Advances in Endometrial Cancer Epidemiology and Biology Enriching TCGA with Patient Information: Potential Uses and Obstacles Marc T. Goodman, PhD, MPH Director, Cancer Prevention and Genetics Samuel Oschin Comprehensive Cancer Institute 1
Type I versus Type II Endometrial Cancer Present Paradigm Type I tumors • Comprise the majority of endometrial cancer p j y • Mostly endometrial adenocarcinomas • Associated with unopposed estrogen stimulation • Often preceded by hyperplasia p y yp p Type II tumors • Predominantly serous and clear cell carcinomas • Less well-differentiated • Commonly estrogen ‘independent’ • Often arise in atrophic endometrium and derive from intraepithelial carcinoma de e o t aep t e a ca c o a • ~40% of deaths but only 10-20% of tumors Sherman ME Mod Pathol 2000;13:295-308 Sherman ME, Mod Pathol 2000;13:295-308 Setiawan W et al J Clin Oncol 2013;31:2607-18 Setiawan W, et al, J Clin Oncol 2013;31:2607-18 2
Type I versus Type II Endometrial Cancer Present Paradigm New E2C2 Results Type I tumors • Risk factor patterns for high-grade endometrioid tumors and type II tumors were • Comprise the majority of endometrial cancer p j y similar • Mostly endometrial adenocarcinomas • Parity, oral contraceptive use, cigarette • Associated with unopposed estrogen smoking, age at menarche, and diabetes were stimulation associated with type I and type II tumors to a • Often preceded by hyperplasia p y yp p similar extent similar extent • Body mass index had a somewhat greater Type II tumors effect on type I tumors than on type II tumors • Predominantly serous and clear cell • Etiology of type II tumors may not be carcinomas completely estrogen independent completely estrogen independent • Less well-differentiated • Commonly estrogen ‘independent’ • Often arise in atrophic endometrium and derive from intraepithelial carcinoma de e o t aep t e a ca c o a • ~40% of deaths but only 10-20% of tumors Sherman ME Mod Pathol 2000;13:295-308 Sherman ME, Mod Pathol 2000;13:295-308 Setiawan W et al J Clin Oncol 2013;31:2607-18 Setiawan W, et al, J Clin Oncol 2013;31:2607-18 3
Understanding Endometrial Cancer Biology Challenge Develop a comprehensive catalogue of endometrial cancer genes to guide prevention and therapeutic development 4
Understanding Endometrial Cancer Biology Challenge Develop a comprehensive catalogue of endometrial cancer genes to guide prevention and therapeutic development Only a handful of cancer genes are mutated at a high frequency; most cancer genes are mutated at an intermediate q y; g frequency (2-20%) 5
Understanding Endometrial Cancer Biology Challenge Develop a comprehensive catalogue of endometrial cancer genes to guide prevention and therapeutic development Only a handful of cancer genes are mutated at a high frequency; most cancer genes are mutated at an intermediate q y; g frequency (2-20%) Characterizing the role of endogenous and exogenous factors in shaping the mutational landscape of endometrial cancer in shaping the mutational landscape of endometrial cancer requires large numbers of well-annotated specimens 6
No. Samples Needed to Detect Significantly Mutated Genes as a Function of Median Background Mutation Frequency and Mutation Rate of Cancer Gene Most of the significant gene x tumor type pairs involve only a tumor type pairs involve only a Current TCGA sample Current TCGA sample small fraction of patients is inadequate to reliably detect genes One half of the significant mutated at <5% pairs involved ≤ 6.1% of above background patients One quarter of the significant pairs involved ≤ 3.1% of patients M Lawrence et al. Nature 2014;505:495-501 7
Understanding Endometrial Cancer Biology Challenge Develop a comprehensive catalogue of endometrial cancer genes to guide prevention and therapeutic development guide prevention and therapeutic development Only a handful of cancer genes are mutated at a high frequency; most cancer genes are mutated at an intermediate frequency (2 20%) frequency (2-20%) Characterizing the role of endogenous and exogenous factors in shaping the mutational landscape of endometrial cancer requires large numbers of well-annotated specimens requires large numbers of well-annotated specimens The best combination therapy for each endometrial cancer patient must be based on cellular pathways disrupted in her tumor and the nature of the specific disruptions tumor and the nature of the specific disruptions 8
