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Exome Study Describes Mutations that May Drive Testicular Cancer Development, Drug Resistance

NEW YORK (GenomeWeb) – In a study appearing online today in Nature Communications, an Institute of Cancer Research-led team described testicular cancer mutations that may drive the disease's development and hasten its transition to drug resistance. 

"Our study is the largest comprehensive sequencing study of testicular tumors published to date, describing their mutational profile in greater detail than has been possible using previous technologies," senior author Clare Turnbull, ICR team leader in predisposition and translational genetics and honorary clinical genetics consultant at the Royal Marsden National Health Service Foundation Trust, said in a statement. 

Through whole-exome sequencing on matched tumor and normal samples from 42 men with testicular germ cell tumors, she and her colleagues verified a testicular cancer-related role for KIT, a gene implicated in past studies of the disease. They also detected a chromosome 12 duplication that wasn't previously linked to the disease, along with XRCC2 gene mutations associated with testicular cancer resistance to platinum-based treatment.

"We now need additional studies with a larger number of patients, focusing in particular on platinum-resistant tumors, to help our discoveries lead to new options for those unlucky men whose cancer progresses in spite of the best available treatments," Turnbull said.

Prior studies have pointed to a role for aneuploidy and gene amplifications in testicular germ cell tumors, a form of testicular cancer that tends to affect young men and is often diagnosed at around the age of 36-years-old.

Although malignant testicular germ cell tumors tend to respond well to platinum chemotherapy, the treatment is not effective in some patients and can cause fertility problems, metabolic conditions, or secondary cancer in others.

In an effort to flesh out the mutational signatures that mark testicular germ cell tumors, Turnbull and colleagues used the Illumina HiSeq 2500 to sequence protein-coding sequences from 42 tumor-normal pairs to depths of 72-fold coverage, on average — an effort supported by the Movember Foundation. 

The testicular tumor collection considered included samples from 16 individuals with so-called seminoma histology, 18 individuals with non-seminoma tumors, four individuals with mixed histology, and four individuals whose tumors had indeterminate histology. 

The team narrowed in on almost 1,200 suspected somatic mutations in its original analysis, though the overall mutation rate in the testicular cancer appeared to fall at the low end of the spectrum compared to other cancer types characterized so far.

The most common glitches included gains affecting a KRAS-containing chromosome 12 region proposed as a testicular germ cell tumor driver in the past, researchers reported. And as described previously, the testicular tumors were prone mutations or amplifications involving the KIT gene.

But the analysis also uncovered previously unknown culprits such as recurrent mutations to CDC27 (a tumor suppressor gene) and a gene called PRKRIR. The team also detected recurrent amplifications affecting the X chromosome and/or FSIP2, a chromosome 2 gene involved in spermatocyte development.

The researchers also identified a suspicious mutation in a chromosome stability and DNA repair-related gene called XRCC2 in the lone testicular cancer patient from the original cohort who developed resistance to platinum chemotherapy.

A distinct XRCC2 mutation turned up in another platinum-resistant tumor selected for their follow-up experiments, supporting the notion that the gene may contribute to patients' response or resistance to the therapy.