The inherited genetics of ovarian and endometrial cancer.
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ABSTRACT:
SUBMITTER: Gayther SA
PROVIDER: S-EPMC3073171 | biostudies-literature | 2010 Jun
REPOSITORIES: biostudies-literature
Publications
The inherited genetics of ovarian and endometrial cancer.
Gayther Simon A SA Pharoah Paul D P PD
Current opinion in genetics & development 20100424 3
Endometrial and epithelial ovarian cancers are the fourth and fifth most common cancers in women in developed countries, after breast, lung, and colorectal cancer. In the United States alone, in 2008 there were about 40,000 new diagnoses of endometrial cancer and 7500 disease-related deaths. For ovarian cancer, there were about 22,000 new diagnoses and 15,000 deaths over the same period. The purpose of this article is to review the recent developments in the inherited genetics of ovarian and end ...[more]
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Project description:The importance of inflammation pathways to the development of many human cancers prompted us to examine the associations between single-nucleotide polymorphisms (SNP) in inflammation-related genes and risk of ovarian cancer. In a multisite case-control study, we genotyped SNPs in a large panel of inflammatory genes in 930 epithelial ovarian cancer cases and 1,037 controls using a custom array and analyzed by logistic regression. SNPs with P < 0.10 were evaluated among 3,143 cases and 2,102 controls from the Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI) post-GWAS collaboration. Combined analysis revealed association with SNPs rs17561 and rs4848300 in the interleukin gene IL1A which varied by histologic subtype (P(heterogeneity) = 0.03). For example, IL1A rs17561, which correlates with numerous inflammatory phenotypes, was associated with decreased risk of clear cell, mucinous, and endometrioid subtype, but not with the most common serous subtype. Genotype at rs1864414 in the arachidonate 5-lipoxygenase ALOX5 was also associated with decreased risk. Thus, inherited variation in IL1A and ALOX5 seems to affect ovarian cancer risk which, for IL1A, is limited to rarer subtypes. Given the importance of inflammation in tumorigenesis and growing evidence of subtype-specific features in ovarian cancer, functional investigations will be important to help clarify the importance of inherited variation related to inflammation in ovarian carcinogenesis.
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Project description:BackgroundEndometrial carcinoma (EC) and serous ovarian carcinoma (OvCa) are both among the common cancer types in women. EC can be divided into two subtypes, endometroid EC and serous-like EC, with distinct histological characterizations and molecular phenotypes. There is an increasing awareness that serous-like EC resembles serous OvCa in genetic landscape, but a clear relationship between them is still lacking.MethodsHere, we took advantage of the large-scale molecular profiling of The Cancer Genome Atlas(TCGA) to compare the two EC subtypes and serous OvCa. We used bioinformatics data analytic methods to systematically examine the somatic mutation (SM) and copy number alteration (SCNA), gene expression, pathway activities, survival gene signatures and immune infiltration. Based on these quantifiable molecular characterizations, we asked whether serous-like EC should be grouped more closely to serous OvCa, based on the context of being serous-like; or if should be grouped more closely to endometroid EC, based on the same organ origin.ResultsWe found that although serous-like EC and serous OvCa share some common genotypes, including mutation and copy number alteration, they differ in molecular phenotypes such as gene expression and signaling pathway activity. Moreover, no shared prognostic gene signature was found, indicating that they use unique genes governing tumor progression. Finally, although the endometrioid EC and serous OvCa are both highly immune infiltrated, the immune cell composition in serous OvCa is mostly immune suppressive, whereas endometrioid EC has a higher level of cytotoxic immune cells. Overall, our genetic aberration and molecular phenotype characterizations indicated that serous-like EC and serous OvCa cannot be simply treated as a simple "serous" cancer type. In particular, additional attention should be paid to their unique gene activities and tumor microenvironments for novel targeted therapy development.
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