Germline mutations in DNA repair and cell cycle checkpoint genes: consequential somatic gene alterations and genome instability

Germline alterations in the BRCA1, BRCA2 and CHK2 genes were analysed in a series of breast cancer cases from the Icelandic population of 285,000 and risk was estimated. By screening 1172 cancer patients for the detected T59K sequence variant in the CHK2 gene, it was detected in a total of four breast cancer patients, two colon cancer patients, one stomach cancer patient and one ovary cancer patient, but not in 452 healthy individuals. The results suggest a tumor suppressor function for CHK2 in a small proportion of breast tumors and that the T59K CHK2 sequence variant is a low-penetrance allele with respect to tumor growth. A rare mutation was detected in the BRCA1 gene and a frequent mutation in the BRCA2 gene. The BRCA2 999del5 is classified as a founder mutation and the Icelandic population-based analysis gives an excellent opportunity to define the risk of this sequence variant for breast cancer and other cancer types. The BRCA2 999del5 mutation is present in 7% of unrelated breast cancer patients in Iceland, the prevalence increases with lower age of diagnosis and the estimated breast cancer risk in mutation carriers at the age of 70 years is 40%. A detailed analysis was done on the somatic events in tumors of 46 BRCA2 999del5 carriers with respect to genomic instability and gene alteration. Chromosome alterations were elevated and of specific architecture compared with sporadic cases, in line with the DNA/chromosome repair function of Brca2. An alternative mechanism of TP53 involvement seems to be specific to the pathogenesis of BRCA2 999del5 tumors. Furthermore, alterations at the FHIT gene located at the FRA3B locus with subsequent reduced expression seem to be of specific relevance in the BRCA2 tumors.