Transcriptomic profiling and validation of early onset estrogen receptor-positive breast cancer patients
Early-onset breast cancer (≤45 years) is an area of debate due to the adverse clinicopathological features and the unfavourable clinical outcomes observed in earlyonset patients compared to late-onset patients (> 45 years). The present study compared the clinicopathological features of early a...
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| Format: | Thesis |
| Language: | English |
| Published: |
2023
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| Subjects: | |
| Online Access: | http://eprints.usm.my/60308/1/ALAA%20ABDELAZIZ%20MAHMOUD%20SIDDIG-FINAL%20THESIS%20P-UD001220%28R%29%20-E.pdf http://eprints.usm.my/60308/ |
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| Summary: | Early-onset breast cancer (≤45 years) is an area of debate due to the adverse
clinicopathological features and the unfavourable clinical outcomes observed in earlyonset
patients compared to late-onset patients (> 45 years). The present study
compared the clinicopathological features of early and late-onset breast cancer patients
diagnosed at Hospital Universiti Sains Malaysia during the period 2013 – 2022
(n=570). Consequently, the transcriptomic profile of Estrogen Receptor (ER)- positive
breast cancer was compared between early and late-onset patients using the Clariom
S gene chip from Affymetrix (n=14), validation in larger sample size conducted using
in silico analysis and real-time polymerase chain reaction (RT-qPCR). The Kaplan-
Meier plot used to assess the prognostic significance of the genes that exhibit
differential expression between early and late-onset breast cancer tissues.
Immunohistochemical analysis utilized to assess the protein expression level of
RANBP3L and GLYATL-1; genes encoded by the differentially expressed genes.
Finally, the distribution of the tumour stroma ratio and the tumour infiltrating
lymphocytes were compared between early and late-onset ER-positive breast cancer
haematoxylin and eosin-stained tissue sections. Results showed that early-onset breast
cancer tend to have large size (> 5cm) (28.3% vs 13.5%), and a higher proportion of
luminal B subtype (22.8% vs 14.2%). The bilateral breast cancer incidence is higher
in early than in late-onset patients (9.4% vs 3.6%). The transcriptomic profile of ERpositive
early-onset breast cancer differentially expressed 11 genes (fold change < 3 or >3; adjusted p-value <0.05). Six genes out of eleven have validated expression.
Enrichment analysis revealed that differentially expressed genes between early and
late-onset ER-positive breast cancer with unadjusted p-value < 0.01 implicated in
pathways related to focal adhesion, axon guidance and complement and coagulation
cascades (FDR p-value <0.05). Survival analysis showed that loss of expression of
SFXN2, GLYATL-1, RANBP3L and ESR-1 which is characteristic of the transcriptomic
profile of early-onset ER-positive breast cancer was significantly associated with
shorter relapse-free survival. IHC analysis showed that the expression of GLYATL-1
and RANBP3L proteins exhibit an association with lymph node positivity and low
histopathological grade (P<0.005 and 0.038) respectively. A low tumour stroma ratio
was significantly associated with ER-positive breast cancer patients with age (50-59
years). The collected evidence indicates that the early onset of breast cancer (≤45
years) exhibits adverse clinicopathological features compared to the late onset of
breast cancer (>45 years). The transcriptomic profile of the early-onset ER-positive
breast cancer differentially expressed genes that are implicated in cancer progression
and metastasis. Breast cancer developed in old age is characterized by a low tumour
stromal ratio which may predict a good prognosis. |
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