Identification of Non-canonical (India-specific) Genetic Alterations in Colorectal Cancer Using Next Generation Sequencing

Conference talk by Dr. Murali Bashyam

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Dr. Murali Dharan Bashyam, Head, Lab of molecular oncology

Talk Abstract: Colorectal Cancer (CRC) is a lifestyle associated disease and a major health problem in the Caucasian population, where it is primarily aging-related cancer with tumors predominantly arising from the colon rather than the rectum. In addition, aberrant constitutive activation of the Wnt signaling cascade causing chromosomal instability (CIN) and mismatch repair (MMR) inactivation leading to microsatellite instability are major drivers of CRC in the West.India has seen a recent rapid rise in CRC incidence during the past 2-3 decades probably owing to rapid urbanization. In contrast to the West, however, CRC in India often occurs in younger individuals with tumors localized to the rectum rather than the colon. Thus, early-onset rectal cancer (EORC) is the predominant but poorly understood CRC subtype in India. We performed a comprehensive evaluation of more than one thousand sporadic CRC samples from Indian patients that revealed distinct clinicopathological and biological features. More importantly, a significant proportion of EORC tumors appeared to be devoid of activated Wnt signaling and MMR inactivation. Genome-wide DNA copy number profiling revealed extensive CIN in both Wnt+ and Wnt- tumors. Transcriptome profiling (using microarrays as well as next-generation sequencing) revealed a (non-Wnt) gene signature surprisingly harboring genes related to the Ca2+/NFAT pathway enriched specifically in Wnt- EORC. Separately, we performed mutation profiling (using next-generation exome sequencing) of Wnt- EORC samples revealing known (APC, KRAS, P53, PIK3CA) and novel frequently mutated genes. Surprisingly, we identified APC mutations in the absence of Wnt activation indicating a possible non-canonical role for APC in CRC. Our study has, therefore, revealed several unique genetic aberrations distinct from the West that drive CRC in India.

 

Dr. Murali Dharan Bashyam is Head, Lab of molecular oncology CDFD, Hyderabad

Meet Dr. Bashyam on November 1, 2017, in Mumbai, India at Emerging Role of Next Generation Sequencing in Clinical Genomics.

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Targeted NGS of Solid Tumors via Liquid Biopsy Providing an Accurate Snapshot of Cancer

Conference talk by Dr. Urvashi

URVASHI bHADUR
Dr. Urvashi Bahadur, Vice President-Clinical Diagnostics, Strand Life Sciences

Talk Abstract: The latest technique to identify and monitor the genetic signature of different types of Cancer, that the medical fraternity is warming up to is a Liquid Biopsy test. Essentially, these tests are a set of new blood tests that enable scientists to extract and analyze DNA shed by cancer cells in a patient’s blood. The presence or absence and the concentration of characteristic mutations in the liquid biopsy provide an accurate snapshot of cancer.  A unique feature of these tests is that these are not ‘one size fits all’ kind of tests. Liquid biopsy tests are personalized tests that are modified to track cancer in each patient in a specific fashion.Genomic profiling of a tumor derived from a liquid biopsy can provide valuable insight into its biology. Next Generation Sequencing (NGS) can simultaneously profile tumors for multiple, therapeutically relevant mutations with far greater sensitivity than other conventional sequencing methods. Results of such testing clubbed together can also suggest a good treatment plan and novel therapeutic approaches indicating the response to a drug approved for other tumor types or drugs in trials.  The liquid biopsy allows for profiling via detection of traces of tumor DNA in the blood of an individual and  is fruitful in investigating new changes in a tumor, such as the development of acquired resistance or recurrence, it provides insights to assess if a patient is prone to a relapse and if a person is likely to respond to therapy or not.

These topics will be discussed in detail in the presentation.

Dr. Urvashi Bahadur is Vice President-Clinical Diagnostics, Strand Life Sciences Meet Dr. Urvashi Bahadur on November 1, 2017, in Mumbai, India at Emerging Role of Next Generation Sequencing in Clinical Genomics.

 

NGS for Inherited Retinal Disorders-Poised to become a Clinical Reality

Conference Talk by Dr. Chakrabarti

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Dr. Subhabrata Chakrabarti, Associate Director-Research, LVPEI

Talk Abstract: Recent advances in genome analyses have resulted in a plethora of information on gene functions in single-gene disorders, but our knowledge on multi-gene involvement in disease manifestation is limited. The rapid advancement of technologies in understanding the genome have further facilitated in providing insights into the underlying molecular mechanisms leading to disease pathogenesis. There are several ocular diseases that manifest simple to complex etiologies and affects humans of all ages. The development of next-generation sequencing (NGS) technology has facilitated novel gene discoveries, a better appreciation of gene-gene interactions that have led to the identification of modifier genes. Using the scenario of Mendelian and complex eye diseases, I shall demonstrate the advances that we have made in this field pertaining to the understanding of the molecular etiology in facilitating better disease management. I will also provide some novel molecular mechanisms in glaucoma (a leading cause of irreversible blindness) that we have discovered using NGS techniques in an attempt towards translational research from bench to bedside to community.

Dr. Chakrabarti is Associate Director-Research at LVPEI, Hyderabad. Meet Dr. Chakrabarti on November 1, 2017, in Mumbai, India at Emerging Role of Next Generation Sequencing in Clinical Genomics.

Ethnicity and Breast Cancer Risk: The Indian Saga & Role of NGS

Conference Talk by Dr. Ahmad

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Dr. Firoz Ahmad 
Research Scientist & Senior Manager-R&D,SRL Diagnostics

Talk Abstract: Carcinoma of the breast is one of the most prevalent cancers in Indian females, and the incidence of breast cancer has been increasing manifolds in India and so the burden of breast cancer on the Indian healthcare system has been steadily on rising also emphasizing the need for a cost-effective method for early detection of these cancers.