Mortality among Patients with Colorectal Cancer, According to Regular Use or Nonuse of Aspirin after Diagnosis and PIK3CA Mutation Status Liao X et al. NEJM 2012;367:1596-1606 . 9
Genetic Heterogeneity versus Environmental Heterogeneity G Genetic Heterogeneity i H i E Environmental heterogeneity i l h i Intratumoral heterogeneity among the Do different endogenous / cells of one tumor exogenous exposures / insults lead t to unique mutations that may affect i t ti th t ff t Intermetastatic heterogeneity among tumor type and prognosis? different metastatic lesions of the same patient Intrametastatic heterogeneity among the cells of an individual metastasis I t Interpatient heterogeneity among the ti t h t it th tumors of different patients 10
Understanding Endometrial Cancer Biology Challenge Develop a comprehensive catalogue of endometrial cancer genes to guide prevention and therapeutic development Only a handful of cancer genes are mutated at a high frequency; most cancer genes are mutated at an intermediate frequency (2- 20%) Characterizing the role of endogenous and exogenous factors in shaping the mutational landscape of endometrial cancer requires large numbers of well-annotated specimens The best combination therapy for each endometrial cancer patient Th b t bi ti th f h d t i l ti t must be based on cellular pathways disrupted in her tumor and the nature of the specific disruptions Solution Identify and understand the pathway-level implications of mutated genes to guide prevention efforts and to provide therapeutic options 11
Number of Somatic Mutations in Representative Human Cancers B V B Vogelstein et al. Science l t i t l S i 2013;339:1546-1558 12
Number of Somatic Mutations in Representative Human Cancers In common solid tumors, ~33-66 genes display subtle somatic mutations that would be that would be expected to alter their protein products B V B Vogelstein et al. Science l t i t l S i 2013;339:1546-1558 13
Number of Somatic Mutations in Representative Human Cancers Certain tumors such Certain tumors such as lung cancer and melanoma display many more nonsynonymous mutations than average, probably b bl reflecting the involvement of potent mutagens B V B Vogelstein et al. Science l t i t l S i 2013;339:1546-1558 14
Mutation Spectra across Endometrial Carcinomas C Kandoth et al. Nature 2013;497:67 15
Tobacco Smoking Associated with Higher Mutation Rate in Lung Cancer Are Hotspot Mutations in POLE Smoking-Related in Endometrial Cancer? Lung Cancer 43% and 13% C:G → A:T transversions are found in smokers and never smokers respectively, suggesting that C:G → A:T transversion events C G in non-synonymous mutations are likely induced by carcinogens in smoke (Ding et al. Nature 2008;455:1069) 16
Tobacco Smoking Associated with Higher Mutation Rate in Lung Cancer Are Hotspot Mutations in POLE Smoking-Related in Endometrial Cancer? Lung Cancer 43% and 13% C:G → A:T transversions are found in smokers and never smokers respectively, suggesting that C:G → A:T transversion events C G in non-synonymous mutations are likely induced by carcinogens in smoke (Ding et al. Nature 2008;455:1069) Endometrial Cancer ~80% of the mutation events from mutations in POLE , a catalytic subunit of DNA polymerase epsilon that is polymerase epsilon that is involved in DNA replication and repair Ultramutated tumors have a distinctive mutation spectrum, p , exemplified by an elevated frequency of C → A transversions similar to lung cancer among smokers C Kandoth et al. Nature 2013;497:67 17
Number of Somatic Mutations in Representative Human Cancers Tumors with u o s mismatch repair defects can harbor thousands of mutations B V B Vogelstein et al. Science l t i t l S i 2013;339:1546-1558 18
Number of Somatic Mutations in Representative Human Cancers Pediatric tumors and leukemias harbor far fewer mutations < 10 / mutations < 10 / tumor B V B Vogelstein et al. Science l t i t l S i 2013;339:1546-1558 19
Number of Somatic Mutations in Representative Human Cancers Uterine endometrioid tumors average ~ 62 mutations versus serous tumors ~29 mutations t ti B V B Vogelstein et al. Science l t i t l S i 2013;339:1546-1558 20
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