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Cowden Syndrome Study Uncovers Mutant Gene With Ties to Sporadic Thyroid Cancer

NEW YORK (GenomeWeb) – A search for mutations behind a cancer predisposition condition called Cowden syndrome has unearthed alterations that also appear to be over-represented in individuals who develop sporadic thyroid cancer.

As they reported online today in the American Journal of Human Genetics, researchers from the US, Singapore, and China did exome sequencing and/or targeted sequencing on members of a multi-generational family affected by Cowden syndrome, thyroid cancer, and other cancer types. In the process, they found a missense alteration in an endoplasmic reticulum transport-related gene called SEC23B that was present in family members with these conditions but absent in those without.

The team tracked down other inherited alterations in the same gene — which was previously implicated in a rare form of anemia — in a handful of unrelated individuals with Cowden syndrome and in a small subset of individuals with sporadic thyroid cancer.

"The discovery of this new cancer-predisposing gene will facilitate predictive genetic testing, risk assessment, genetic counseling, and clinical management of the disease," senior author Charis Eng, director of the Cleveland Clinic's Genomic Medicine Institute, said in a statement.

In 1998, Eng and colleagues published a Human Molecular Genetics paper that pointed to the presence of germline mutations in the cancer-related gene PTEN in a substantial subset of individuals with Cowden syndrome — an autosomal dominant condition characterized by the presence of multiple non-cancerous growths called hamartomas.

The disease ramps up the chances of developing breast, thyroid, endometrial, and other cancers, authors of the new study explained, with around half of Cowden syndrome-affected individuals carrying alterations in genes implicated in cancer susceptibility.

Even so, many individuals with Cowden syndrome lack PTEN mutations, despite showing the sorts of clinical features that are used in the Cleveland Clinic's PTEN mutation risk predictor.

To delve into such cases in more detail, the researchers looked at families affected by Cowden syndrome or Cowden syndrome-like conditions, focusing in on four generations of one Cowden syndrome-affected family that frequently developed cancer, particularly early-onset thyroid cancer.

The presence of germline mutations in PTEN or other cancer-associated genes such as SDHB, SDHC, SDHD, AKT1, and PIK3CA had already been ruled out in affected members of the family, they noted.

In an effort to find other cancer and Cowden syndrome susceptibility culprits, the team used the Illumina TruSeq kit and HiSeq 2000 to do exome sequencing on a 60-year-old woman from the family who had been diagnosed with papillary thyroid cancer of follicular histology, fibrocystic breast disease, and other conditions.

The researchers' analysis of her protein-coding sequences, which were covered to an average depth of more than 96-fold, uncovered 44 suspicious mutations.

All but five of the genetic glitches were verified by Sanger sequencing, leaving the team with 39 candidate gene variants to test by targeted sequencing in four Cowden syndrome-affected and three unaffected members of the same family.

After weeding out variants based on their predicted pathogenicity and descriptions in sequence databases, the researchers narrowed in on a missense mutation in SEC23B.

Rare mutations in the same gene — which codes for a component of the endoplasmic reticulum trafficking complex — subsequently turned up in three of 96 unrelated individuals with Cowden syndrome or Cowden syndrome-like conditions, each of whom had developed papillary thyroid cancer.

Finally, the team scoured hundreds of germline samples from individuals with sporadic thyroid, breast, or endometrial cancers who had been tested for the Cancer Genome Atlas Project. There, it saw higher-than-usual levels of SEC23B variation in the 494 thyroid cancer cases tested, where 4 percent of individuals had heterozygous alterations in the gene.

On the other hand, rare, deleterious variants in the gene were far less common in exomes generated for the National Heart, Lung, and Blood Institute's Exome Sequencing Project.