has not been investigated. Both are relevant for breast cancer (BC), as the interplay between age, pregnancy, and cancer risk has not been fully characterized 11 . We describe whole genome sequencing analysis of epithelial and stromal compartments from the normal breast. We show that, in a similar way to other normal organs, the mutational burden of the mammary nulliparous epithelium significantly increases with age. In a nulliparous status, mutated clones are maintained at a consistently small size throughout the life of the individual; however, at parity, pre-existent clones significantly increase in size with age. Both epithelial and stromal compartments of the healthy breast contain pre-existing known cancer mutations, albeit at low rate, indicative of subsequent positive selection for mutations in tissue-specific driver genes. In line with this, both compartments also present gene enrichment in preferentially mutated cancer pathways. Our results show that mutational landscapes differ between the parous and nulliparous epithelium and suggest an explanation for both differential breast cancer risk and development of pregnancy-associated BC (PABC).
Passman AM, Haughey MJ, Carlotti E, et al., 2020, CLONAL DYNAMICS AND CELL-OF-ORIGIN OF NORMAL HEPATOCYTE EXPANSIONS IN HOMEOSTATIC HUMAN LIVERS AND THEIR ASSOCIATION WITH THE BILIARY EPITHELIUM, Crohn's and Colitis Congress, Publisher: W B SAUNDERS CO-ELSEVIER INC, Pages: S1276-S1276, ISSN: 0016-5085
Baker A-M, Gabbutt C, Williams MJ, et al., 2019, Crypt fusion as a homeostatic mechanism in the human colon, Gut, Vol: 68, Pages: 1986-1993, ISSN: 0017-5749
Objective The crypt population in the human intestine is dynamic: crypts can divide to produce two new daughter crypts through a process termed crypt fission, but whether this is balanced by a second process to remove crypts, as recently shown in mouse models, is uncertain. We examined whether crypt fusion (the process of two neighbouring crypts fusing into a single daughter crypt) occurs in the human colon.Design We used somatic alterations in the gene cytochrome c oxidase (CCO) as lineage tracing markers to assess the clonality of bifurcating colon crypts (n=309 bifurcating crypts from 13 patients). Mathematical modelling was used to determine whether the existence of crypt fusion can explain the experimental data, and how the process of fusion influences the rate of crypt fission.Results In 55% (21/38) of bifurcating crypts in which clonality could be assessed, we observed perfect segregation of clonal lineages to the respective crypt arms. Mathematical modelling showed that this frequency of perfect segregation could not be explained by fission alone (p<10−20). With the rates of fission and fusion taken to be approximately equal, we then used the distribution of CCO-deficient patch size to estimate the rate of crypt fission, finding a value of around 0.011 divisions/crypt/year.Conclusions We have provided the evidence that human colonic crypts undergo fusion, a potential homeostatic process to regulate total crypt number. The existence of crypt fusion in the human colon adds a new facet to our understanding of the highly dynamic and plastic phenotype of the colonic epithelium.
Passman A, Williams M, Carlotti E, et al., 2019, The Cell of Origin of Normal Human Hepatocytes has a Common Ancestor with Biliary Epithelium and Hepatocyte Clonal Expansions Arise from the Portal Tract and Drift to the Central Vein, 12th Joint Meeting of the British-Division-of-the-International-Academy-of-Pathology and the Pathological-Society-of-Great-Britain-and-Ireland (Leeds Pathology), Publisher: WILEY, Pages: S16-S16, ISSN: 0022-3417
Baker A-M, Cereser B, Melton S, et al., 2019, Quantification of Crypt and Stem Cell Evolution in the Normal and Neoplastic Human Colon (vol 8, pg 940, 2014), CELL REPORTS, Vol: 27, Pages: 2524-2524, ISSN: 2211-1247
Chandrasinghe P, Cereser B, Moorghen M, et al., 2019, SMAD7 shows a biphasic expression pattern during progression of ulcerative colitis-associated colorectal cancer, Publisher: OXFORD UNIV PRESS, Pages: S124-S124, ISSN: 1873-9946
Cereser B, Tabassum N, Carter P, et al., 2018, Study of the mutational landscape of normal and pregnant breast to predict pregnancy-associated breast cancer risk, San Antonio Breast Cancer Symposium 2018
Background: Amongst the various risk factors for breast cancer (BC), the molecular basis which may explain the correlation between age at first full-term and breast cancer risks is still understudied. Epidemiology studies indicate that an early first full-term pregnancy (before 25 years of age) confers a significant level of protection towards the development of post-menopausal BC compared to the risk in nulliparous or late-parous women. On the other hand, any pregnancy relates to a higher risk in developing cancer during or within one year of pregnancy (pregnancy-associated breast cancer, PABC). Thus, the relation between age of pregnancy and breast cancer risk may be too difficult to explain using only epidemiology data.Aims of the study: With our research study, we aim to study a cohort of 60 normal breast samples of nulliparous and age-matched early- and late-parous women collected from Komen Tissue Bank, University of Indiana, and to create for the first time a mathematical model of cell clone expansion in the normal breast growth. This will allow us to determine how the rates of both cancer drivers, passenger mutations and genetic variations are affected by pregnancy. We then aim to translate this in cancer tissues, and to determine how the rate of the same mutations in both pregnancy and non pregnancy-associated cancers (post-menopausal). At the same time, we intend to create a mouse model which will be used to further validate our model, where driver mutations will be induced in the mammary epithelium of pregnant mice of different ages. This will allow us to test our model of growth of a mutated clone in a pregnancy environment, and to determine what are the molecular changes in the pregnant mammary gland which can trigger a different BC risk in the early-parous cohort.Results: To examine the mutational landscape in the normal parous and nulliparous women, we extracted DNA from laser-capture microdissected epithelium and the stroma, the latter of which wi
Carter P, Alifrangis CC, Cereser B, et al., 2018, Molecular profiling of advanced breast cancer tumors is beneficial in assisting clinical treatment plans, Oncotarget, Vol: 9, Pages: 17589-17596, ISSN: 1949-2553
We used data obtained by Caris Life Sciences, to evaluate the benefits of tailoring treatments for a breast carcinoma cohort by using tumor molecular profiles to inform decisions. Data for 92 breast cancer patients from the commercial Caris Molecular Intelligence database was retrospectively divided into two groups, so that the first always followed treatment recommendations, whereas in the second group all patients received at least one drug after profiling that was predicted to lack benefit. The biomarker and drug associations were based on tests including fluorescent in situ hybridization and DNA sequencing, although immunohistochemistry was the main test used.Patients whose drugs matched those recommended according to their tumor profile had an average overall survival of 667 days, compared to 510 days for patients that did not (P=0.0316). In the matched treatment group, 26% of patients were deceased by the last time of monitoring, whereas this was 41% in the unmatched group (P=0.1257). We therefore confirm the ability of tumor molecular profiling to improve survival of breast cancer patients. Immunohistochemistry biomarkers for the androgen, estrogen and progesterone receptors were found to be prognostic for survival.
Carter P, Alifrangis C, Cereser B, et al., 2018, Correction: Assessing tumor molecular profiling to guide treatments for patients with advanced female genital tract malignancy, Oncotarget, Vol: 9, Pages: 15164-15164, ISSN: 1949-2553
Correction to article DOI: https://dx.doi.org/10.18632/oncotarget.23675
Carter P, Alifrangis C, Chandrasinghe P, et al., 2018, Correction: The benefit of tumor molecular profiling on predicting treatments for colorectal adenocarcinomas, Oncotarget, Vol: 9, Pages: 15165-15165, ISSN: 1949-2553
Corrections for article DOI: https://dx.doi.org/10.18632/oncotarget.24257.].
