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Some Testicular Cancer Cases Involve Rare Ciliary Gene Mutations

NEW YORK (GenomeWeb) – Rare germline mutations that alter genes involved in cilia and/or microtubule function may enhance an individual's risk of developing testicular germ cell tumors (TGCT), a testicular cancer that is relatively common in men between the ages of 15- and 45 years old.

Researchers from the Institute of Cancer Research, Queen Mary University, and elsewhere did exome sequencing on germline samples from nearly 1,000 individuals with familial and sporadic TGCT, and more than 1,600 unaffected controls. Their findings, published online today in Nature Communications, suggested that at least a subset of TGCT cases involve heterozygous alterations that affect genes coding for cilia or microtubule components.

"[W]e report the largest WES study to date of familial and sporadic TGCT, identifying rare mutations in [cilia-microtubule genes] as determinants of disease susceptibility," senior author Clare Turnbull, a genetics and epidemiology researcher at the Institute of Cancer Research, and her co-authors wrote. They further noted that homozygotic mutations in such genes have previously been implicated in autosomal recessive ciliopathy cases.

Past genome-wide association studies — including work that Turnbull's team published last year — have uncovered common variants associated with TGCT risk. Given the strong heritability of the disease that has been described from prior family studies, the researchers set out to expand the view of genetic features involved in TGCT risk by focusing on rare mutations predicted to upend functions of the resulting proteins.

Using Illumina HiSeq2000 or 2500 instruments, the team sequenced protein-coding portions of the genome that had been captured with TruSeq kits in 328 TGCT patients from 153 TGCT-prone families, and 1,644 unaffected controls. From these exomes, it identified 13 families affected by mutations involving the dynein arm-coding gene DNAAF1 or other cilia-microtubule genes.

The researchers' gene set enrichment analyses supported the notion that cilia-microtubule gene mutations can contribute to TGCT risk, as did exome sequencing analyses on 634 individuals with sporadic TGCT from their replication cohort.

When the team used immunohistochemistry to test for DNAAF1 expression in TGCT tumor samples from three individuals with germline mutations in the gene, it found a corresponding drop in DNAAF1 expression in the tumors. Moreover, the group's follow-up experiments in mutant zebrafish suggested TGCT risk is ratcheted up dramatically when the DNAAF1 is altered or missing.

"The functional basis of inactivation of [cilia-microtubule genes] in oncogenesis remains to be established; however, ciliation and the cell cycle are mutually exclusive with both processes competing for the centrosome," the authors wrote. "Hence, cilia inactivation may bias towards cell cycle progression and proliferative growth."