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ObjectivesThe ability to stratify a patient's risk of metastasis and survival permits more refined care. A proof of principle study was undertaken to investigate the relationship between single nucleotide polymorphisms (SNPs) in literature based candidate cancer genes and the risk of nodal metastasis and clinical outcome in endometrioid endometrial cancer (EEC) patients.MethodsSurgically-staged EEC patients from the Gynecologic Oncology Group or Washington University School of Medicine with germline DNA available were eligible. Fifty-four genes represented by 384 SNPs, were evaluated by Illumina Custom GoldenGate array. Association with lymph node metastases was the primary outcome. Progression-free survival (PFS) and overall survival (OS) was also evaluated.Results361 SNPs with high quality genotype data were evaluated in 337 patients with outcome data. Five SNPs in CXCR2 had an odds ratio (OR) between 0.68 and 0.70 (p-value ≤ 0.025). The A allele rs946486 in ABL had an OR of 1.5 (p-value = 0.01) for metastasis. The G allele in rs7795743 in EGFR had an OR for metastasis of 0.68 (p-value = 0.02) and hazard ratio (HR) for progression of 0.66 (p-value = 0.004). Importantly, no SNP met genome wide significance after adjusting for multiple test correcting and clinical covariates. The A allele in rs2159359 SNP in NME1 and the G allele in rs13222385 in EGFR were associated with worse OS. Both exhibited genome wide significance; rs13222385 remained significant after adjusting for prognostic clinical variables.ConclusionSNPs in cancer genes including rs2159359 SNP in NME1 and rs13222385 in EGFR may stratify risk in EEC and are prioritized for further investigation.

The initial molecular events that lead to malignant transformation of the fimbria of the fallopian tube (FT) through high-grade serous ovarian carcinoma (HGSC) remain poorly understood. In this study, we report that increased expression of signal transducer and activator of transcription 3 (pSTAT3 Tyr705) and suppression or loss of protein inhibitor of activated STAT3 (PIAS3) in FT likely drive HGSC. We evaluated human tissues-benign normal FT, tubal-peritoneal junction (TPJ), p53 signature FT tissue, tubal intraepithelial lesion in transition (TILT), serous tubal intraepithelial carcinoma (STIC) without ovarian cancer, and HGSC for expression of STAT3/PIAS3 (compared with their known TP53 signature) and their target proliferation genes. We observed constitutive activation of STAT3 and low levels or loss of PIAS3 in the TPJ, p53 signature, TILT, and STIC through advanced stage IV (HGSC) tissues. Elevated expression of pSTAT3 Tyr705 and decreased levels of PIAS3 appeared as early as TPJ and the trend continued until very advanced stage HGSC (compared with high PIAS3 and low pSTAT3 expression in normal benign FT). Exogenous expression of STAT3 in FT cells mediated translocation of pSTAT3 and c-Myc into the nucleus. In vivo experiments demonstrated that overexpression of STAT3 in FT secretory epithelial cells promoted tumor progression and metastasis, mimicking the clinical disease observed in patients with HGSC. Thus, we conclude that the STAT3 pathway plays a role in the development and progression of HGSC from its earliest premalignant states.Significance: Concomitant gain of pSTAT3 Tyr705 and loss of PIAS3 appear critical for initiation and development of high-grade serous carcinoma. Cancer Res; 78(7); 1739-50. ©2018 AACR.

