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Researchers Find Examples of Rare, Germline CNVs in Individuals with Sporadic Testicular Cancer

NEW YORK (GenomeWeb News) – A subset of non-inherited, early-onset testicular cancer cases involve rare, germline copy number alterations, according to a study appearing online today in the American Journal of Human Genetics.

Researchers from Memorial Sloan-Kettering Cancer Center and other centers in the US used array-based comparative genomic hybridization to search for germline copy number variants in blood or saliva samples from more than 100 individuals with early-onset breast, testicular, or colorectal cancer and their parents, focusing on de novo changes not inherited from either parent.

Though they did not track down suspicious copy number patterns in samples from individuals with breast or colon cancer, investigators did find examples of de novo germline CNVs in some of the testicular cancer trios. Three of the 43 individuals with testicular cancer had rare amplifications or deletions not found in their family members or in unrelated individuals tested in follow-up experiments.

All three of these individuals had been diagnosed with the testicular cancer in their 20s. And while studies representing more individuals and cancer types are needed to fully understand the role of de novo germline CNVs in cancer, authors of the current study theorized that this type of genetic alteration may contribute to a subset of certain cancers that manifest themselves fairly early in life.

"We speculate that the paradigm of a de novo germline disease etiology may be less applicable to late-onset cancers," senior author Kenneth Offit, a medical oncologist at MSKCC and chief of the center's clinical genetics service, said in a statement, "in part explaining the lower frequency of de novo events we found in adult-onset breast and colon cancer cases."

Rare CNVs have been implicated in some neurodevelopmental or psychiatric conditions such as autism and schizophrenia, the team noted, and in some forms of congenital heart disease. And somatic CNVs — for instance, those duplications or deletions that are found in tumors but missing from matched normal tissue samples from the same individual — have been evaluated as part of genomic analyses on several cancer types.

But the contributions that de novo CNVs found in every tissue type in an individual's body might make to cancer risk, if any, are less well studied.

"The role of de novo germline [CNVs] in cancer susceptibility is largely unknown," Offit and his colleagues explained, "although de novo mutations in cancer susceptibility genes … are common."

In an effort to understand whether rare, spontaneously occurring germline CNVs are contributors to adult cancer risk in those who develop the disease at relatively young ages, the researchers used NimbleGen HD2 arrays to assess CNV patterns by array CGH in blood or saliva samples from 116 individuals with early onset cancers.

These included 60 individuals diagnosed with breast cancer when they were 45 years old or younger, 13 individuals diagnosed with colorectal cancer between the ages of 25 and 50 years old, and 43 individuals who'd been diagnosed with testicular germ cell tumors when they were between 19 and 35 years old.

The team also tested each individual's unaffected parents to round out each of the 116 trios, as well as 34 unaffected siblings.

The analysis did not uncover any new germline CNVs in individuals with breast or colon cancers. But in samples from three of the 43 individuals with early-onset testicular cancer, the researchers found CNVs that had not been inherited from the individual's mother or father.

Two of the men — one diagnosed with testicular cancer when he was 27 years old and another diagnosed with the disease at 23 years old — carried amplifications in or around the AUTS2 and SSH1 genes, respectively. A third patient, diagnosed with testicular cancer when he was 27 years old, had a germline deletion affecting a chromosome 6 region that houses the KIF6, KNCK16, and KNCK17 genes.

Using Taqman CNV assays, researchers verified each of these CNVS. They also showed that the same amplification was present in DNA from both blood and spit samples for one of the individuals, supporting the notion that this alteration affects the germline and did not spring up in just one tissue.

The team did not see any of the same copy number alterations when they tested 113 other sporadic testicular cancer cases nor were the CNVs present in samples from 1,500 unaffected controls.

From the patterns identified in this and other studies, researchers speculated that de novo copy number changes affecting the germline might be more apt to underlie conditions that affect an individual's reproductive potential, noting that successful treatment for testicular cancer often comes at the cost of fertility.

"The de novo mutation paradigm might be important but less readily evident in early-onset human diseases in which the natural history of the disease would normally result in decreased fecundity," they noted.