Establishing the sensitivity and specificity of the gynaecological cancer distress screen.

OBJECTIVE: Nuanced distress screening tools can help cancer care services manage specific cancer groups' concerns more efficiently. This study examines the sensitivity and specificity of a tool specifically for women with gynaecological cancers (called the Gynaecological Cancer Distress Screen or DT-Gyn). METHODS: This paper presents cross-sectional data from individuals recently treated for gynaecological cancer recruited through Australian cancer care services, partner organisations, and support/advocacy services. Receiver operating characteristics analyses were used to evaluate the diagnostic accuracy of the DT-Gyn against criterion measures for anxiety (GAD-7), depression (patient health questionnaire), and distress (IES-R and K10). RESULTS: Overall, 373 individuals aged 19-91 provided complete data for the study. Using the recognised distress thermometer (DT) cut-off of 4, 47% of participants were classified as distressed, while a cut-off of 5 suggested that 40% had clinically relevant distress. The DT-Gyn showed good discriminant ability across all measures (IES-R: area under the curve (AUC) = 0.86, 95% CI = 0.82-0.90; GAD-7: AUC = 0.89, 95% CI = 0.85-0.93; K10: AUC = 0.88, 95% CI = 0.85-0.92; PHQ-9: AUC = 0.85, 95% CI = 0.81-0.89) and the Youden Index suggested an optimum DT cut-point of 5. CONCLUSIONS: This study established the psychometric properties of the DT-Gyn, a tool designed to identify and manage the common sources of distress in women with gynaecological cancers. We suggest a DT cut point ≥5 is optimal in detecting 'clinically relevant' distress, anxiety, and depression in this population.

Erosive Lichen Sclerosus-A Clinicopathologic Subtype.

OBJECTIVE: The aim of the study was to identify whether erosive lichen sclerosus (LS) is a distinct clinicopathologic subtype. MATERIALS AND METHODS: The pathology database was searched for "erosion," "erosive," "ulcer," and "lichen sclerosus." Inclusion criteria were histopathologic diagnosis of LS and erosion or ulcer overlying a band of hyalinization and/or fibrosis. Exclusions were concurrent neoplasia and insufficient tissue. Histopathologic review documented site, epithelial thickness, adjacent epidermal characteristics, infiltrate, and dermal collagen abnormality. Clinical data included demographics, comorbidities, examination findings, microbiologic results, treatment, and response. RESULTS: Ten examples of erosive LS and 15 of ulcerated LS occurred in 24 women with a mean age of 67 years. Ulcerated LS was associated with diabetes and nontreatment at time of biopsy. Clinicians identified red patches in all but 1 case of erosive LS. Ulcerated LS was documented as fissure, ulcer, or white plaque, with 8 (53%) described as lichenified LS with epidermal breaches. Erosive LS favored hairless skin with normal adjacent stratum corneum sloping gently into erosion, whereas most ulcers in LS had an abrupt slope from hair-bearing skin. All cases were treated with topical steroids; 2 patients with erosive LS and 10 with ulcerated LS also had oral antifungals, topical estrogen, antibiotics, and/or lesional excision. Treatment yielded complete resolution in 50%. CONCLUSIONS: Erosive LS is an unusual clinicopathologic subtype characterized by red patches on hairless skin seen microscopically as eroded epithelium overlying a band of hyalinized or fibrotic collagen. In contrast, ulcerated LS is usually a traumatic secondary effect in an uncontrolled dermatosis.

Nucleotide excision repair protein ERCC1 and tumour-infiltrating lymphocytes are potential biomarkers of neoadjuvant platinum resistance in high grade serous ovarian cancer.

OBJECTIVE: ERCC1 is a nucleotide excision repair protein that may have a role in drug resistance in high grade serous ovarian cancer (HGSOC). We hypothesized that ERCC1 expression and tumour infiltrating lymphocytes (TILS) are induced by chemotherapy in HGSOC, which may be prognostically useful. METHODS: 115 HGSOC patients were used for this study. 92 (80%) of the tissue analysed had not been exposed to platinum chemotherapy. The remaining 20% (n = 23) of cases received combination or monotherapy with carboplatin before tissue was collected. Immunohistochemistry was used to score for ERCC1 expression and morphology to score for TILs. Correlation analysis of all clinical parameters, TILs and ERCC1 and Kaplan-Meier survival analysis was performed using the ERCC1 and TILs scoring parameters (0, 1, 2 or 3). RESULTS: ERCC1 expression was 2-fold higher in the neoadjuvant chemotherapy group compared to the primary cytoreductive surgery group (p < 0.0001). The mean overall survival for the neoadjuvant group with high ERCC1 was 141.6 ±â€¯20.2 months which was significantly longer than absent ERCC1 survival of 61 + 22.6 months (p = 0.028). ERCC1 score strongly correlated with TILs score across the whole cohort (0.349, p = 1.3 × 10-4) suggesting there is a relationship between ERCC1 expression and TILs, but this requires further investigation. CONCLUSION: In conclusion, ERCC1 was identified as a potential biomarker of platinum response overall survival in HGSOC undergoing neoadjuvant HGSOC treatment.

