BRCA1

Course: PATH 6200 – Molecular Genetics & Cytogenetics of Cancer

Name: Lee Ka Wai Jenny
Student Number: 2007944322
BRCA1
The breast and ovarian cancer
susceptibility gene, encoded as a
tumor suppressor gene, located
at chromosome 17q21, mapped
in 1996
The BRCA1 protein normally
resides in a nuclear multiprotein
complex, including BRCA2,
BARD1 and RAD51, and the 9
DNA damage repair proteins
(e.g. MSH2, MLH1, MSH6, etc)
BRCA1
 BRCA1-associated genome surveillance complex functions:
- sensor of abnormal DNA structures
- executive repair proteins
- a transcriptional regulator of genes
 Mutations of BRCA1 lead to impair the repair damaged DNA
- Prone to malignant transformation
 Germline mutations in BRCA1 & BRCA2 associated with familial
breast & ovarian cancers, detected in up to 28%
 Have a lifetime risk of 49 – 87% for developing breast cancer
 ~ 1 in 40 of Ashkenazi Jewish are the BRCA mutations carriers
Histopathology
BRCA1 tumors are frequently high-grade (grade 3),
ductal carcinomas with necrotic areas & lymphocytic
infiltration
Typically with ER–, PR– & HER2- (Triple-negative)
In contrast, BRCA2 are ER+ & HER2 in majority
Common or Founder Mutations
Amount 41 human breast cancer cell lines, up to now, the
HCC1937 cell line was the only human breast cancer cell line with
identified BRCA1 mutation. In the Breast Cancer Information Core
(BIC),
 reports the most common BRCA1 mutations identified are
185delAG (16.5%), 5382insC (8.8%) and the missense
alternation C61G (1.8%)
 Several different founder mutations are confounded to
geographically isolated regions or specific populations.
 The 185delAG mutation is a well-described pathogenic BRCA1
mutation prevalent in the Ashkenazi Jewish population. With
the addition of 5382insC and one in BRCA2 (6174delT), which
account for 98 – 99% of identified mutations in this population.
Investigating
Immunostaining
DNA Sequencing
Immunostaining
BRCA1 protein localization in frozen and contiguous
formalin-fixed, paraffin embedded (FFPE) tissue with a
BRCA1 mutation (185delAG).
DNA Sequencing
DNA sequencing chromatogram illustrates the mutation,
185delAG, resulting from the deletion of two consecutive
nucleotides AG at position 185
Reference
1. Natalie Tulchin, Leonard Ornstein, Steven Dikman, et al (2013)
Localization of BRCA1 protein in breast cancer tissue and cell lines with
mutations. BioMed Central Ltd. Cancer Cell International 2013, 13:70
2. Martin J. Larsen, Torben A. Kruse, Qihua Tan, et al, (2013) Classifications
within Molecular Subtypes Enables Identification of BRCA1/BRCA2
Mutation Carriers by RNA Tumor Profiling. PLOS ONE Vol. 8 Issue 5,
e64268
3. Susan J. Ramus, Simon A. Gayther (2009) The Contribution of BRCA1
and BRCA2 to Ovarian Cancer. Gynaecological Cancer Research
Laboratory, Molecular Oncology 3 (2009) 138–150
4. Fons Elstrodt, Antoinette Hollestelle, Jord H.A. Nagel, et al (2006) BRCA1
Mutation Analysis of 41 Human Breast Cancer Cell Lines Reveals Three
New Deleterious Mutants. American Association for Cancer Research.
5. en.wikipedia.org