Mutations in the cell cycle checkpoint
kinase 2 (CHEK2) tumor suppressor gene are associated with multi-organ
cancer susceptibility including
cancers of the breast and prostate. A genetic association between thyroid and
breast cancer has been suggested, however little is known about the determinants of this association. To characterize the association of CHEK2 mutations with
thyroid cancer, we genotyped 468 unselected patients with
papillary thyroid cancer and 468 (matched)
cancer-free controls for four founder mutations of CHEK2 (1100delC, IVS2 + 1G>A, del5395 and I157T). We compared the family histories reported by patients with a CHEK2 mutation to those of non-carriers. A CHEK2 mutation was seen in 73 of 468 (15.6%) unselected patients with
papillary thyroid cancer, compared to 28 of 460 (6.0%) age- and sex-matched controls (OR 3.3; p < 0.0001). A truncating mutation (IVS2 + 1G>A, 1100delC or del5395) was associated with a higher risk of
thyroid cancer (OR = 5.7; p = 0.006), than was the missense mutation I157T (OR = 2.8; p = 0.0001). CHEK2 mutation carriers reported a family history of
breast cancer 2.2 times more commonly than non-carriers (16.4% vs.8.1%; p = 0.05). A CHEK2 mutation was found in seven of 11 women (63%) with multiple primary
cancers of the breast and thyroid (OR = 10; p = 0.0004). These results suggest that CHEK2 mutations predispose to
thyroid cancer, familial aggregations of breast and
thyroid cancer and to double primary
cancers of the breast and thyroid.