The Research Of Hereditary Breast Cancer Susceptibility Genes Of Hunan Population In China With Familial Breast Cancer Or Early-onset Breast Cancer

Objectives:The purpose of this study was to investigate the prevalence of BRCA1,BRCA2 and PALB2,BRIPlgene mutations among breast cancer patients with familial or early-onset in Hunan Province,China,so as to explore the location,nationality,age of onset,pathological characteristics of the hereditary breast cancer in Hunan,additionally to find the speciality and clinical significance of the mutations in Hunan high risk breast cancer families and to create a more effective and feasible approach for genetic screen in clinic.Methods50 familial breast cancer and early onset breast cancer patients in Hunan province are enrolled.The inclusion criteria were:(1) at least one first or second degree relatives with breast cancer and/or ovarian cancer, regardless of age;(2) the age diagnosed breast cancer was below 35 years. In total,21 cases in the study are familial but not early onset,24 cases are early onset without family history,and 5 cases are both familial and early onset.150 healthy women were chosen as normal controls in the study. Genomic DNA was isolated from each peripheral blood sample,and all the 50 cases have been detected for the entire coding sequence and splicing sites of BRCA1/BRCA2 genes by using PCR-DHPLC-DNA sequencing analysis。46 BRCA1/BRCA2-negative patients were selected for screen of PALB2 and BRIP1 genes mutations by the same techniques. Mutation frequency is analyzed in case-control study,and the DNA sequence of the pathogenic mutation and possible pathogenic mutation is also tested in the proband's first and second relatives for pedigree analysis.Further analysis of the pathologic and biologic characteristics of the mutation tumor was carried out by IHC and FISH methods;LOH study in mutation tumor tissue is also performed in this study.ResultsFive mutations including 2 novel mutations(nonsense mutation 2372C＞G and frameshift mutation 2808delACAA in BRCA2 gene) and 3 previously reported mutations(nonsense mutation 220C＞T in BRCA1 gene,frameshift mutations 1796delTTTAT and 6275delTT in BRCA2 gene) were identified in BRCA1/2 mutation studies.The mutation frequency of BRCA1/2 in 50 genetic-predisposed breast cancer population from Hunan Province in China is 10%.A novel PALB2 truncating mutation c.751C＞T(Q251X) was found in one of the 46 BRCA1/2 negative patients,and the mutation frequency is about 2.2%in this study. The pedigree analysis showed the penetrance of c.751C＞T(Q251X) mutation and another possible pathogenic variant c.1636G＞T(p.V546F) in our series is 33.3%and 57.1%,respectively.The partial co-segregation of PALB2 was also observed in this study.DNA sequence test showed the existence of LOH in PALB2 mutation tumor.Besides,there are no truncating mutations in BRIP1 genes in this study.ConclusionNovel mutations as BRCA2₂372C＞G,BRCA2₂808delACAA and PALB₇51C＞T may be special changes in Hunan breast cancer population.The mutation frequency of BRCA1 and BRIP1 gene in high-risk breast cancer patients from Hunan is obviously low(2%and 0%),but the mutation frequency of BRCA2 and PALB2 gene in the study is similar to that in the western country(8%and 2.2%),which probably is the characteristic of breast cancer susceptibility gene mutations in Hunan population.The penetrance of PALB2 genes is relatively high in this research may confirmed the significance of PALB2 in breast cancer disease.Loss of heterozygosity(LOH) occurring in the PALB2 mutation-associated tumor conformed to the inactivation model of a classic tumor-suppressor gene.Our study enriches the clinical data of genotype and phenotype characteristics of PALB2 gene mutations.In general,the BRCA2 and PALB2 gene mutations may contribute greatly to Hunan hereditary breast cancer population in Chinese.The study also advises that intensive screen of 11 exon in BRCA2 and 4 exon in PALB2 is a cost effective approach in clinical genetic counseling.