TITLE

Whole genome sequencing reveals potential targets for therapy in patients with refractory KRAS mutated metastatic colorectal cancer

AUTHOR(S)
Shanmugam, Vijayalakshmi; Ramanathan, Ramesh K.; Lavender, Nicole A.; Sinari, Shripad; Chadha, Manpreet; Liang, Winnie S.; Kurdoglu, Ahmet; Izatt, Tyler; Christoforides, Alexis; Benson, Hollie; Phillips, Lori; Baker, Angela; Murray, Christopher; Hostetter, Galen; Von Hoff, Daniel D.; Craig, David W.; Carpten, John D.
PUB. DATE
July 2014
SOURCE
BMC Medical Genomics;2014, Vol. 7 Issue 1, p3
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background The outcome of patients with metastatic colorectal carcinoma (mCRC) following first line therapy is poor, with median survival of less than one year. The purpose of this study was to identify candidate therapeutically targetable somatic events in mCRC patient samples by whole genome sequencing (WGS), so as to obtain targeted treatment strategies for individual patients. Methods Four patients were recruited, all of whom had received > 2 prior therapy regimens. Percutaneous needle biopsies of metastases were performed with whole blood collection for the extraction of constitutional DNA. One tumor was not included in this study as the quality of tumor tissue was not sufficient for further analysis. WGS was performed using Illumina paired end chemistry on HiSeq2000 sequencing systems, which yielded coverage of greater than 30X for all samples. NGS data were processed and analyzed to detect somatic genomic alterations including point mutations, indels, copy number alterations, translocations and rearrangements. Results All 3 tumor samples had KRAS mutations, while 2 tumors contained mutations in the APC gene and the PIK3CA gene. Although we did not identify a TCF7L2-VTI1A translocation, we did detect a TCF7L2 mutation in one tumor. Among the other interesting mutated genes was INPPL1, an important gene involved in PI3 kinase signaling. Functional studies demonstrated that inhibition of INPPL1 reduced growth of CRC cells, suggesting that INPPL1 may promote growth in CRC. Conclusions Our study further supports potential molecularly defined therapeutic contexts that might provide insights into treatment strategies for refractory mCRC. New insights into the role of INPPL1 in colon tumor cell growth have also been identified. Continued development of appropriate targeted agents towards specific events may be warranted to help improve outcomes in CRC.
ACCESSION #
97048929

 

Related Articles

  • Genetic Instability Influences Drug Response in Cancer Cells. Damia, G.; D'Incalci, M. // Current Drug Targets;Oct2010, Vol. 11 Issue 10, p1317 

    No abstract available.

  • DNA Sequence Profiles of the Colorectal Cancer Critical Gene Set KRAS-BRAF-PIK3CA-PTEN-TP53 Related to Age at Disease Onset. Berg, Marianne; Danielsen, Stine A.; Ahlquist, Terje; Merok, Marianne A.; Ågesen, Trude H.; Vatn, Morten H.; Mala, Tom; Sjo, Ole H.; Bakka, Arne; Moberg, Ingvild; Fetveit, Torunn; Mathisen, Øystein; Husby, Anders; Sandvik, Oddvar; Nesbakken, Arild; Thiis-Evensen, Espen; Lothe, Ragnhild A. // PLoS ONE;2010, Vol. 5 Issue 11, p1 

    The incidence of colorectal cancer (CRC) increases with age and early onset indicates an increased likelihood for genetic predisposition for this disease. The somatic genetics of tumor development in relation to patient age remains mostly unknown. We have examined the mutation status of five...

  • Genomic Instability.  // Encyclopedic Reference of Cancer;2001, p362 

    A definition of the term "genomic instability" is presented. The term refers to the failure of tumor cells to maintain genomic integrity. Genomic instability results from mutations or alterations in genes involved in DNA repair, such as DNA sequence mismatch repair, or in maintaining chromosome...

  • In vitro stability of APC gene sequences and the influence of DNA repair status. Turnbull, Charlotte L.; Bacon, Andrea L.; Dunlop, Malcolm G.; Farrington, Susan M. // Mutagenesis;Mar2012, Vol. 27 Issue 2, p233 

    APC is a key ‘gatekeeper’ gene in colorectal tumorigenesis. The high frequency of APC defects observed in colorectal cancer tissue is the result of selective growth advantage of cells with loss-of-function mutations at that locus. However, mutations may also arise due to inherent...

  • The prognostic and therapeutic values of long noncoding RNA PANDAR in colorectal cancer. Rivandi, Mahdi; Pasdar, Alireza; Hamzezadeh, Leila; Tajbakhsh, Amir; Seifi, Sima; Moetamani‐Ahmadi, Mehrdad; Ferns, Gordon A.; Avan, Amir // Journal of Cellular Physiology;Feb2019, Vol. 234 Issue 2, p1230 

    Long noncoding RNAs (lncRNAs) consist of 200 nucleotide sequences that play essential roles in different processes, including cell proliferation, and differentiation. There is evidence showing that the dysregulation of lncRNAs promoter of CDKN1A antisense DNA damage‐activated RNA (PANDAR)...

  • P-0271DETECTION OF DNA STOOL MUTATIONS IN COLORECTAL CANCER PATIENTS. De Lima, Jacqueline; Saad, Sidney; Murray, Helena; Forones, Nora // Annals of Oncology;Jun2013, Vol. 24 Issue suppl_4, piv112 

    No abstract available.

  • KRAS mutations in tumor tissue and plasma by different assays predict survival of patients with metastatic colorectal cancer. Jian-Ming Xu; Xiao-Jing Liu; Fei-Jiao Ge; Li Lin; Yan Wang; Sharma, Manish R.; Ze-Yuan Liu; Tommasi, Stefania; Paradiso, Angelo // Journal of Experimental & Clinical Cancer Research (17569966);2014, Vol. 33 Issue 1, p51 

    Background The optimal laboratory assay for detecting KRAS mutations in different biospecimens from patients with metastatic colorectal cancer (mCRC), and the clinical relevance of these gene alterations is still in question. We analyzed the prognostic--predictive relevance of KRAS status,...

  • KRAS mutational status analysis of peripheral blood isolated circulating tumor cells in metastatic colorectal patients. GUTIÉRREZ, CRISTINA; RODRIGUEZ, JAVIER; PATIÑO-GARCÍA, ANA; GARCÍA-FONCILLAS, JESÚS; SALGADO, JOSEFA // Oncology Letters;2013, Vol. 6 Issue 5, p1343 

    The present study describes an optimized method for isolating peripheral blood circulating tumor cells (CTCs) and performing KRAS mutation analysis. The approach combines isolation of peripheral blood mononuclear cells and immunomagnetic labeling with CD45 and CD326 human microbeads with KRAS...

  • Médecine génomique et oncologie. Michielin, Olivier; Coukos, George // Praxis (16618157);5/7/2014, Vol. 103 Issue 10, p591 

    Progress in genomics with, in particular, high throughput next generation sequencing is revolutionizing oncology. The impact of these techniques is seen on the one hand the identification of germline mutations that predispose to a given type of cancer, allowing for a personalized care of...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics