In this study, we directly sequenced the Melanocortin 1 Receptor (MC1R) gene in 2,212 individuals to detect all variants and assessed their associations with cutaneous melanoma (CM) risk in a hospital-based study of 1,106 CM patients and 1,106 control subjects. Of 61 MC1R variants identified, 16 rare variants have not been previously reported by others; three MC1R variants were associated with a significant CM risk [c.451C>T (OR = 1.78, 95% CI = 1.44–2.20), c.478C>T (OR = 1.31, 95% CI = 1.05–1.63), and c.880G>C (OR = 1.69, 95% CI = 1.15–2.48)]; and two with borderline CM risk [c.942A>G (OR =1.23, 95% CI =1.00–1.51, and c.274G>A (OR = 1.23,95% CI = 0.99–1.53)] under a dominant model. When combined these five MC1R variants for cumulative effect analysis, we found that subjects with an increased number of variant genotypes from any of these five variants had significantly increased risk of CM with ORs of 1.68 (95% CI = 1.39–2.04), 1.61 (95% CI = 1.27–2.04), and 2.64 (95% CI = 1.72–4.05) for one, two, and three or more variant genotypes, respectively (trend test: P <0.001). Further haplotype and diplotype analyses based on the above-mentioned five SNPs suggested that the c.451T allele contributed to the high risk of CM and that the five variants may have joint effects on the risk of CM. Additional analysis suggests that the three most significant SNPs may be the molecular mechanisms underlying the known risk factors of the colors of the eyes, skin and hair in this study population. In conclusion, our study provided confirmatory evidence that both common and rare variants in the MC1R coding region may be biomarkers for susceptibility to CM in US populations.
melanocortin 1 receptor gene; direct sequencing; interaction; melanoma; case-control
Recently, we reported on the associations of seven single-nucleotide polymorphisms (SNPs) in the promoter region of MMP1 gene with susceptibility to cutaneous melanoma (CM). Considering the reported correlation between MMP1 expression and melanoma progression, we hypothesized that these promoter SNPs might affect CM progression and prognosis. In this study, we examined the associations of the seven SNPs with overall survival as well as six clinicopathologic factors in 754 patients with CM. After adjustment for 11 covariates, we observed significant association of the SNP −422A > T (rs475007) with ulceration status (P = 0.012), primary tumor thickness (P = 0.040), and anatomic site (P = 0.030). We also observed significant association of the SNP −755T > G (rs498186) with ulceration status (P = 0.038) and anatomic site (P = 0.003). Two SNPs −839G > A and −519A > G were marginally associated with primary tumor thickness, ulceration status, and anatomic site. Furthermore, the frequency of haplotype 2G-G-G-A-A-G-T was higher in patients with ulceration (odds ratio [OR] = 2.18, 95% confidence interval [CI] 1.08–4.40, P = 0.030) than that in those without ulceration. However, we did not find significant associations of these SNPs with overall survival and other clinical factors. Since primary tumor thickness and ulceration status are two important indicators of tumor progression and have significant associations with melanoma prognosis, our results suggested that these promoter SNPs in MMP1 might have potential effects on melanoma progression and prognosis by influencing related clinical factors.
Genotypes; Melanoma; Survival; Tumor characters; Molecular epidemiology
We performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to melanoma from markers on chromosome 9p21.3 in the p16/ARF region and on chromosome 1q21.3 (ARNT/LASS2/ANXA9 region). The most significant single-nucleotide polymorphisms (SNPs) in the 15q13.1 locus (rs1129038 and rs12913832) lie within a genomic region that has profound effects on eye and skin color; notably, 50% of variability in eye color is associated with variation in the SNP rs12913832. Because eye and skin colors vary across European populations, we further evaluated the associations of the significant SNPs after carefully adjusting for European substructure. We also evaluated the top 10 most significant SNPs by using data from three other genome-wide scans. Additional in silico data provided replication of the findings from the most significant region on chromosome 1q21.3 rs7412746 (P = 6 × 10−10). Together, these data identified several candidate genes for additional studies to identify causal variants predisposing to increased risk for developing melanoma.
Clinical trials on adoptive T-cell therapy (ACT) using expanded tumor-infiltrating lymphocytes (TIL) have shown response rates of over 50% in refractory melanoma. However, little is known how clinical and pathologic features impact TIL outgrowth isolated from metastatic melanoma tumors.
We analyzed the impact of clinical and pathologic features on initial TIL outgrowth in 226 consecutive patients undergoing tumor resection. Successful initial TIL outgrowth was defined as ≥40 million viable lymphocytes harvested from all tumor fragments in a 5-week culture. To normalize for the different size of resected tumors and thus available tumor fragments, we divided the number of expanded TIL by the starting number of tumor fragments (TIL/fragment).
Overall, initial TIL outgrowth was successful in 62% of patients, with patients ≤30 years of age (94%; p=0.01) and female patients (71% vs. 57% for males; p=0.04) having the highest rate of success. Systemic therapy 30 days prior to tumor harvest negatively impacted initial TIL outgrowth compared to patients who never received systemic therapy (47% versus 71%, p=0.02). Biochemotherapy within 0–60 days of tumor harvest negatively impacted the initial TIL outgrowth with a success rate of only 16% (p<0.0001).
Parameters such as age, sex, and the type and timing of prior systemic therapy significantly affect the success rate of the initial TIL outgrowth from tumor fragments for ACT; these parameters may be helpful in selecting patients for melanoma ACT.
We and others have demonstrated that additional positive lymph nodes (LNs) are identified in only 8% to 33% of patients with melanoma who have positive sentinel LNs (SLNs) and undergo complete therapeutic LN dissection (cTLND). We sought to determine predictors of additional regional LN involvement in patients with positive SLNs.
Patients and Methods
Patients with clinically node-negative melanoma who underwent SLN biopsy (1991 to 2003) and had positive SLNs were identified. Clinicopathologic factors, including extent of microscopic disease within SLNs, were evaluated as potential predictors of positive non-SLNs.
Overall, 359 (16.3%) of the 2,203 patients identified had a positive SLN. Positive non-SLNs were identified in 48 (14.0%) of the 343 patients with positive SLNs who underwent cTLND. On univariate analysis, several measures of SLN microscopic tumor burden, one versus three or more SLNs harvested, tumor thickness more than 2 mm, age older than 50 years, and Clark level higher than III were predictive of positive non-SLNs; primary tumor ulceration and number of positive SLNs had no apparent impact. On multivariable logistic regression analysis, measures of SLN microscopic tumor burden were the most significant independent predictors of positive non-SLNs; tumor thickness more than 2 mm and number of SLNs harvested also predicted additional disease. A model was developed that stratified patients according to their risk for non-SLN involvement.
In melanoma patients with positive SLNs, SLN tumor burden, primary tumor thickness, and number of SLNs harvested may be useful in identifying a group at low risk for positive non-SLNs and be spared the potential morbidity of a cTLND.
Meta-analyses were performed to examine the utility of ultrasonography, computed tomography (CT), positron emission tomography (PET), and a combination of both (PET-CT) for the staging and surveillance of melanoma patients.
Patient-level data from 74 studies containing 10 528 patients (between January 1, 1990, and June, 30, 2009) were used to derive characteristics of the diagnostic tests used. Meta-analyses were conducted by use of Bayesian bivariate binomial models to estimate sensitivity and specificity. Diagnostic odds ratios [ie, true-positive results/false-negative results)/(false-positive results/true-negative results)] and their 95% credible intervals (CrIs) and positive predictive values were used as indicators of test performance.
Among the four imaging methods examined for the staging of regional lymph nodes, ultrasonography had the highest sensitivity (60%, 95% CrI = 33% to 83%), specificity (97%, 95% CrI = 88% to 99%), and diagnostic odds ratio (42, 95% CrI = 8.08 to 249.8). For staging of distant metastases, PET-CT had the highest sensitivity (80%, 95% CrI = 53% to 93%), specificity (87%, 95% CrI = 54% to 97%), and diagnostic odds ratio (25, 95% CrI = 3.58 to 198.7). Similar trends were observed for melanoma surveillance of lymph node involvement, with ultrasonography having the highest sensitivity (96%, 95% CrI = 85% to 99%), specificity (99%, 95% CrI = 95% to 100%), and diagnostic odds ratio (1675, 95% CrI = 226.6 to 15,920). For distant metastases, PET-CT had the highest sensitivity (86%, 95% CrI = 76% to 93%), specificity (91%, 95% CrI = 79% to 97%), and diagnostic odds ratio (67, 95% CrI = 20.42 to 229.7). Positive predictive values were likewise highest for ultrasonography in lymph node staging and for PET-CT in detecting distant metastases.
Among the compared modalities, ultrasonography was superior for detecting lymph node metastases, and PET-CT was superior for the detection of distant metastases in both the staging and surveillance of melanoma patients.
Matrix Metallopeptidase 1 (MMP1) is one of the interstitial collagens in the extracellular matrix metalloproteinase family and involved in tumor behaviors. However, there is no report on the role of genetic variation in MMP1 in risk of cutaneous melanoma (CM). We investigated the association between genotypes and haplotypes of seven reported MMP1 promoter polymorphisms (-1607 G ins/del, -839G>A, -755T>G, -519A>G, -422A>T, -340A>G, and -320T>C, genotyped by the TaqMan assay) and CM risk in 872 patients and 873 cancer-free controls. These seven polymorphisms were not in linkage disequilibrium among each other (r2 < 0.63). Compared to their common homozygous genotypes, the variant -519GG was associated with significantly decreased CM risk (adjusted odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.52-0.99), whereas variant -422TT and -320CC were associated with significantly increased CM risk (OR = 1.50, 95% CI = 1.11-2.03 and OR = 1.72, 95% CI = 1.05-2.81, respectively) after adjustment for age, sex, family history, and sun-exposure related risk factors. The number of risk alleles of these three polymorphisms was associated with CM risk in a dose- response manner (Ptrend = 0.0002). In the stratification analysis, we found that the associations of these polymorphisms with CM risk were modified by some of the risk factors. Furthermore, the haplotypes Gdel-A-G-A-T-G-T and G-G-G-A-T-A-T were associated with significantly increased CM risk (ORs = 1.56 and 2.13, 95% CIs = 1.02-2.38 and 1.22-3.70, respectively). These findings suggest that MMP1 promoter polymorphisms may individually or jointly play roles in the development of CM.
genotypes; haplotypes; genetic susceptibility; molecular epidemiology; skin neoplasms
We prospectively assessed the incidence, risk factors, and costs associated with wound complications and lymphedema in melanoma patients undergoing inguinal lymph node dissection (ILND).
Materials and Methods
A total of 53 melanoma patients were accrued to 2 trials (June 2005 to July 2008) that included prospective evaluations of postoperative complications; 30-day wound complications included infection, seroma, and/or dehiscence. There were 20 patients who underwent limb volume measurement and completed a 19-item lymphedema symptom assessment questionnaire preoperatively and 3 months postoperatively. A multivariate analysis was performed to evaluate potential risk factors for complications. A microcosting analysis was also performed to evaluate the direct costs associated with wound complications.
The 30-day wound complications were noted in 77.4% of patients. A BMI ≥ 30 (n = 28) increased the risk for wound complications (odds ratio [OR] = 11.4, 95% confidence interval [95%CI] 1.6–78.5, P = .01), while advanced nodal disease approached significance (OR = 9.0, 95%CI: 0.79–103.1, P = .08). Other risk factors, including diabetes, smoking, and the addition of a deep pelvic (iliac/obturator) dissection to ILND, were not significant. Of 20 patients, 9 (45%) developed limb volume change (LVC) ≥5% at 3 months, with associated mean symptom scores of 6.1 versus 4.6 for those without LVC. Costs for patients with wound complications were significantly higher than for those without wound complications.
