Ghazali, Mohamad Bazli
(2014)
BRCA1, BRCA2 mutations and the association with the clinicopathological characteristics of women with early-onset breast cancer.
Masters thesis, Universiti Sains Malaysia.
Abstract
Introduction: BRCA1 and BRCA2 mutations have been associated with early-onset
breast cancers and adverse clinico-pathological features. To date, there is paucity of
studies in Malaysia investigating the relationship between types of BRCA1/2
mutations and clinicopathological characteristics of breast cancers. This study
therefore aims to ascertain whether there are differences between different types of
BRCA1/2 mutations in terms of clinico-pathological attributes of breast cancers
amongst females with early-onset breast cancers in Malaysia.
Methodology: Seventy females aged 40 or less with confirmed breast cancer
diagnosis that underwent follow-ups at Seberang Jaya Hospital, Penang were
recruited into this study. Clinical (age, ethnicity, stage, neo adjuvant therapy, family
history of ovarian and breast cancers) and pathological (ER, PR, Her2 status, triple
negativity, tumour grades and stages) characteristics of the breast cancers were
obtained by retrospectively reviewing the medical records. Three mls of blood was
taken from each subject and subjected to DNA extraction. These were then screened
for germline mutations of BRCA1 gene (exons 11, 13 and 16) for BRCA2 gene
(exons 10 and 11) using allele-specific PCR.
Results: The prevalence of BRCA2-only and combined BRCA1 and BRCA1
mutations were 28.6% (95% CI: 18%, 39.2%) and 71.4% (95% CI: 60.8%, 82.0 %),
respectively. No wild-type BRCA1 or BRCA2 and BRCA1-only mutations were
observed in this study cohort. No significant associations were found between types
of BRCA mutations (BRCA2-only mutations vs combined BRCA1 and BRCA2
mutations) and clinico-pathological characteristics of breast tumour. However, three
BRCA1 mutations (3232A>G (rs16941, exon 11), 3667A>G (rs16942, exon 11) and
4427T<C (rs1060915, exon 13) were significantly associated with a more advanced
tumour size group (p values = 0.032, 0.049 and 0.043, respectively). Besides,
3232A>G (rs16941, exon 11) mutation was also significantly associated with higher
risk of HER2-negative (OR 7.50 (95% CI: 1.439, 39.089), p value = 0.017) and
triple negative breast carcinoma (OR 4.375 (95% CI: 1.193, 16.038), p value
=0.042). No significant associations were found between BRCA2 genotypes and
clinico-pathological features of breast carcinoma.
Conclusion: Combined BRCA1 and BRCA2 mutations are the most prevalent types
of BRCA mutations amongst females with early onset breast cancers, followed by
BRCA2-only mutations. Three BRCA1 germline mutations were found to be
significantly predictive of a more advanced tumour size group whilst only one
BRCA1 mutation was significantly associated with HER2-negative and triple
negative breast tumours. Nevertheless, further studies are warranted to address the
unresolved issues encountered by this study.
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