Isolation and sequencing of BRCA3: Another clue in
quest for holly grail?
Introduction:
Breast cancer is the oldest and second most common cancer in world
population, accounting for approximately 10.4% of population affected with
cancer (McPherson K et al, 2000). Of all breast cancer cases, 10-15% is
hereditary (McPherson K et al, 2000) out of which ~60- 70% are with either
BRCA1 or BRCA2 mutations, since they are high penetrating genes. The
remaining 25- 30% are due to the mutation in the low penetrating genes
(Nathanson KL and Weber BL, 2001).
Out of several low penetrance genes, “BRCA3” can show more potential as, if
it is found to be associated with either BRCA1 or BRCA2 gene then using the
hypothesis; “genes that modify the penetrance of BRCA1 and BRCA2 are
good candidates for low-penetrance susceptibility alleles in general” the
localization and sequencing of this gene can provide a better explanation in
studying the mechanism of low penetrating genes (Nathanson KL, Wooster R
and Weber BL, 2001).
Method:
Considering families having familial hereditary breast cancer, without BRCA1
or BRCA2 mutation, wherein there are minimum 3 cases of early onset of
breast cancer (below age of 50). Samples from these patients can be used for
genotyping. Genotyping can be carried out using microsatellite markers within
a region of chromosome 13q21 as this region is supposed to correspond with
purative BRCA3 locus (Thompson D et al, 2002). These microsatellites can
be amplified using peripheral blood lymphocytic genomic DNA. After PCR and
fragment analysis, the allele frequency can be calculated against samples
with known allele size (Thompson D et al, 2002).
Expected results:
The location of BRCA3 mutation on chromosome 13, if present in the patients
can be confirmed. As the contribution of locus 13q21 is less in breast cancer
cases, there will be very small number of patient showing the positive result,
through which a percentage of patients with BRCA3 mutation can be
calculated.
Discussion:
Since BRCA3 gene has no such association of a particular phenotype like
ovarian cancer for BRCA1 and male breast cancer for BRCA2, so only
families with cases of early onset of breast cancer are considered for studies
(Nathanson KL and Weber BL, 2001). Other techniques which can be used to
isolate this gene are Linkage analysis, CGH (Comparative Genomic
Hybridization) and LOD scoring. Thus, if this gene is isolated and sequenced
it can be useful in finding the appropriate phenotype which can help in
targeting a particular sequence for further in-depth studies.
Reference:
 McPherson K, Steel C M, and Dixon J M (2000). Breast cancerepidemiology, risk factors, and genetics. British Medical Journal;
321(7261): 624–628.

Nathanson KL and Weber BL, 2001. ‘other’ breast cancer susceptible
genes: searching for more holy grail. Human Molecular Genetics;
10(7): 715-720.

Nathanson KL, Wooster R and Weber BL, 2001. Breast cancer
genetics: What we know and what we need. NATURE MEDICINE;
7(5):552-556.

Thompson D et al, 2002. Evaluation of linkage of breast cancer to the
putative BRCA3 locus on chromosome 13q21 in 128 multiple case
families from the Breast Cancer Linkage Consortium. PNAS; 99(2):
827-831.