Unfortunately, it has been established that Indian patients develop breast cancer at a younger age than their Caucasian counterparts, the contributions of BRCA1 and BRCA2 (BRCA1/2) mutations in Indians are expected to be different than in Caucasians. Although identification of BRCA1 and BRCA2 has greatly increased our understanding of breast cancer genetics in populations of Western European descent, reports about the role of these genes in Indian patients are still very limited. In the current report results found by using next-generation sequencing (NGS) tools, the prevalence and distribution pattern of BRCA1/2 gene mutations in Indian patients will be discussed, this presentation also aims to present the current status of knowledge about the spectrum of BRCA pathogenic variants in Indian populations.The study highlights how Next-generation sequencing (NGS) based testing increases the sensitivity of mutation detection, and help in identifying patients at high risk of developing cancer. New advances in genomic technologies, such as next-generation sequencing (NGS), allow the sequencing and analysis of genes associated with a disease/cancer efficiently at a significantly lower cost as compared with the traditional methods.

Studies such as these will provide physicians and researchers much-needed evidence on the clinical utility of NGS for incorporation into routine genetic testing in clinical oncology practice and thrust the clinical research.

Meet Dr. Firoz Ahmad at Emerging Role of Next Generation Sequencing in Clinical Genomics in Mumbai on November 01, 2017.

 

Histone Acetyltransferase Inhibitors, From Screening to Optimization – A Tricky Track

Conference Talk by Dr Baell

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Jonathan Baell Professor of Medicinal Chemistry (MIPS), Monash University Australia

Talk Abstract: There is currently great interest in compounds that modulate epigenetics. With respect to some epigenetic targets, such as histone decacetylases (HDACs), many inhibitors have been successfully developed and are in clinical trials for a variety of indications. Similarly, bromodomains have been shown, somewhat unexpectedly by some, to be highly druggable. However, there is an elephant in the room, and that is the histone acetyltransferase (HAT) family, which is large but essentially “undrugged” and barely has any compounds that could be considered to be useful tools. Why is it so hard to find good tool compounds for these enzymes?

Not so long ago we undertook HTS against a MYST HAT and eventually discovered a genuine hit that we have recently just optimized to nanomolar levels of inhibition. However, we encountered many problems en route. In this talk we will discuss such issues and how these could help explain why there are so few, if any, useful tool compounds for these enzymes.

Grab the chance to get in touch with Dr Jonathan Baell, from Monash University, Australia at SELECTBIO MedChem 2017” meeting on 14- 15 September, 2017 at Hotel Le Meridien, Bengaluru.

Freezing Essential Enzyme Motion for Catalysis: An Efficient Approach for Shikimate Kinase Inhibition

Conference Talk by Dr. Conception

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Dr Concepción González-Bello,

Talk Abstract: Most of the approaches used in the structure-based design of inhibitors of enzymes are based on docking or virtual screening studies using the available crystal structures in which the enzyme is considered a rigid mold. However, enzymes are “dynamic” systems that are able to adopt diverse conformations during catalysis and this could also be exploited in inhibitor design since the flexibility is essential for catalysis. It seems reasonable that for enzyme inhibitor design, in addition to stabilizing a closed disposition of the active site that prevents the entry of the substrate(s), disabling the closure of the active site for catalysis could also be an interesting alternative strategy. This motion-based approach allows the design of ligands that target additional cavities generated during this motion but have limited (or no) access in the closed conformation.

The possible development of new antibiotics by the selective and effective inhibition of shikimate kinase (SK), which is an essential enzyme in bacteria that does not have any counterpart in human cells, is presented. Competitive reversible inhibitors of the SK enzyme from M. tuberculosis and H. pylori that block the closure of the active site by reducing the flexibility of the LID and SB domains were identified showing to have good in vitro activity.

Interact with Dr Concepción González-Bello, Professor, Universidad de Santiago de Compostela at “MedChem India 2017” meeting to be held on 14 -15 September, 2017 in Bengaluru.

Newer Metabolite and Pathway Identification Approaches to Metabolomics

Conference Talk by Dr. Pal

Dr Debnath
Dr Debnath Pal, Professor, Indian Institute of Science, India

Talk Abstract: Identification of metabolites and inference of differentially regulated metabolic pathways are the key aims of metabolomics research. A common approach to this problem is to compare the experimental spectrum with the database archived metabolite information. However, databases store metabolite information at “standard condition” which are in most cases in variance to the experimental condition data is obtained. Consequently, a considerable fraction of the metabolites remains unidentified and the experimental spectrum unharvested.

Dr. Pal has developed a method based on matching the pattern of spectrum peaks rather than absolute tolerance thresholds, using a combination of geometric hashing and similarity scoring techniques. When applied to 2D NMR metabolomics data, tests with 719 metabolites from the Human Metabolome Database show that 100% of the metabolites can be assigned correctly when accurate data are available. A high success rate is obtained even in the presence of large chemical shift deviations such as 0.5 ppm in 1H and 3 ppm in 13C and missing peaks (up to 50%), compared to nearly no assignments obtained under these conditions with existing methods that employ a direct database search approach. A variation of the approach has been extended to obtain “peaks to pathways” information from NMR spectral data.

Dr. Debnath Pal is noted for his contributions in the area of protein structure, function, interaction and dynamics.

He will be speaking at Metabolomics India 2017 conference on 15 September in Hotel Le Meridien, Bengaluru.