Carter P, Alifrangis C, Cereser B, et al., 2018, Correction: Does molecular profiling of tumors using the Caris molecular intelligence platform improve outcomes for cancer patients?, Oncotarget, Vol: 9, Pages: 15166-15166, ISSN: 1949-2553
Corrections for article DOI: 10.18632/oncotarget.24258
Alifrangis C, Carter P, Cereser B, et al., 2018, Investigating the benefits of molecular profiling of advanced non-small cell lung cancer tumors to guide treatments., Oncotarget, Vol: 9, Pages: 12805-12811, ISSN: 1949-2553
In this study we utilized data on patient responses to guided treatments, and we evaluated their benefit for a non-small cell lung cancer cohort. The recommended therapies used were predicted using tumor molecular profiles that involved a range of biomarkers but primarily used immunohistochemistry markers. A dataset describing 91 lung non-small cell lung cancer patients was retrospectively split into two. The first group's drugs were consistent with a treatment plan whereby all drugs received agreed with their tumor's molecular profile. The second group each received one or more drug that was expected to lack benefit. We found that there was no significant difference in overall survival or mortality between the two groups. Patients whose treatments were predicted to be of benefit survived for an average of 402 days, compared to 382 days for those that did not (P = 0.7934). In the matched treatment group, 48% of patients were deceased by the time monitoring had finished compared to 53% in the unmatched group (P = 0.6094). The immunohistochemistry biomarker for the ERCC1 receptor was found to be a marker that could be used to predict future survival; ERCC1 loss was found to be predictive of poor survival.
Carter P, Alifrangis CC, Cereser B, et al., 2018, Does molecular profiling of tumors using the Caris molecular intelligence platform improve outcomes for cancer patients?, Oncotarget, Vol: 9, Pages: 9456-9467, ISSN: 1949-2553
We evaluated the effect of tailoring treatments based on predictions informed by tumor molecular profiles across a range of cancers, using data from Caris Life Sciences. These included breast carcinoma, colorectal adenocarcinoma, female genital tract malignancy, lung non-small cell lung cancer, neuroendocrine tumors, ovarian surface epithelial carcinomas, and urinary tract cancers.Molecular profiles using mostly immunohistochemistry (IHC) and DNA sequencing for tumors from 841 patients had been previously used to recommend treatments; some physicians followed the suggestions completely while some did not. This information was assessed to find out if the outcome was better for the patients where their received drugs matched recommendations.The IHC biomarker for the progesterone receptor and for the androgen receptor were found to be most prognostic for survival overall. The IHC biomarkers for P-glycoprotein (PGP), tyrosine-protein kinase Met (cMET) and the DNA excision repair protein ERCC1 were also shown to be significant predictors of outcome. Patients whose treatments matched those predicted to be of benefit survived for an average of 512 days, compared to 468 days for those that did not (P = 0.0684). In the matched treatment group, 34% of patients were deceased at the completion of monitoring, whereas this was 47% in the unmatched group (P = 0.0001).
Carter P, Alifrangis CC, Chandrasinghe P, et al., 2018, The benefit of tumor molecular profiling on predicting treatments for colorectal adenocarcinomas, Oncotarget, Vol: 9, Pages: 11371-11376, ISSN: 1949-2553
We evaluated the benefit of tailoring treatments for a colorectal adenocarcinoma cancer cohort according to tumor molecular profiles, by analyzing data collected on patient responses to treatments that were guided by a tumor profiling technology from Caris Life Sciences. DNA sequencing and immunohistochemistry were the main tests that predictions were based upon, but also fragment analysis, and in situ hybridization. The status of the IHC biomarker for the thymidylate synthase receptor was a good indicator for future survival. Data collected for the clinical treatments of 95 colorectal adenocarcinoma patients was retrospectively divided into two groups: the first group was given drugs that always matched recommended treatments as suggested by the tumor molecular profiling service; the second group received at least one drug after profiling that was predicted to lack benefit. In the matched treatment group, 19% of patients were deceased at the end of monitoring compared to 49% in the unmatched group, indicating a benefit in mortality by tumor molecular profiling colorectal adenocarcinoma patients.
