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Heterogeneity in etiology and prognosis of breast cancer by intrinsic subtypes : 유방암 아형에 따른 발생 및 예후인자의 이질성 연구

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dc.contributor.advisor강대희-
dc.contributor.author송난-
dc.date.accessioned2017-07-14T01:15:22Z-
dc.date.available2017-07-14T01:15:22Z-
dc.date.issued2015-02-
dc.identifier.other000000026113-
dc.identifier.urihttps://hdl.handle.net/10371/121772-
dc.description학위논문 (박사)-- 서울대학교 대학원 : 협동과정 종양생물학전공, 2015. 2. 강대희.-
dc.description.abstractBackground: Breast cancer is heterogeneous in clinical behavior by intrinsic subtypes. However, it is unclear whether the intrinsic subtypes reflect underlying etiological classification. Furthermore, the etiological heterogeneity of breast cancer might differently contribute to tumor progression by intrinsic subtypes. This study aims to evaluate heterogeneity in etiology and prognosis of intrinsic subtypes in breast cancer.
Materials and methods: From the Seoul Breast Cancer Study (SEBCS), a total of 3,433 breast cancer patients and 3,870 healthy controls were included in the analysis. The intrinsic subtype of breast cancer was defined based on hormone receptor (HR), composed of estrogen receptor (ER) and progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status. As explanatory variables, the genetic risk factors previously identified by genome-wide association study (GWAS) and established or probable non-genetic risk factors of breast cancer were considered. The distribution of intrinsic subtypes was compared among age groups, menopausal status, and tumor-node-metastasis (TNM) stages in the study subjects and among races by a systematic review and meta-analysis of previous studies. To evaluate the etiological heterogeneity of intrinsic subtypes, associations of genetic and non-genetic factors on breast cancer risk between age frequency matched cases and controls were tested by a multivariate logistic regression model. To evaluate that the etiological heterogeneity of intrinsic subtypes affect prognosis, associations of identified genetic and non-genetic risk factors on breast cancer survival were tested by a multivariate Cox proportional hazard model. Furthermore, a two-stage GWAS was conducted to identify novel genetic markers for breast cancer survival in 2,023 patients for discovery and additionally independent 1,616 patients for replication.
Results: The distribution of subtypes was as follows
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dc.description.abstract1,617 HR+ HER2- (56.1%), 398 HR+ HER2+ (13.8%), 395 HR- HER2+ (13.7%), 473 HR- HER2- (16.4%) with differences between age groups and TNM stages (P<0.01). The difference in distribution of subtypes was observed among Asian (HR+ HER2-: 57.7%, HR+ HER2+: 13.3%, HR- HER2+: 11.8%, HR- HER2-: 16.3%), Caucasian (HR+ HER2-: 62.4%, HR+ HER2+ 16.3%, HR- HER2+: 7.8%, HR- HER2-: 13.1%), and African population (HR+ HER2-: 49.5%, HR+ HER2+: 16.2%, HR- HER2+: 12.7%, HR- HER2-: 20.9%) by meta-analysis. In the case-control analyses, earlier menarche and lifetime endogenous estrogen exposure consistently increased the risk of all subtypes. The higher body mass index (BMI) in premenopausal women showed the association with the risk of HR- HER2- tumors (odds ratio (OR)=1.08, 95% confidence interval (CI)=1.02-1.13), but not the other subtypes. Having more number of children also showed the expected association with the risk of HR- HER2+ (OR=1.15, 95% CI=1.02-1.29) and HR- HER2- tumors (OR=1.13, 95% CI=1.01-1.26). Among identified genetic factors by previous GWAS, rs2046210 in 6q25 (ESR1, C6orf97) was related to the risk of all subtypes with no heterogeneity. However, rs10069690 in 5p15 (TERT, CLPTM1L) was associated with the risk of HR+ HER2+ (OR=0.71, 95% CI=0.52-0.99, Ptrend=4.10×10-2) and HR- HER2+ tumors (OR=0.63, 95% CI=0.45-0.89, Ptrend=8.53×10-3) and rs9485372 in 6q25 (ESR1, C6orf97) with risk of HR+ HER2- (OR=0.82, 95% CI=0.73-0.91, Ptrend=3.76×10-4) and HR- HER2+ tumors (OR=0.69, 95% CI=0.56-0.84, Ptrend=2.51×10-4) with statistically significant heterogeneity across subtypes (Prs10069690<0.01 and Prs9485372=0.02). In survival analyses, earlier menarche and longer endogenous estrogen exposure rather tended to show better survival, specifically in HR+ HER2- and HR+ HER2+ tumors. The higher BMI related to HR- HER2- tumors and more number of children related to HR- HER2+ and HR- HER2- tumors were not associated with survival. The prognostic relevance of identified single nucleotide polymorphisms (SNPs) which were associated with specific subtype was also not observed. In the two-stage GWAS stratified by intrinsic subtypes, rs166870 at 15q25 (MTHFS) and rs100825036 at 10q21 (PCDH15) were associated with survival of HR+ HER2- and HR- HER2- tumors, respectively (Prs166870=2.88×10-7 and Prs10825036=3.54×10-7 in the combined set).
