Validation of CIP2A as a Biomarker of Subsequent Disease Progression and Treatment Failure in Chronic Myeloid Leukaemia
AuthorsClark, Richard E.; email: email@example.com
Basabrain, Ammar A.; email: firstname.lastname@example.org
Austin, Gemma M.; email: email@example.com
Holcroft, Alison K.; email: firstname.lastname@example.org
Loaiza, Sandra; email: email@example.com
Apperley, Jane F.; email: firstname.lastname@example.org
Law, Christopher; email: K.C.Law@liverpool.ac.uk
Scott, Laura; email: email@example.com
Parry, Alexandra D.; email: firstname.lastname@example.org
Bonnett, Laura; orcid: 0000-0002-6981-9212; email: L.J.Bonnett@liverpool.ac.uk
Lucas, Claire M.; email: email@example.com
MetadataShow full item record
AbstractBackground: It would be clinically useful to prospectively identify the risk of disease progression in chronic myeloid leukaemia (CML). Overexpression of cancerous inhibitor of protein phosphatase 2A (PP2A) (CIP2A) protein is an adverse prognostic indicator in many cancers. Methods: We examined CIP2A protein levels in diagnostic samples from the SPIRIT2 trial in 172 unselected patients, of whom 90 received imatinib and 82 dasatinib as first-line treatment. Results: High CIP2A levels correlated with inferior progression-free survival (p = 0.04) and with worse freedom from progression (p = 0.03), and these effects were confined to dasatinib recipients. High CIP2A levels were associated with a six-fold higher five-year treatment failure rate than low CIP2A levels (41% vs. 7.5%; p = 0.0002), in both imatinib (45% vs. 11%; p = 0.02) and dasatinib recipients (36% vs. 4%; p = 0.007). Imatinib recipients with low CIP2A levels had a greater risk of treatment failure (p = 0.0008). CIP2A levels were independent of Sokal, Hasford, EUTOS (EUropean Treatment and Outcome Study), or EUTOS long-term survival scores (ELTS) or the presence of major route cytogenetic abnormalities. No association was seen between CIP2A levels and time to molecular response or the levels of the CIP2A-related proteins PP2A, SET, SET binding protein 1 (SETBP1), or AKT. Conclusions: These data confirm that high diagnostic CIP2A levels correlate with subsequent disease progression and treatment failure. CIP2A is a simple diagnostic biomarker that may be useful in planning treatment strategies.
CitationCancers, volume 13, issue 9, page e2155
DescriptionFrom MDPI via Jisc Publications Router
History: accepted 2021-04-01, pub-electronic 2021-04-29
Publication status: Published
Funder: Bristol-Myers Squibb; Grant(s): CA180 659
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Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?Park, JooYong; email: firstname.lastname@example.org; Choi, Ji-Yeob; email: email@example.com; Choi, Jaesung; email: firstname.lastname@example.org; Chung, Seokang; email: email@example.com; Song, Nan; orcid: 0000-0002-9182-1060; email: firstname.lastname@example.org; Park, Sue K.; orcid: 0000-0001-5002-9707; email: email@example.com; Han, Wonshik; email: firstname.lastname@example.org; Noh, Dong-Young; email: email@example.com; Ahn, Sei-Hyun; email: firstname.lastname@example.org; Lee, Jong Won; email: email@example.com; et al. (MDPI, 2021-05-14)In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.
No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database StudyDominguez-Valentin, Mev; orcid: 0000-0001-7856-0057; email: Mev.Dominguez.Valentin@rr-research.no; Plazzer, John-Paul; orcid: 0000-0001-5114-4301; email: firstname.lastname@example.org; Sampson, Julian R.; email: Sampson@cardiff.ac.uk; Engel, Christoph; orcid: 0000-0002-7247-282X; email: email@example.com; Aretz, Stefan; orcid: 0000-0002-5228-1890; email: firstname.lastname@example.org; Jenkins, Mark A.; email: email@example.com; Sunde, Lone; email: firstname.lastname@example.org; Bernstein, Inge; email: email@example.com; Capella, Gabriel; orcid: 0000-0002-4669-7320; email: firstname.lastname@example.org; Balaguer, Francesc; orcid: 0000-0002-0206-0539; email: email@example.com; et al. (MDPI, 2021-06-28)Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.
A case study of Liverpool City Council's Speke One Stop Shop and South Liverpool Housing partnership arrangement: Is it successful from an employee's viewpoint?Yates, Shelia (University of ChesterLiverpool City Council, 2005-05)In 1999 a new Chief Executive was appointed to Liverpool City Council (LCC). The nine original directorates were stream lined into the five current portfolio areas. LCC has dramatically changed and improved the way it delivers its services to the customer, which has been developed through the introduction of the Customer Contact Strategy (CCS) Through the CCS there are a number of contact channels, which give a first point of contact choice of access to a citizen. A key component of the strategy is the development of a network of fourteen One-Stop Shops (OSS's) across the city. There are currently ten in operation. The Shops provide face-to-face contact for customers for council and partner services. This study focuses its attention on the partnership arrangement between the Speke OSS and South Liverpool Housing (SLH), who are a registered social landlord (RSL). Staff based in the Speke OSS share the same building and counter facility with staff from SLH. Both organisations are located in the Parklands Building, which is a Public Finance Initiative (PFI). This is a unique partnership in England and Wales and the first of its kind in delivering "joined up" services. From the findings of the initial research, the author proposes and introduces a model named the "CHANGED" model. A contrasting merger between Chester College and Warrington Collegiate Institute is examined as a case study in appendix 7. In order to further test the validity of the aforementioned model, the author has carried out further research with a focus group of LCC 2nd year MBA students. The findings of which are described in Chapter Five. Adopting both qualitative and quantitative research methods, this research aims to treat the partnership arrangement as a "case study" to establish the success of the partnership: where success is taken to mean a process beneficial to staff in meeting organisational goals. The research aims and questions that are to be explored in this study are: 1. How has the partnership arrangement managed to enable staff to provide a seamless service in dealing with customers? 2. What evidence is there to suggest that a single culture has developed between staff from both organizations? The study illustrates the investigation and analysis of data, tests the data against established theory, discusses the findings and uses the results as a basis to identify possible recommendations. These recommendations could be incorporated into the development of a tool kit (CHANGED model) or similar model, which may be adopted in the success of future partnership arrangements which LCC may choose to embark upon.