Carter P, Alifrangis C, Cereser B, et al., 2017, Assessing tumor molecular profiling to guide treatments for patients with advanced female genital tract malignancy, Oncotarget, Vol: 9, Pages: 6007-6014, ISSN: 1949-2553
Tumor molecular profiling has enabled selection of targeted therapies in a host of solid tumors. Here we used a retrospective clinical cohort, to evaluate the benefit of tailoring treatments for female genital tract malignancy, using tumor molecular profiles. Clinical outcome data for 112 patients was retrospectively separated into two groups. These either followed a matched treatment plan that incorporated at least one drug recommended according to their tumor profile and none that were expected to have no benefit (64 patients), or was unmatched with suggested treatments and received at least one drug that was anticipated to lack benefit for that tumor (48 patients).In the group of patients whose drugs matched those recommended by molecular profiling of their tumor, their overall survival was 593 days on average, compared to 449 days for patients that did not; removing drugs predicted to have no benefit from treatment regimens received after profiling increased survival by 144 days on average (P = 0.0265). In the matched treatment group, 30% of patients had died by the last time of monitoring, whereas this was 40% in the unmatched group (P = 0.2778). The IHC biomarker for the progesterone receptor was demonstrated to be prognostic for survival.
Cereser B, Jansen M, Austin E, et al., 2017, Analysis of clonal expansions through the normal and premalignant human breast epithelium reveals the presence of luminal stem cells., Journal of Pathology, Vol: 244, Pages: 61-70, ISSN: 0022-3417
It is widely accepted that the cell of origin of breast cancer is the adult mammary epithelial stem cell, however demonstrating the presence and location of tissue stem cells in the human breast has proved difficult. Furthermore, we do not know the clonal architecture of the normal and premalignant mammary epithelium or its cellular hierarchy. Here we use deficiency in the mitochondrial enzyme cytochrome c oxidase (CCO), typically caused by somatic mutations in the mitochondrial genome, as a means to perform lineage tracing in the human mammary epithelium. PCR sequencing of laser-capture microdissected cells in combination with immunohistochemistry for markers of lineage differentiation was performed to determine the clonal nature of the mammary epithelium. We have shown that in the normal human breast, clonal expansions (defined here by areas of CCO-deficiency) are typically uncommon and of limited size, but can occur at any site within the adult mammary epithelium. The presence of a stem cell population was shown by demonstrating multilineage differentiation within CCO-deficient areas. Interestingly, we observed infrequent CCO-deficiency that was restricted to luminal cells, suggesting that niche succession and by inference stem cell location, is located within the luminal layer. CCO-deficient areas appeared large within areas of ductal carcinoma in situ, suggesting that the rate of clonal expansion was altered in the premalignant lesion.
Chandrasinghe P, Cereser B, Moorghen M, et al., 2017, Role of SMAD proteins in colitis-associated cancer: from known to the unknown., Oncogene, Vol: 37, Pages: 1-7, ISSN: 0950-9232
Small mothers against decapentaplegic (SMAD) proteins are a family of signal transduction molecules in transforming growth factor β (TGFβ) ligand pathways that have been found to have a key role in the pathogenesis of inflammatory bowel disease (IBD). Long standing IBD predisposes individuals to colitis-associated colorectal cancer (CAC), an entity that possess unique characteristics compared to hereditary and sporadic cancer. The ligands of the TGFβ super family along with SMADs have also been implicated in several aspects of colorectal cancer formation. SMAD proteins are shown to be involved in a number of potentially carcinogenic mechanisms such as altering gene transcription, controlling stem cell differentiation to causing epigenetic changes. Modulation of these proteins has emerged as a novel therapeutic intervention for IBD although its effect on carcinogenesis remains elusive. This account reviews available evidence linking SMAD proteins to CAC and explores the potential areas for future research in this area.Oncogene advance online publication, 4 September 2017; doi:10.1038/onc.2017.300.