Conclusions: There were heterogeneity in distribution, risk factors, and prognostic factors of different intrinsic subtypes. Although the prognostic relevance of etiologically heterogeneous factors was not observed, novel genetic prognostic factors, rs166870 and rs10825036, were identified in HR+ HER2- and HR- HER2- tumors.
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dc.description.tableofcontentsAbstract i
Contents v
List of tables ix
List of figures xii
List of appendix xiv
List of abbreviations xvi
I. Introduction 1
I. 1. Background 1
I. 1. 1. Breast cancer statistics 1
I. 1. 2. Heterogeneity of breast cancer 2
I. 1. 3. Previous studies on distribution of intrinsic subtypes 6
I. 1. 4. Previous studies on risk factors of breast cancer by intrinsic subtypes 6
I. 1. 5. Previous studies on prognostic factors of breast cancer by intrinsic subtypes 18
I. 2. Hypothesis and objectives 21
I. 2. 1. Hypothesis 21
I. 2. 2. Objectives 21
II. Materials and methods 23
II. 1. Subject selection 23
II. 2. Data collection and follow-up 26
II. 3. Definition of intrinsic subtypes of breast cancer 26
II. 4. Literature search strategy and selection criteria 31
II. 5. Genotyping and quality controls 33
II. 6. Statistical analysis 38
II. 6. 1. Explanatory variables 38
II. 6. 2. Distribution of intrinsic subtypes 42
II. 6. 3. Heterogeneity in etiology of breast cancer by intrinsic subtypes 42
II. 6. 4. Heterogeneity in prognosis of breast cancer by intrinsic subtypes 44
III. Results 46
III. 1. Distribution of intrinsic subtypes 46
III. 1. 1. Baseline characteristics 46
III. 1. 2. Distribution of intrinsic subtypes in study subjects 48
III. 1. 3. Distribution of intrinsic subtypes by meta-analysis 51
III. 2. Heterogeneity in etiology of breast cancer by intrinsic subtypes 56
III. 2. 1. Baseline characteristics by intrinsic subtypes 56
III. 2. 2. Association of non-genetic factors on breast cancer risk by intrinsic subtypes 63
III. 2. 3. Association of genetic factors on breast cancer risk of intrinsic subtypes 75
III. 3. Heterogeneity in prognosis of breast cancer by intrinsic subtypes 82
III. 3. 1. Association of intrinsic subtypes on breast cancer survival 82
III. 3. 2. Association of non-genetic factors on breast cancer survival by intrinsic subtypes 88
III. 3. 3. Association of known genetic factors on breast cancer survival by intrinsic subtypes 93
III. 3. 4. Genome-wide association study on breast cancer survival by intrinsic subtypes 100
IV. Discussions 106
IV. 1. Distribution of intrinsic subtypes 106
IV. 2. Heterogeneity in etiology of breast cancer by intrinsic subtypes 108
IV. 2. 1. Association of non-genetic factors on breast cancer risk by intrinsic subtypes 108
IV. 2. 2. Association of genetic factors on breast cancer risk by intrinsic subtypes 111
IV. 3. Heterogeneity in prognosis of breast cancer by intrinsic subtypes 112
IV. 3. 1. Association of non-genetic factors on breast cancer survival by intrinsic subtypes 112
IV. 3. 2. Association of genetic factors on breast cancer survival by intrinsic subtypes 113
IV. 4. Strength and limitation 116
IV. 5. Translational relevance and impact 119
V. Summary and conclusion 121
VI. References 124
VII. Appendix 168
국문 초록 193
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dc.formatapplication/pdf-
dc.format.extent4442342 bytes-
dc.format.mediumapplication/pdf-
dc.language.isoen-
dc.publisher서울대학교 대학원-
dc.subjectBreast cancer-
dc.subjectintrinsic subtype-
dc.subjectheterogeneity-
dc.subjectrisk factor-
dc.subjectprognostic factor-
dc.subjectgenome-wide association study-
dc.subject.ddc616-
dc.titleHeterogeneity in etiology and prognosis of breast cancer by intrinsic subtypes-
dc.title.alternative유방암 아형에 따른 발생 및 예후인자의 이질성 연구-
dc.typeThesis-
dc.contributor.AlternativeAuthorNan Song-
dc.description.degreeDoctor-
dc.citation.pagesxvii, 196-
dc.contributor.affiliation의과대학 협동과정 종양생물학전공-
dc.date.awarded2015-02-
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