Postoperative wound complications and early onset lymphedema occur frequently following ILND for melanoma. Obesity is an adverse risk factor for 30-day wound complications that can significantly increase postoperative costs, as is likely the case for advanced disease. Risk reduction practices and novel treatment approaches are needed to reduce postoperative morbidity.
Conditional survival (CS) has emerged as a clinically relevant measure of prognosis for cancer survivors. The objective of this analysis was to provide melanoma-specific CS estimates to help clinicians promote more informed patient decision-making.
Patients with melanoma and at least 5 years of follow-up were identified from the Surveillance Epidemiology and End Results (SEER) registry (1988–2000). Using the methods of Kaplan and Meier, stage-specific 5-year CS estimates were independently calculated for survivors for each year following diagnosis. Stage-specific multivariate Cox regression models including baseline survivor functions were used to calculate adjusted melanoma-specific CS for different subgroups of patients further stratified by age, gender, race, marital status, anatomic tumor location, and tumor histology.
Five-year CS estimates for stage I patients remained constant at 97% annually, while for patients with stages II, III and IV disease, 5-year CS estimates from time 0 (diagnosis) to 5 years improved from 72% to 86%, 51% to 87%, and 19% to 84%, respectively. Multivariate CS analysis revealed that differences in stages II through IV CS based on age, gender and race decreased over time.
Five-year melanoma-specific CS estimates improve dramatically over time for survivors with advanced stages of disease. These prognostic data are critical to patients for both treatment and non-treatment related life decisions.
melanoma; conditional survival; SEER
Caspase-8 (CASP8) and caspase-10 (CASP10) play key roles in regulating apoptosis, and functional polymorphisms of them may alter apoptosis and cancer risk. However, no reported studies have investigated the association between such polymorphisms and the risk of cutaneous melanoma (CM). In a hospital-based study of 805 non-Hispanic white patients with CM and 835 cancer-free age- sex- and ethnicity-matched controls, we genotyped three reported putatively functional polymorphisms of CASP8 and CASP10--CASP8 D302H (rs1045485:G>C), CASP8-652 6N del (rs3834129:–/CTTACT), and CASP10 I522L (rs13006529:A>T)--and assessed their associations with risk of CM and interactions with known risk factors for CM. We also calculated the false-positive-report probability (FPRP) for significant findings. CASP8 302H variant genotypes (DH: adjusted odds ratio [OR], 0.70 [95% confidence interval (CI), 0.50-0.98]; DH+HH: unadjusted OR, 0.78 [95% CI, 0.62-0.98]; FPRP, 0.79) and CASP8 -652 6N del variant genotypes (ins/del: OR, 0.74 [95% CI, 0.57-0.97]; ins/del+del/del: OR, 0.76 [95% CI, 0.61-0.95]; FPRP, 0.61) were associated with significantly lower CM risk than were the ins/ins genotypes. The CASP10 522L variant genotypes were not associated with significantly altered CM risk. Also, the D-del-I haplotype was associated with a significantly lower CM risk (OR, 0.52 [95% CI, 0.37-0.74]; FPRP, 0.116) than was the most common haplotype, D-ins-I. Furthermore, multivariate logistic regression analysis revealed that CASP8 D302H, CASP8 -652 6N del, and CASP10 I522L were independent risk factors for CM. Therefore, these CASP8 and CASP10 variant polymorphisms may be biomarkers for susceptibility to CM.