Lavery DL, Martinez P, Gay LJ, et al., 2015, Evolution of oesophageal adenocarcinoma from metaplastic columnar epithelium without goblet cells in Barrett's oesophagus, Gut, Vol: 65, Pages: 907-913, ISSN: 1468-3288
OBJECTIVE: Barrett's oesophagus commonly presents as a patchwork of columnar metaplasia with and without goblet cells in the distal oesophagus. The presence of metaplastic columnar epithelium with goblet cells on oesophageal biopsy is a marker of cancer progression risk, but it is unclear whether clonal expansion and progression in Barrett's oesophagus is exclusive to columnar epithelium with goblet cells. DESIGN: We developed a novel method to trace the clonal ancestry of an oesophageal adenocarcinoma across an entire Barrett's segment. Clonal expansions in Barrett's mucosa were identified using cytochrome c oxidase enzyme histochemistry. Somatic mutations were identified through mitochondrial DNA sequencing and single gland whole exome sequencing. RESULTS: By tracing the clonal origin of an oesophageal adenocarcinoma across an entire Barrett's segment through a combination of histopathological spatial mapping and clonal ordering, we find that this cancer developed from a premalignant clonal expansion in non-dysplastic ('cardia-type') columnar metaplasia without goblet cells. CONCLUSION: Our data demonstrate the premalignant potential of metaplastic columnar epithelium without goblet cells in the context of Barrett's oesophagus.
Alison M, Cereser B, Kocher H, et al., 2015, Clonal analysis of the human liver reveals adaptable stem cell dynamics, 66th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD), Publisher: WILEY-BLACKWELL, Pages: 260A-260A, ISSN: 0270-9139
Wong P-P, Demircioglu F, Ghazaly E, et al., 2015, Dual-Action Combination Therapy Enhances Angiogenesis while Reducing Tumor Growth and Spread, CANCER CELL, Vol: 27, Pages: 123-137, ISSN: 1535-6108
- Author Web Link
- Cite
- Citations: 152
Wong P-P, Demircioglu F, Ghazaly E, et al., 2015, NOVEL DUAL-ACTION COMBINATION THERAPY ENHANCES ANGIOGENESIS WHILST REDUCING TUMOR GROWTH AND SPREAD, Joint Meeting of the European-Society-for-Microcirculation (ESM) and European-Vascular-Biology-Organisation (EVBO), Publisher: KARGER, Pages: 6-6, ISSN: 1018-1172
Baker AM, Cereser B, Melton S, et al., 2014, Quantification of Crypt and Stem Cell Evolution in the Normal and Neoplastic Human Colon, Cell Reports, Vol: 8, Pages: 940-947, ISSN: 2211-1247
Human intestinal stem cell and crypt dynamics remain poorly characterized because transgenic lineage-tracing methods are impractical in humans. Here, we have circumvented this problem by quantitatively using somatic mtDNA mutations to trace clonal lineages. By analyzing clonal imprints on the walls of colonic crypts, we show that human intestinal stem cells conform to one-dimensional neutral drift dynamics with a "functional" stem cell number of five to six in both normal patients and individuals with familial adenomatous polyposis (germline APC(-/+)). Furthermore, we show that, in adenomatous crypts (APC(-/-)), there is a proportionate increase in both functional stem cell number and the loss/replacement rate. Finally, by analyzing fields of mtDNA mutant crypts, we show that a normal colon crypt divides around once every 30-40 years, and the division rate is increased in adenomas by at least an order of magnitude. These data provide in vivo quantification of human intestinal stem cell and crypt dynamics.
Jansen M, Baker A-M, Cereser B, et al., 2014, Clonal evolution of stem cells and crypts in normal, preneoplastic and neoplastic colon, Publisher: SPRINGER, Pages: S237-S237, ISSN: 0945-6317
Jawad N, Crook J, Baker A-M, et al., 2014, DETERMINING STEM CELL AND CRYPT DYNAMICS IN INFLAMMATORY BOWEL DISEASE, Annual Meeting of the British-Society-of-Gastroenterology (BSG), Publisher: BMJ PUBLISHING GROUP, Pages: A161-A162, ISSN: 0017-5749
Humphries A, Cereser B, Gay LJ, et al., 2013, Lineage tracing reveals multipotent stem cells maintain human adenomas and the pattern of clonal expansion in tumor evolution, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: E2490-E2499, ISSN: 0027-8424
- Author Web Link
- Cite
- Citations: 73
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.