Faulty genes to tame pancreatic cancer
doi:10.1038/nindia.2012.30 Published online 29 February 2012
The runaway growth of pancreatic cancer has puzzled scientists for long. Now, a joint research team from US, India and Spain has homed in on new genetic mutations that may be linked to pancreatic cancer. This may open up new therapeutic avenues to treat the lethal disease.
The researchers have identified genetic aberrations — deletions, mutations, and rearrangements — in sub-units of a multi-protein tumour suppressive complex. The aberrations were found to happen in genes that encode sub-units of the chromatin remodeling complex — SWItch/Sucrose NonFermentable (SWI/SNF) — in pancreatic cancer cells isolated from patients.
"Findings from this study define SWI/SNF to be a major tumor suppressor in pancreatic cancer, and provide a new foothold to study this deadly disease," says lead researcher Jonathan R. Pollack.
Pancreatic ductal adenocarcinoma, commonly known as pancreatic cancer, remains a leading cause of cancer deaths across the globe. Though the roles of several faulty genes and defective cell cycle regulator proteins have been found in pancreatic cancer, a clear picture of molecular alterations underlying the cancer is still elusive.
The researchers isolated tumours from 70 pancreatic cancer patients and grew them in mice with weak immune system. They also analysed 22 pancreatic cancer cell lines.
Using high-resolution genomic profiling, they looked specifically at deletion and genetic mutations in five sub-units of SWI/SNF complex — ARID1A, ARID1B, PBRM1, SMARCA2 and SMARCA4 — in all the pancreatic cancer cells. SWI/SNF complex with its suite of DNA-binding sub-units were found to function in diverse processes, including development and differentiation, and in control of the cell cycle.
The study found that the gene that codes for ARID1B sub-unit was completely deleted in 2 of 70 cancer samples isolated from patients. All the genes in our body have duplicate copies. For ARID1B gene, a single copy of the gene was found deleted in 74% of the rest of the samples. The study also identified two deleterious mutations in the gene that codes for ARID1A sub-unit on chromosome one.
Located on chromosome 3, the gene coding for PBRM1 sub-unit was found to be frequently deleted in the cancer samples. From sequencing studies, the gene coding for SMARCA4 sub-unit was also found mutated in 4 of 35 pancreatic cancer samples.
In several pancreatic cancer cell lines, deficiency of a single SWI/SNF sub-unit was identified, which occurred due to an underlying genomic alteration (deletion, rearrangement or mutation). One cell line was deficient in two SWI/SNF sub-units. Reduced expression of one or more sub-units was also apparent in several cell lines.
The finding of multiple deletions, rearrangements, and inactivating mutations in the sub-units of the SWI/SNF complex strongly implies a tumor-suppressive role. The results of this research are significant as it corroborates other studies which have reported ARID1A to be mutated in about half of ovarian clear cell cancer and PBRM1 in about 40% of renal clear cell cancer.
"Analysis of genes regulated by the ARID1B sub-unit would yield important targets for pancreatic cancer therapy," says co-researcher Murali D. Bashyam.
The tumour suppressive complex is akin to p53, another tumour suppressor protein, says Prantar Chakrabarti, who studies blood cancer at the Institute of Haematology and Transfusion Medicine of Medical College, Kolkata. Besides the promise of early identification, the study raises hope for novel therapies aimed at modulating gene expression by small molecules thereby eradicating pancreatic cancers, Chakrabarti points out.
The authors of this work are from: Department of Pathology, Stanford University, Stanford, and Departments of Pathology and Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, US, Laboratory of Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad, India and Clinical Research Program, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.