Whole-exome sequencing of Finnish hereditary breast cancer families

Abstract

A remarkable proportion of factors causing genetic predisposition to breast cancer (BC) are unknown in non-BRCA1/2 families. Exome sequencing was performed for 13 high-risk Finnish hereditary breast and/or ovarian cancer (HBOC) families to detect variants contributing to BC susceptibility. After filtering, 18 candidate variants in DNA damage response (DDR) pathway genes were screened in 129 female HBOC patients, up to 989 female controls, and 31 breast tumours by Sanger sequencing/TaqMan assays. In addition, two variants were further studied in 49 male BC patients and 909 male controls. Second, all variants predicted to affect function in six early-onset BC patients were analysed in detail. Variants in ATM, MYC, PLAU, RAD1, and RRM2B were enriched in female HBOC patients compared with controls (odds ratio 1.16-2.16). A rare nonsynonymous variant in RAD50 was detected in a male BC patient. In addition, a very rare BRCA1 variant was identified in a single high-risk family. None of the variants showed wild-type allele loss in breast tumours. Furthermore, novel variants predicted to affect function were detected in early-onset patients in genes, which target DNA repair and replication, signalling, apoptosis, and cell cycle pathways. Family-specific enrichment of multiple DDR pathway gene defects likely explains BC predisposition in the studied families. These findings provide new information on potential BC-related pathways and an excellent premise for future studies. INTRODUCTIONBreast cancer (BC) is the most common cancer and the leading cause of cancer-related deaths in women in both developed and developing countries. Worldwide, 1.67 million new BC cases are diagnosed each year, and the number of BC-related deaths is 522 000. 1 In Finland, BC was diagnosed in 4694 women in 2012, and the annual number of BC diagnoses is predicted to increase (Finnish Cancer Registry). Up to 10% of all BCs are familial. 2 Approximately 20-25% of familial BCs are due to germline variants in two high-risk genes, BRCA1 and BRCA2, which are tumour suppressor genes that encode large proteins that act in a common pathway of genome protection and have important roles at different stages in DNA damage response (DDR) and DNA repair. 3,4 Variant in BRCA1/2 confer a high risk of breast and ovarian cancers; the average cumulative cancer risks in a population-based series of unselected breast or ovarian cancer patients have been estimated to be 65% and 39% for BRCA1 variant carriers and 45% and 11% for BRCA2 variant carriers, respectively, by age of 70. 5 In the Finnish population, the contribution of BRCA1/2 -variants to the breast/ovarian cancer families and ovarian cancer-only families is~20% and 26%, respectively. 6,7 In addition to BRCA1/2, rare germline variants in the known highrisk genes TP53, CDH1, STK11, and PTEN predispose to familial cancer syndromes, among which BC is also observed. 4 Moreover, genes for which their protein products interact with BRCA1/2 in the DDR pathway are strong candidates for breast and/or ovarian cancer

The impact of rare and low-frequency genetic variants in common disease

“…However, the prevalence of BRCA1 and BRCA2 mutations is only approximately 24% [ 149 , 150 ]. Recently, exome sequencing has uncovered substantial locus heterogeneity among affected families without BRCA1 or BRCA2 mutations [ 151 , 152 ]. The new pathogenic variants are rare, posing challenges to estimation of risk attribution through patient cohorts.…”

High Frequency of ERBB2 Activating Mutations in Invasive Lobular Breast Carcinoma with Pleomorphic Features

“…Among them, some variants that are considered of “uncertain significance” in familial breast cancer studies testing BRCA1 and BRCA2 . Other germline variants were located in ESR1 , ERBB2 , PIK3CA , KMT2C and ZNF217 , genes considered of great importance in the development and outcome of breast cancer [1,8,31,37,38,39,40,41]. These infrequent germline variants could be risk factors for the development of PLC, although further studies are necessary to confirm their role in breast cancer development.…”

Applications of Next Generation Sequencing to the Analysis of Familial Breast/Ovarian Cancer

“…The same gene was also identified as potentially associated with BC by Sun et al [50], who analyzed the exomes of Chinese non-BRCA patients. Maatta et al [51] performed exome sequencing of 13 non-BRCA high-risk Finnish families. After filtering, 18 candidate variants in the DNA damage-response (DDR) pathway were identified and further validated by conventional methods in cohorts of BC/OC female patients, female controls and breast tumors.…”