Researchers identify a new thyroid cancer gene via another disease.

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Thyroid cancer, the most common cancer of the endocrine glands, is the fastest rising cancer in women and second fastest rising in men in the U.S.  Thyroid cancer is a cancer originating from follicular or parafollicular thyroid cells. These cells give rise to both well-differentiated cancers (i.e., papillary and follicular) and analastic thyroid cancer.  The second cell type, the C or parafollicular cell, produces the hormone calcitonin and is the cell of origin for medullary thyroid carcinoma.

Due to the heterogeneity of the disease there is an acknowledged difficulty in identifying hereditary and genetic risk factors for the diseases with conventional methods.  Now, researchers from Cleveland Clinic state that they have identified a new gene associated with Cowden syndrome (CS), an inherited condition that carries a high risk of thyroid cancer.  The team state that this new cancer-predisposing gene will facilitate predictive genetic testing, risk assessment, genetic counseling, and clinical management of thyroid cancer and CS.  The opensource study is published in the American Journal of Human Genetics.

Previous studies show that Cowden syndrome is an under-diagnosed, difficult-to-recognize autosomal-dominant disorder characterized by multiple hamartomas and an increased predisposition to breast, thyroid, endometrial, and other cancers.  Individuals with the syndrome have an 85 percent lifetime risk of breast cancer and a 35 percent risk for epithelial thyroid cancer, respectively. At least one in 200,000 people are affected by the disease.
Earlier studies from the group showed that Cowden syndrome is caused by a faulty tumour suppressor gene called PTEN (phosphatase and tensin homolog). The gene has since been implicated in a number of other conditions, including a rare form of autism.  The lab also examined a multi-generational family with early-onset thyroid cancers.  Results show that all affected family members had inherited a harmful mutation in this gene. The mutation was not found in any unaffected family members.  The new CS-linked gene identified in the current study, SEC23B, encodes a protein involved in the transport of all proteins within cells.

The current shows that normal thyroid cells expressing mutated SEC23B grew faster, formed larger colonies, invaded more aggressively, and were able to survive in a very stressful microenvironment, all major hallmarks of cancer.  The researchers searched their clinical database for accrued CS- affected families. Eligible families consisted of at least one unaffected and two affected family members.  To identify the SEC23B gene, a multi-generation CS-affected family (family 616) presenting with different types of CS-related cancers, particularly thyroid cancer, across four generations was selected.

Results show that SEC23B mutations are present in up to 3 percent of unrelated Cowden syndrome patients and in 4 percent of patients with non-syndromic thyroid cancer.  Data findings show that approximately 50 percent of Cowden syndrome patients tested negative for all known genetic mutations.

The team surmise that their not only identified a novel cancer-predisposing gene, particularly in thyroid cancer, it also highlights how cellular stress responses can be hijacked by cancer cells to promote their survival.  For the future, the researchers have also linked this gene to anemia and as they cannot ascertain anemia-related clinical phenotypes unrelated to cancer in these individuals, they plan to clarify this.

Source: Cleveland Clinic

Cellular and Biochemical Characterization of Family 616 Variant p.Val594Gly in a Normal Thyroid Cell Line. Normal thyroid Nthy-ori 3-1 cells were stably transduced with wild-type and mutant c.1781T >G (p.Val594Gly) SEC23B fused with GFP. Wild-type cells (Nthy- SEC23B-WT) showed SEC23B localization typical of ER proteins, whereas a subset of mutantcells(Nthy-SEC23B-V594G) showed aberrant aggregation of SEC23B. Germline Heterozygous Variants in SEC23B Are Associated with Cowden Syndrome and Enriched in Apparently Sporadic Thyroid Cancer. Eng et al 2015.

Cellular and Biochemical Characterization of Family 616 Variant p.Val594Gly in a Normal Thyroid Cell Line. Normal thyroid Nthy-ori 3-1 cells were stably transduced with wild-type and mutant c.1781T >G (p.Val594Gly) SEC23B fused with GFP. Wild-type cells (Nthy-SEC23B-WT) showed SEC23B localization typical of ER proteins, whereas a subset of mutant cells(Nthy-SEC23B-V594G) showed aberrant aggregation of SEC23B. Germline Heterozygous Variants in SEC23B Are Associated with Cowden Syndrome and Enriched in Apparently Sporadic Thyroid Cancer. Eng et al 2015.

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