Background: Mismatch‐repair (MMR)/microsatellite instability (MSI) status has therapeutic implications in endometrial cancer (EC). The authors evaluated the concordance of testing and factors contributing to MMR expression heterogeneity. Methods: Six hundred sixty‐six ECs were characterized using immunohistochemistry (IHC), MSI testing, and mut‐L homolog 1 (MLH1) methylation. Select samples underwent whole‐transcriptome analysis and next‐generation sequencing. MMR expression of metastatic/recurrent sites was evaluated. Results: MSI testing identified 27.3% of cases as MSI‐high (n = 182), MMR IHC identified 25.1% cases as MMR‐deficient (n = 167), and 3.8% of cases (n = 25) demonstrated discordant results. A review of IHC staining explained discordant results in 18 cases, revealing subclonal loss of MLH1/Pms 1 homolog 2 (PMS2) (n = 10) and heterogeneous MMR IHC (mut‐S homolog 6 [MSH6], n = 7; MLH1/PMS2, n = 1). MSH6‐associated Lynch syndrome was diagnosed in three of six cases with heterogeneous expression. Subclonal or heterogeneous cases had a 38.9% recurrence rate (compared with 16.7% in complete MMR‐deficient cases and 9% in MMR‐proficient cases) and had abnormal MMR IHC results in all metastatic recurrent sites (n = 7). Tumors with subclonal MLH1/PMS2 demonstrated 74 differentially expressed genes (determined using digital spatial transcriptomics) when stratified by MLH1 expression, including many associated with epithelial–mesenchymal transition. Conclusions: Subclonal/heterogeneous MMR IHC cases showed epigenetic loss in 66.7%, germline mutations in 16.7%, and somatic mutations in 16.7%. MMR IHC reported as intact/deficient missed 21% of cases of Lynch syndrome. EC with subclonal/heterogeneous MMR expression demonstrated a high recurrence rate, and metastatic/recurrent sites were MMR‐deficient. Transcriptional analysis indicated an increased risk for migration/metastasis, suggesting that clonal MMR deficiency may be a driver for tumor aggressiveness. Reporting MMR IHC only as intact/deficient, without reporting subclonal and heterogeneous staining, misses opportunities for biomarker‐directed therapy. Plain Language Summary: Endometrial cancer is the most common gynecologic cancer, and 20%–40% of tumors have a defect in DNA proofreading known as mismatch‐repair (MMR) deficiency.These results can be used to guide therapy.Tests for this defect can yield differing results, revealing heterogeneous (mixed) proofreading capabilities.Tumors with discordant testing results and mixed MMR findings can have germline or somatic defects in MMR genes.Cells with deficient DNA proofreading in tumors with mixed MMR findings have DNA expression profiles linked to more aggressive characteristics and cancer spread.These MMR‐deficient cells may drive tumor behavior and the risk of spreading cancer. Intratumoral heterogeneity, including subclonal and heterogeneous mismatch‐repair (MMR) expression, can yield discordant results from diagnostic assays, such as immunohistochemistry and polymerase chain reaction‐based microsatellite instability testing. Within endometrial cancers, subclonal or heterogeneous MMR expression may be attributed to germline or somatic mutations in MMR proteins, and the authors demonstrate that these tumors are characterized by clonal selection favoring the propagation of MMR deficiency at sites of metastasis or recurrence. [ABSTRACT FROM AUTHOR]

PurposeHereditary nonpolyposis colon cancer is caused by mutations in DNA mismatch repair genes, predominantly MLH1 and MSH2. Classic MLH1 mutations cause an approximately 20-fold increase in colorectal cancer susceptibility. Recently, we identified a hypomorphic allele, MLH1 D132H , which impairs, but does not completely eliminate the function of MLH1 in tumor suppression. MLH1 D132H confers an approximately fivefold increase in colorectal cancer susceptibility and was first described in a cohort of Israeli colorectal cancer patients, with an estimated allele frequency of 1.3 percent. Because MLH1 D132H has only recently been described, the ethnic distribution of this risk allele is not well understood. This study was undertaken to determine both the frequencies of this risk allele in ethnic groups outside of Israel and whether families harboring this mutation have susceptibility to extracolonic cancers in the hereditary nonpolyposis colon cancer spectrum.MethodsWe genotyped two independent cohorts: 629 population-based colorectal cancer patients ascertained from clinics in Orange, Imperial, and San Diego Counties, and 515 endometrial cancer patients ascertained from gynecologic oncology clinics in the Midwestern United States.ResultsMLH1 D132H was not detected in either study cohort, which together totaled more than 1,100 American colorectal cancer and endometrial cancer patients.ConclusionsThe MLH1 D132H risk variant has significantly lower allele frequency in American compared with Israeli cancer patients and, alone, is unlikely to explain significant amounts of American sporadic colorectal cancer or uterine cancer susceptibility. Genetic testing for the MLH1 D132H allele exclusively is therefore unlikely to be cost effective for genetic risk assessment in American population-based and clinic-based colorectal cancer and endometrial cancer patients.