Researchers Reveal Massive Genome Chaos in Breast Cancer

A breast cancer cell. (Credit: Anne Weston/ LRI, CRUK, Wellcome Images)

Scientists have published one of the most detailed maps ever made of structural variations in a cancer cell’s genome.

In cancer cells, genetic errors wreak havoc. Misspelled genes, as well as structural variations,  disturb carefully balanced mechanisms that have evolved to regulate cell growth. 

Genes that are normally silent are massively activated and mutant proteins are formed. These and other disruptions cause a plethora of problems that cause cells to grow without restraint, cancer’s most infamous hallmark. 

The detailed map, published in Genome Research, reveals about 20,000 structural variations, few of which have ever been noted due to technological limitations on a long-popular method of genome sequencing. 

The team, led by Michael C. Schatz and W. Richard McCombie of Cold Spring Harbor Laboratory, read genomes of the cancer cells with so-called long-read sequencing technology. 

They demonstrated the power of long-read sequencing technology by using it to read the genomes of cells derived from a cell line called SK-BR-, an important model for breast cancer cells with variations in a gene called HER2.

About 20% of breast cancers are HER2-positive, meaning they overproduce HER2 protein. These cancers tend to be the most aggressive. 

“Most of the 20,000 variants we identified in this cell line were missed by short-read sequencing,” says Maria Nattestad, PhD, who performed the work. “Of particular interest, we found a highly complex set of DNA variations surrounding the HER2 gene.” 

Long-read sequencing enabled the team to reconstruct in great detail the history of how the HER2 gene gets massively amplified in HER2-positive breast cancer cells, says Dr. Schatz. Top rectangle shows a 2 million base-pair segment of chromosome 17 occupied by the HER2 gene (also called ERBB2). A small segment of the gene, already massively amplified, breaks off and fuses with chromosome 8 (lower rectangle). On that chromosome, parts of the gene are copied as many as 1000 times, with various segments jumping around within the chromosome (green arcs). This shows why we want to identify HER2-positive patients as early as possible, to prevent the kind of chaos that we register here cumulatively, says Schatz. (Credit: Schatz Lab, CSHL/JHU)

In their analysis, the team combined the results of long-read sequencing with results of another kind of experiment that reads the messages, or transcripts, that are being generated by activated genes. 

This fuller picture yielded an extraordinarily detailed account of how structural variations disrupt the genome in cancer cells and sheds light on how cancer cells rapidly evolve. 

Schatz and McCombie stress that it’s “essential to continue building a catalogue of variant cancer cell types using the best available technologies.” 

“Lond-read sequencing is an invaluable tool to capture the complexity of structural variations, so we expect widespread adoption for use in research and clinical practice, especially as sequencing costs further decline,” they add.