apoptosis; death pathway; genetic susceptibility; molecular epidemiology; skin cancer
In a hospital-based case-control study of 805 non-Hispanic whites with cutaneous melanoma and 841cancer-free age-, sex- and ethnicity-matched control subjects, three VDR polymorphisms (i.e., TaqI, BsmI, and FokI) were genotyped using blood samples collected between 1994 and 2006. We tested the hypothesis that the haplotypes and combined genotypes of these polymorphisms were associated with melanoma risk by interacting with known risk factors. Haplotypes t-B-F (adjusted odds ratio [OR], 0.52; 95 percent confidence interval [CI], 0.34–0.80) and t-B-f (adjusted OR, 0.51; CI, 0.27–0.94) were associated with a reduced risk when compared with T-b-f. The combined genotypes Tt+tt/Bb+BB/Ff+ff (adjusted OR, 0.69; CI, 0.52, 0.90) and Tt+tt/Bb+BB/FF (adjusted OR, 0.58; CI, 0.43, 0.78) were also associated with reduced risk, whereas the combined genotype TT/Bb+BB/Ff+ff genotype (adjusted OR, 2.35; CI, 1.13, 4.98) was associated with increased risk when compared with TT/bb/Ff+ff genotypes. On multivariate analysis, only the TaqI polymorphism was an independent risk factor, while the FokI polymorphism interacted with skin color (p = 0.029), moles (p = 0.017), and first-degree relatives with any cancer (p = 0.013) in modifying risk. Together, these findings suggest that VDR polymorphisms may directly effect or modify the risk associated with known melanoma risk factors. Larger, population-based studies are needed to replicate our findings.
case-control studies; vitamin D receptor; genetic polymorphisms; genotypes; melanoma
case-control study; cell cycle; DNA repair; genetic polymorphism; skin cancer
The objectives of this analysis were to compare various measures associated with lymph node (LN) dissection and to identify threshold values associated with disease-specific survival (DSS) outcomes in patients with melanoma.
Patients with node positive melanoma who underwent therapeutic LN dissection of the neck, axilla, and inguinal region were identified from the SEER database (1988–2005). We performed Cox multivariate analyses to determine the impact of the total number of LNs removed, number of negative LNs removed, and LN ratio on DSS. Multivariate cut-point analyses were conducted for each anatomic region to identify the threshold values associated with the largest improvement in DSS.
The LN ratio was significantly associated with DSS for all LN regions. The LN ratio thresholds resulting in the greatest difference in 5-year DSS were 0.07, 0.13, and 0.18 for neck, axillary, and inguinal regions, respectively, corresponding to 15, 8, and 6 LNs removed per positive node. After adjustment for other clinicopathologic factors, the hazard ratios (HRs) were 0.53 (95% confidence intervals (CIs), 0.40 to 0.71) in the neck, 0.52 (95% CI, 0.42 to 0.65) in the axillary, and 0.47 (95% CI, 0.36 to 0.61) in the inguinal regions for patients in whom the LN ratio threshold was met.
Among the prognostic factors examined, LN ratio was the best indicator of the extent of LN dissection, regardless of anatomic nodal region. These data provide evidence-based guidelines for defining adequate LN dissections in melanoma patients.
melanoma; lymphadenectomy; lymph node ratio; disease-specific survival
This study assessed the impact of closed suction drains and evaluated whether the intraoperative use of a fibrin sealant decreased time to drain removal and wound complications in melanoma patients undergoing inguino-femoral lymph node dissection.
A pilot study (n = 18) assessed the impact of a closed suction drain following inguino-femoral lymph node dissection. A single-institution, prospective trial was then performed in which patients were randomized to a group that received intraoperative application of a fibrin sealant following inguino-femoral lymph node dissection or to a control group that did not receive sealant.
The majority of the patients enrolled felt the drains caused moderate or severe discomfort and difficulties with activities of daily living. Thirty patients were then randomized; the median time to drain removal in the control group (n = 14) was 30 days (range, 13–74) compared to 29 days (range, 11–45) in the fibrin sealant group (n = 16; P = 0.6). Major and minor complications were similar in the two groups.
