Both Independent and Germline Cadherin Mutations Underlie Diffuse Gastric Cancer

NEW YORK JUN 07, 2007 (Reuters Health) - Mutations in the epithelial cadherin (CDH1) gene -- linked to increased risk of diffuse gastric cancer and lobular breast cancer --  can arise by either common ancestry or by an independent mutational event, a research team reports in the Journal of the American Medical Association for June 6. 

"Epithelial cadherin is a transmembrane glycoprotein and plays a major role in epithelial architecture, cell adhesion, and cell invasion," Dr. David Huntsman, of the British Columbia Cancer Agency, Vancouver, and associates explain.

Thirty-eight families diagnosed clinically with diffuse gastric cancer were referred to the Cancer Agency by genetics clinics in North America.  The researchers detected 13 mutations, of which 6 were "novel," in 15 of 38 families.

The investigators performed 129 CDH1 mutation carrier tests for asymptomatic individuals from 11 families.  Their results showed the cumulative risk of gastric cancer in two of the largest families is approximately 40% in men and 60% in women; women also have a corresponding 52% risk of breast cancer.

To further characterize CDH1 mutations, they screened the coding sequence and flanking intronic portions of the CDH1 gene, and looked for mutations classified as deletions or insertions, splicing, nonsense, or missense.

With haplotype analysis of five mutations, Dr. Huntsman"s team showed that four were associated with identical or near identical haplotypes in more than 1 HDGC family.  Only one mutation was identified several times within a genetically homogeneous, ethnically or geography defined population, and thus is a likely founder mutation, they say.

"Between 30% and 40% of families with a positive family history of gastric cancer and more than 50% of families with 2 diffuse gastric cancer cases diagnosed prior to age 50 years will carry germline mutations in the CDH1 gene," they add.

CDH1 gene mutations have caused death from HDGC among patients in their teens.  Therefore, Dr. Huntsman and colleagues recommend prophylactic gastrectomy for male mutation carriers in their 20s. 

Women may want to postpone the procedure so that dietary consequences won"t affect future pregnancies.

Moreover, because of the additional risk of breast cancer in female carriers of CDH1 mutations, the authors recommend that routine mammography and MRI imaging of the breasts begin before age 40.  Prophylactic treatment with tamoxifen may be in order.  Some women may determine that a prophylactic mastectomy may be their best recourse, especially when their family history includes multiple cases of lobular breast cancer.

SOURCE;

• JAMA 2007;297:2360-2372.