Mutation analysis of five candidate genes in familial breast cancer
Anna Marsh1, Sue Healey, Aaron Lewis
1Cancer and Cell Biology, Queensland Institute of Medical Research, c/o RBH Post Office, Herston, Brisbane, QLD , 4029 , Australia.
Abstract:
Most of the known breast cancer susceptibility genes (BRCA1, BRCA2, CHEK2 and ATM) are involved in the damage response pathway. Other members of this pathway are therefore good candidates for additional breast cancer susceptibility genes. ATR, along with ATM, plays a central role in DNA damage recognition and Chk1 relays checkpoint signals from both ATR and ATM. PPP2R1B and PPP2R5B code for subunits of protein phosphatase 2A (PP2A), which regulates autophosphorylation of ATM. In addition, EIF2S6/Int-6, which was originally identified as a common integration site for the mouse mammary tumour virus in virally induced mouse mammary tumours, is a candidate breast cancer susceptibility gene because of its putative role in maintaining chromosome stability. To investigate the role of ATR, CHK1, PPP2R1B, PPP2R5B and EIF2S6/Int-6, we carried out mutation analysis of these genes in the index cases from non-BRCA1/BRCA2 breast cancer families. We also screened sporadic breast tumours for somatic mutations in PPP2R1B and PPP2R5B. Although we identified many novel variants, we found no evidence that highly penetrant germline mutations in these five genes contribute to familial breast cancer susceptibility.
Insights
This study investigated five DNA damage response genes for breast cancer susceptibility. No evidence was found that mutations in ATR, CHK1, PPP2R1B, PPP2R5B, or EIF2S6/Int-6 contribute to familial breast cancer.
Area of Science:
- Genetics and Molecular Biology
- Oncology
- Cancer Research
Background:
- Known breast cancer susceptibility genes like BRCA1/2 are involved in DNA damage response.
- The DNA damage response pathway contains other potential candidate genes for breast cancer susceptibility.
- Genes such as ATR, CHK1, PPP2R1B, PPP2R5B, and EIF2S6/Int-6 are implicated in DNA repair and chromosome stability.
Purpose of the Study:
- To investigate the role of ATR, CHK1, PPP2R1B, PPP2R5B, and EIF2S6/Int-6 in familial breast cancer susceptibility.
- To screen for germline mutations in these candidate genes in non-BRCA1/BRCA2 breast cancer families.
- To screen for somatic mutations in PPP2R1B and PPP2R5B in sporadic breast tumors.
Main Methods:
- Mutation analysis of ATR, CHK1, PPP2R1B, PPP2R5B, and EIF2S6/Int-6 in index cases from familial breast cancer cohorts.
- Screening of sporadic breast tumors for somatic mutations in PPP2R1B and PPP2R5B.
- Identification and characterization of genetic variants within the studied genes.
Main Results:
- Numerous novel genetic variants were identified across the investigated genes.
- No highly penetrant germline mutations in ATR, CHK1, PPP2R1B, PPP2R5B, or EIF2S6/Int-6 were found to contribute to familial breast cancer.
- No significant contribution of somatic mutations in PPP2R1B and PPP2R5B to sporadic breast cancer was detected.
Conclusions:
- The studied genes (ATR, CHK1, PPP2R1B, PPP2R5B, EIF2S6/Int-6) do not appear to be major contributors to familial breast cancer susceptibility.
- Further research may be needed to explore the role of other DNA damage response genes in breast cancer.
- The identified variants warrant further investigation for potential roles in other cancer types or less penetrant disease.