Excess of rare cancers in Werner syndrome (adult progeria).

The association between genetic disorders and diverse cancers has provided clues for laboratory research into carcinogenesis. Such an opportunity now arises from studies of cancer in Werner syndrome (WRN). Soft-tissue sarcoma (STS) and benign meningioma have been associated with WRN, an autosomal recessive disorder characterized by premature aging, more commonly reported in Japan than elsewhere, in part because of inbreeding. In the literature we found 124 case-reports of neoplasia and WRN from Japan and 34 from outside Japan, 1939-August, 1995. They reveal a greater diversity of neoplasia in WRN than was previously known. In Japanese, there were 127 cancers, 14 benign meningioma, and 5 myeloid disorders, as compared with 30, 7 and 2 respectively in non-Japanese. The ratio of epithelial to non-epithelial cancers was about 1:1 for Japanese and for non-Japanese instead of the usual 10:1. Both series had excess of STS, osteosarcoma, myeloid disorders, and benign meningioma. In addition, the Japanese had an excess of thyroid cancer (20 versus 2 cases in non-Japanese) and melanoma (21 versus 3 cases), including 5 intranasal and 13 of the feet. STS, osteosarcoma, melanoma, and thyroid carcinoma accounted for 57% of all cancer in WRN as compared with 2% expected based on the Osaka population at 25-64 years of age. Multiple tumors were reported in 19 Japanese and 5 non-Japanese. In Japan, nine first-degree relatives had WRN and cancer, six of whom were concordant as to site and/or cell type. The WRN gene has been mapped to chromosome 8p. The high frequency of thyroid cancer and melanoma in Japanese, not found in Caucasians, may be related to a report of linkage disequilibrium with the WRN gene in Japanese but not in Caucasians and to haplotype differences within and between the two races, suggesting multiple independent mutations.