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Genomics in the Journals Nov 7, 2013

NEW YORK (GenomeWeb News) – A pair of Nature Genetics studies by independent research teams explored the genetic glitches characterizing cancers that affect the biliary tract or bile ducts of the liver.

In the first of the papers, a Johns Hopkins University- and Sidney Kimmel Comprehensive Cancer Center-led team used exome sequencing to profile matched tumor and normal samples from 32 individuals with a form of bile duct cancer known as intrahepatic cholangiocarcinoma.

By sifting through these protein-coding sequences, researchers determined that around half of the cholangiocarcinomas contained alterations affecting chromatin-remodeling genes such as BAP1, ARID1A, and PBRM1 — results that they verified through targeted sequencing on almost three-dozen more intrahepatic cholangiocarcinoma samples.

Mutations in the genes tended to be inactivating, they noted, and typically corresponded with poor survival outcomes, highlighting the potential importance of chromatin modifier gene mutations in the condition.

The group saw alterations at known mutation hotspots in IDH1 and IDH2 genes in nearly one-fifth of the biliary duct tumors. Those alterations also appeared to coincide with relatively poor survival patterns.

On the other hand, mutations in BAP1, ARID1A, IDH1 and IDH2 genes weren't detected in nine gallbladder carcinomas that the study's authors assessed by exome sequencing. Instead, those tumors tended to be marked by TP53 gene mutations.

Meanwhile, researchers from Singapore, Thailand, Romania, and the US did whole-exome sequencing on 15 matched tumor-normal pairs for their own cholangiocarcinoma study.

That team considered samples from more than 200 individuals with cholangiocarcinoma, including those with or without liver fluke infection.

Again, the analysis uncovered an apparent role for the chromatin modifiers BAP1 and ARID1A and for the IDH1 and IDH2 enzyme-coding genes in cholangiocarcinoma.

But at least some of those genes were more apt to be mutated in the liver fluke-free cases, particularly BAP1, IDH1 and IDH2. In contrast, TP53 mutations were more common in liver fluke-associated cholangiocarcinoma cases than in those without.

That team's follow-up experiments indicated that both BAP1 and ARID1A genes may act as tumor suppressors in cholangiocarcinoma, prompting enthusiasm about the possibility of targeting chromatin-related genes in a subset of bile duct cancer cases.

"While further research needs to be done, this may pave the way for identifying which bile-duct cancer patients may benefit from chromatin-modifier drugs," co-corresponding author Bin Tean Teh, a researcher affiliated with the National Cancer Centre Singapore and the Duke-National University of Singapore Graduate Medical School, said in a statement.


A Cell study by researchers from the US and Korea provided a catalogue of microsatellite instability events found in hundreds of endometrial and colorectal cancer genomes characterized as part of the Cancer Genome Atlas effort.

Using computational methods, the group started by sifting through protein-coding sequences from tumor and normal samples representing 147 individuals with colorectal cancer and 130 individuals with endometrial cancer. Of those, 57 tumors had already been flagged as being particularly high in microsatellite instability.

Patterns in the exome sequence data suggested that microsatellite instability tends to turn up at recurrent coding sites that differ from one tumor type to another. And by adding in whole-genome sequence data on seven colon cancers and 10 endometrial cancers, researchers saw that microsatellite instability is more apt to occur in DNA packaged in relatively accessible euchromatin than in it is in tightly packaged heterochromatin.

Likewise, they detected a jump in microsatellite instability events in the introns of genes relative to intergenic sequences stretching between protein-coding genes.

"Our results provide a panoramic view of [microsatellite instability] in cancer genomes," senior author Peter Park, a biomedical informatics researcher affiliated with Harvard Medical School and Brigham and Women's Hospital, and his colleagues wrote, "highlighting their tumor type specificity, impact on gene expression, and the role of chromatin organization."


The University of Michigan's Gonçalo Abecasis and colleagues have come up with a scheme for using off-target reads produced during exome sequencing experiments to help infer local ancestry in admixed individuals — work that they described in the American Journal of Human Genetics.

The group's approach, called "local-ancestry inference for sequenced admixed individuals," or SEQMIX, hinges on the realization that sequences from parts of the genome not targeted for exome sequencing can yield ancestry-related information that's missed by focusing on the coding regions alone.

After validating their method with simulated data, researchers demonstrated that SEQMIX software could also tease apart local European and African ancestry tracts using exome sequence data for 49 African American individuals assessed for the 1000 Genomes Project and more than 2,300 African Americans tested through the National Heart, Lung, and Blood Institute's Exome Sequencing Project.

For 79 African American participants in the NHLBI ESP, the ancestry information obtained by SEQMIX also compared favorably with results obtained using available array-based genotyping information for the same individuals.

Based on their findings so far, the study's authors expressed enthusiasm about the prospect of applying their computational method to data from admixed individuals assessed by exome sequencing or other targeted sequencing strategies.

"In African Americans, ancestry blocks as short as [three megabases] can be correctly identified with 0.1-0.5X off-target coverage," they noted. "When admixture is more ancient … the ancestral blocks are much smaller and higher sequence coverage or methods that better model haplotype structure may be required."

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