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Genomic Signatures Offer Insights Into Non-Invasive Bladder Cancer

NEW YORK (GenomeWeb) – A genomic study of non-invasive bladder cancer has identified genomic subtypes of the disease, along with pathways that are more frequently altered relative to muscle-invasive forms of the disease.

"Our improved ability to identify these specific molecular features of individual tumors should allow a more personalized approach to therapy and disease management in the future," senior author Margaret Knowles, a molecular oncology researcher at Leeds Institute of Cancer and Pathology, said in a statement.

Knowles and colleagues from the UK and US used low-coverage genome sequencing-based copy number analyses, array comparative genomic hybridization, exome sequencing, and/or expression profiling to characterize tumor and matched normal samples from 140 individuals with non-invasive bladder cancer. From these data, they defined chromosomally stable and unstable genomic subtypes of non-invasive bladder cancer, which appeared to differ in their recurrence-free survival patterns.

As reported in Cancer Cell online today, the team identified recurrent changes affecting genes involved in chromatin modification, which appeared more common in the non-invasive bladder cancers than in muscle-invasive bladder cancers. The analysis also uncovered mutations in the histone demethylase enzyme-coding gene KDM6A that marked more female than male cases.

Roughly three-quarters of the bladder cancer cases diagnosed globally each year involve non-muscle invasive forms of the disease, the team noted. But while survival outcomes are often favorable for non-invasive bladder cancer relative to other tumor types, the disease is prone to recurrence and requires long-term monitoring.

To take a closer look at the disease, the researchers focused on grade 1 or 2 primary bladder cancers at a non-invasive stage known as Ta, using low-coverage genome sequencing and array-CGH approaches to profile CNVs in tumor and matched immortalized lymphoblast samples from 141 individuals with Ta transitional cell carcinomas.

From these data, they identified 78 non-invasive bladder cancers falling in the GS1 genomic subtype, with limited or non-existent copy number changes, and 63 GS2 subtype tumors with frequent copy number shifts and recurrent changes involving chromosome 9 q deletions.

The team went on to assess gene expression patterns in a subset of 79 tumors, including 48 samples from the genomically stable GS1 subtype and 31 GS2 tumors, using Affymetrix expression arrays. Using the Illumina HiSeq 2000 instrument, the group also evaluated exome sequences from two dozen of the tumors, capturing protein-coding sequences with SureSelect exon kits. Targeted sequencing was done on 58 non-invasive bladder cancers.

Consistent with the copy number data, the researchers saw significant gene expression differences between GS1 and GS2 tumors. In particular, they found 363 differentially expressed genes between the genomic subtypes, including 248 chromosome 9 genes and multiple genes from the mTORC1 signaling pathway.

Within the set of 2,851 single nucleotide mutations and the 122 small insertions or deletions detected in 17GS1 and seven GS2 tumors, meanwhile, the team saw alterations related to the APOBEC cytidine deaminase as well as recurrent somatic changes to chromatin modification genes and non-hotspot mutations in cancer-related genes such as PIK3CA.

Chromatin modifier gene mutations were over-represented in the non-invasive bladder cancers, the researchers reported, based on comparisons with 308 muscle-invasive bladder cancers profiled in the past.

KDM6A mutations turned up in some 74 percent of female non-invasive bladder cancer cases and 42 percent of tumors from affected men. That finding was notable since women are far less likely to develop bladder cancer but often fare worse than their male counterparts when facing muscle-invasive forms of the disease.

"[T]hese data provide an improved view of the genomic landscape of [non-invasive bladder cancer] that points to [chromatin modification] as a key oncogenic driver for future therapeutic evaluation and to provide vulnerability as a therapeutic target in tumors with loss of [chromosome] 9q," Knowles and co-authors concluded. "Our results also highlight the potential need for gender stratification in an era of precision oncology."