Genetic overlap between endometriosis and endometrial cancer: evidence from cross-disease genetic correlation and GWAS meta-analyses.

Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (rg  = 0.23, P = 9.3 × 10-3 ), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10-3 ) and concordance in effect direction (P = 2.0 × 10-3 ) between the two diseases. Cross-disease GWAS meta-analysis highlighted 13 distinct loci associated at P ≤ 10-5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10-8 , OR = 1.11, 95% CI = 1.07-1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross-disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.

Expression of renin-angiotensin system (RAS) components in endometrial cancer.

A dysfunctional endometrial renin-angiotensin system (RAS) could aid the growth and spread of endometrial cancer. To determine if the RAS is altered in endometrial cancer, we measured RAS gene expression and protein levels in 30 human formalin-fixed, paraffin-embedded (FFPE) endometrioid carcinomas and their adjacent endometrium. All components of the RAS were expressed in most tumours and in adjacent endometrium; mRNA levels of (pro)renin receptor (ATP6AP2), angiotensin II type 1 receptor (AGTR1), angiotensin-converting enzyme (ACE1) and angiotensin-converting enzyme 2 (ACE2) mRNA levels were greater in tumour tissue than adjacent non-cancerous endometrium (P = 0.023, 0.008, 0.004 and 0.046, respectively). Prorenin, ATP6AP2, AGTR1, AGTR2 and ACE2 proteins were abundantly expressed in both cancerous and adjacent non-cancerous endometrium. Staining was most intense in cancerous glandular epithelium. One potential target of the endometrial RAS, transforming growth factor beta-1 (TGFB1), which is essential for epithelial-to-mesenchymal transition, was also upregulated in endometrial cancer tissue (P = 0.001). Interestingly, TGFB1 was strongly correlated with RAS expression and was upregulated in tumour tissue. This study is the first to characterise the mRNA and protein expression of all RAS components in cancerous and adjacent non-cancerous endometrium. The greater expression of ATP6AP2, AGTR1 and ACE1, key elements of the pro-angiogenic/proliferative arm of the RAS, suggests that the RAS plays a role in the growth and spread of endometrial cancer. Therefore, existing drugs that inhibit the RAS and which are used to treat hypertension may have potential as treatments for endometrial cancer.

Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer.

BACKGROUND: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist-hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. METHODS: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. RESULTS: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10-17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89-2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44-1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10-1.39; P = 5.3 × 10-4). There was evidence of directional pleiotropy (P = 1.5 × 10-4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10-4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS. CONCLUSIONS: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. IMPACT: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503-10. ©2016 AACR.

Renin-angiotensin system gene polymorphisms and endometrial cancer.

Endometrial cancer (EC) is the most common gynaecological malignancy and its incidence is increasing. Dysregulation of the endometrial renin-angiotensin system (RAS) could predispose to EC; therefore, we studied the prevalence of RAS single nucleotide polymorphisms (SNPs) in Australian women with EC. SNPs assessed were AGT M235T (rs699); AGTR1 A1166C (rs5186); ACE A240T and T93C (rs4291, rs4292) and ATP6AP2 (rs2968915). They were identified using TaqMan SNP Genotyping Assays. The C allele of the AGTR1 SNP (rs5186) was more prevalent in women with EC (odds ratio (OR) 1.7, 95% confidence interval (CI) (1.2-2.3), P=0.002). The CC genotype of this SNP is associated with upregulation of the angiotensin II type 1 receptor (AGTR1). The G allele of AGT rs699, which is associated with higher angiotensinogen (AGT) levels, was less prevalent in women with EC (OR 0.54, 95% CI (0.39-0.74), P<0.001) compared with controls. AGT and AGT formed by removal of angiotensin I (des(Ang I)AGT) are both anti-angiogenic. In women with EC who had had hormone replacement therapy (HRT), the prevalence of the AGTR1 SNP (rs5186) and the ACE SNPs (rs4291 and rs4292) was greater than in women who had no record of HRT; SNP rs4291 is associated with increased plasma ACE activity. These data suggest there is an interaction between genotype, oestrogen replacement therapy and EC. In conclusion, the prevalence of two SNPs that enhance RAS activity was different in women with EC compared with healthy controls. These genetic factors may interact with obesity and hyperoestrogenism, predisposing ageing, obese women to EC.

Targeted next-generation sequencing of 22 mismatch repair genes identifies Lynch syndrome families.