Postoperative closed suction drains were associated with major patient inconvenience. Applying a fibrin sealant at the time of inguino-femoral lymph node dissection in melanoma patients did not reduce the time to drain removal or postoperative morbidity. Alternative strategies are needed.
Therapeutic antibody development is one of the fastest growing areas of the pharmaceutical industry. Generating high-quality monoclonal antibodies against a given therapeutic target is crucial for successful drug development. However, due to immune tolerance, making it difficult to generate antibodies using conventional approaches.
Mixed four human gastric cancer (GC) cell lines were used as the immunogen in A/J mice; sixteen highly positive hybridoma colonies were selected via fluorescence-activated cell sorting-high throughput screening (FACS-HTS) using a total of 20,000 colonies in sixty-seven 96-well plates against live cells (mixed human GC cells versus human PBMC controls). MS17-57 and control commercial Alkaline Phosphatase (ALP) mAbs were used to confirm the target antigens (Ags), which were identified as ALPs expressed on the GC cell surface through a combination of western blot, immunoprecipitation and mass spectrometry (MS).
MS identified the Ags recognized by MS17-57 to be two variants of a secreted ALP, PALP and IALP (Placental and intestinal ALP). These proteins belong to a hydrolase enzyme family responsible for removing phosphate groups from many types of molecules. Immunofluorescence staining using MS17-57 demonstrated higher staining of gastrointestinal (GI) cancer tissues compared to normal GI tissues (P<0.03), and confirmed binding of MS17-57 to be restricted to a functional epitope expressed on the cancer cell surface. Proliferation assays using the PALP/IALP-expressing GC cell lines demonstrated that MS17-57 inhibited cell growth by 32±8%. Transwell cell migration assays documented that MS17-57 can inhibit PALP/IALP-expressing GI cancer cell migration by 25±5%. MS17-57 mAb inhibited tumor growth in nude mice.
Our findings indicate that PALP and IALP can be ectopically expressed on extracellular matrix of GI cancers, and that MS17-57 directed against PALP/IALP can inhibit GI cancer cells growth and migration in
vitro and in
vivo. This investigation provides an example of identification of cancer biomarkers representing promising therapeutic targets using mAb generated through a novel HTS technology.
Substrate engagement by F-box proteins promotes NEDD8 modification of cullins, which is necessary for the activation of cullin-RING E3 ubiquitin ligases (CRLs). However, the mechanism by which substrate recruitment triggers cullin neddylation remains unclear. Here, we identify DCNL1 (defective in cullin neddylation 1-like 1) as a component of CRL2 called ECV (elongins BC/CUL2/VHL) and show that molecular suppression of DCNL1 attenuates CUL2 neddylation. DCNL1 via its DAD patch binds to CUL2 but is also able to bind VHL independent of CUL2 and the DAD patch. The engagement of the substrate hypoxia-inducible factor 1α (HIF1α) to the substrate receptor VHL increases DCNL1 binding to VHL as well as to CUL2. Notably, an engineered mutant form of HIF1α that associates with CUL2, but not DCNL1, fails to trigger CUL2 neddylation and retains ECV in an inactive state. These findings support a model in which substrate engagement prompts DCNL1 recruitment that facilitates the initiation of CUL2 neddylation and define DCNL1 as a “substrate sensor switch” for ECV activation.
Standard estimates of survival do not reflect temporal changes in risk and are applicable only at the initial diagnosis of cancer. Conditional survival estimates provide more accurate prognostic information for cancer survivors. We sought to calculate conditional survival estimates for patients with pancreatic adenocarcinoma.
We identified patients with pancreatic adenocarcinoma diagnosed between 1988 and 2005 in the Surveillance Epidemiology End Results (SEER) cancer registry. We constructed separate multivariate survival models, adjusted for seven clinicopathologic factors, for patients who did and did not undergo radical surgical resection.