Causative germline mutations in mismatch repair (MMR) genes can only be identified in ~50% of families with a clinical diagnosis of the inherited colorectal cancer (CRC) syndrome hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome (LS). Identification of these patients are critical as they are at substantially increased risk of developing multiple primary tumors, mainly colorectal and endometrial cancer (EC), occurring at a young age. This demonstrates the need to develop new and/or more thorough mutation detection approaches. Next-generation sequencing (NGS) was used to screen 22 genes involved in the DNA MMR pathway in constitutional DNA from 14 HNPCC and 12 sporadic EC patients, plus 2 positive controls. Several softwares were used for analysis and functional annotation. We identified 5 exonic indel variants, 42 exonic nonsynonymous single-nucleotide variants (SNVs) and 1 intronic variant of significance. Three of these variants were class 5 (pathogenic) or class 4 (likely pathogenic), 5 were class 3 (uncertain clinical relevance) and 40 were classified as variants of unknown clinical significance. In conclusion, we have identified two LS families from the sporadic EC patients, one without a family history of cancer, supporting the notion for universal MMR screening of EC patients. In addition, we have detected three novel class 3 variants in EC cases. We have, in addition discovered a polygenic interaction which is the most likely cause of cancer development in a HNPCC patient that could explain previous inconsistent results reported on an intronic EXO1 variant.

CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer.

Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10(-11)). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.

Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1.

High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10(-9)) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10(-8)), with the alleles showing opposite effects on the risks of the two cancers.

The problem of late ovarian metastases from primary cervical adenocarcinoma.

•Ovarian metastases can occur after hysterectomy for cervical adenocarcinoma.•Cervical adenocarcinoma and ovarian metastases showed common genetic profiles.•Most likely mechanism is trans-tubal spread of neoplastic cells via ovarian stroma.

Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer.

Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86×10(-5)), which was stronger for cancers of endometrioid subtype (P=3.76×10(-6)). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types.

Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk.

Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.

Unusual locations of primary subepithelial squamous cell carcinomas of the vulva.

OBJECTIVE: This study aimed to report 2 cases of squamous cell carcinoma (SCC) of the vulva, arising from unusual subepithelial locations. MATERIALS AND METHODS: The first case was of an 85-year-old woman with a 65-year history of a mass in the left labium majus. The second case was of a 54-year-old woman who presented with a 1-week history of a painful left inguinal mass. She had previously sought medical attention for a 2-year history of a left-sided painless vestibular mass. RESULTS: In the first case, a simple excision showed a purely dermal SCC with no attachment to the epidermis. After the diagnosis of SCC, a wide, deep local excision of the left side of the vulva and left inguinofemoral lymph node dissection were performed. Pathological findings showed no residual tumor in the vulva, and the lymph nodes were clear. Based on the long history of a mass at the same site, the pathogenesis of the SCC was considered to be malignant degeneration of a previously benign epidermal cyst.In the second case, SCC was diagnosed on fine-needle aspirations of the vulvar and groin masses. The patient was treated with primary chemoradiation. Subsequently, wide, deep local excision of the left side of the vulva and left inguinofemoral lymph node dissection were performed. No residual tumor was found in the vulva, although atrophic Bartholin gland tissue was found at the site of the SCC. One 5-mm inguinofemoral lymph node metastasis was found in the groin node dissection. In the absence of any evidence of another pathogenesis, it was believed that the SCC had arisen from an unusually anterior located Bartholin gland. CONCLUSIONS: Subepithelial SCC should be considered in the differential diagnosis of unusually located vulvar masses.

Genome-wide association study identifies a possible susceptibility locus for endometrial cancer.

BACKGROUND: Genome-wide association studies (GWAS) have identified more than 100 genetic loci for various cancers. However, only one is for endometrial cancer. METHODS: We conducted a three-stage GWAS including 8,492 endometrial cancer cases and 16,596 controls. After analyzing 585,963 single-nucleotide polymorphisms (SNP) in 832 cases and 2,682 controls (stage I) from the Shanghai Endometrial Cancer Genetics Study, we selected the top 106 SNPs for in silico replication among 1,265 cases and 5,190 controls from the Australian/British Endometrial Cancer GWAS (stage II). Nine SNPs showed results consistent in direction with stage I with P < 0.1. These nine SNPs were investigated among 459 cases and 558 controls (stage IIIa) and six SNPs showed a direction of association consistent with stages I and II. These six SNPs, plus two additional SNPs selected on the basis of linkage disequilibrium and P values in stage II, were investigated among 5,936 cases and 8,166 controls from an additional 11 studies (stage IIIb). RESULTS: SNP rs1202524, near the CAPN9 gene on chromosome 1q42.2, showed a consistent association with endometrial cancer risk across all three stages, with ORs of 1.09 [95% confidence interval (CI), 1.03-1.16] for the A/G genotype and 1.17 (95% CI, 1.05-1.30) for the G/G genotype (P = 1.6 × 10(-4) in combined analyses of all samples). The association was stronger when limited to the endometrioid subtype, with ORs (95% CI) of 1.11 (1.04-1.18) and 1.21 (1.08-1.35), respectively (P = 2.4 × 10(-5)). CONCLUSIONS: Chromosome 1q42.2 may host an endometrial cancer susceptibility locus. IMPACT: This study identified a potential genetic locus for endometrial cancer risk.