Conditional survival probabilities increased over time for all patients with pancreatic cancer regardless of patient characteristics, disease stage, or treatment. For patients with resected stage I, II and III disease, 3-year conditional cancer-specific survival increased from 38% to 70%, 19% to 54%, and 8% to 39%, respectively, over the three years following diagnosis. The relative improvement in survival over time was larger for patients with advanced disease. A customizable, internet browser-based clinical calculator was implemented that may be used to compute, in real time, personalized conditional survival estimates based on an individual’s unique clinicopathologic profile.
Conditional survival estimates provide a more accurate—and typically more optimistic—assessment of prognosis for patients with pancreatic cancer than do traditional survival estimates that apply only at the initial diagnosis.
pancreatic cancer; conditional survival; pancreaticoduodenectomy; SEER; cancer outcomes
Studies have shown that superior mesenteric vein/portal vein (SMV/PV) resection with pancreaticoduodenectomy (PD) is safe and feasible for patient with pancreatic adenocarcinoma (PAC). However, the prognostic significance of tumor involvement of the resected vein in patients who received neoadjuvant therapy is unclear.
We evaluated 225 consecutive patients with stage II PAC who received neoadjuvant therapy and PD with or without SMV/PV resection. The resected SMV/PV was entirely submitted for histologic assessment and reviewed in all cases. Tumor involvement of the SMV/PV was correlated with clinicopathologic features and survival.
Among the 225 patients, SMV/PV resection was performed in 85 patients. Histologic tumor involvement of the resected SMV/PV was identified in 57 patients. Histologic tumor involvement of the SMV/PV was associated with larger tumor size, higher rates of positive margin and local/distant recurrence. By multivariate analysis, tumor involvement of the SMV/PV was an independent predictor of both disease-free survival (DFS) and overall survival (OS). However, addition of venous resection to PD itself had no impact on either DFS or OS compared to those with PD alone.
Tumor involvement of the SMV/PV is an independent predictor of both DFS and OS in patients with stage II PAC treated with neoadjuvant therapy and PD. Complete histologic evaluation of the resected SMV/PV is important for the prognosis in patients with PAC who received neoadjuvant therapy and PD.
pancreatic adenocarcinoma; survival; prognosis; SMV/PV
Protein phosphatase 4 (PP4) has been reported to be overexpressed in breast and lung cancers. PP4 plays an important role in the regulation of centrosome maturation, DNA repair, NFκB and JNK signaling pathways. However, the expression and functions of PP4 in pancreatic cancer have not been studied.
We examined the expression of PP4 catalytic subunit (PP4C) protein in 133 patients with stage II pancreatic ductal adenocarcinoma (PDAC) and their paired benign pancreatic samples (N=113) by immunohistochemistry (IHC). To confirm the IHC results, we measured PP4C protein and mRNA levels by Western blotting and real time RT-PCR. Using univariate and multivariate analysis, we correlated PP4C expression with survival and other clinicopathologic features.
PP4C was overexpressed in 75 of 133 (56.4%) stage II PDAC samples, which was significantly higher than the paired benign pancreatic tissue (15%, 17/113). PP4C mRNA expression levels were also higher in PDAC samples than the paired benign pancreatic tissue. Overexpression of PP4C in PDAC samples was associated with higher frequencies of distant metastasis (p=0.02) and poor disease-free and overall survivals in patients with stage II PDAC (p = 0.006 and 0.02) independent of tumor size, margin status, and lymph node status (stage).
Our study showed that PP4C is overexpressed in PDAC. Overexpression of PP4C in PDAC samples is associated with poor prognosis in patients with stage II PDAC. Therefore, targeting PP4 signaling pathway may represent a new approach for the treatment of PDAC.
Our study demonstrated that PP4C is an independent prognostic factor in patients with stage II PDAC.
PP4; Pancreatic cancer; Survival; Prognosis
To mine possibly hidden causal single nucleotide polymorphisms (SNPs) in the etiology of melanoma, we investigated the association of SNPs in 76 M/G1 transition genes with melanoma risk using our published genome-wide association study (GWAS) dataset with 1804 melanoma cases and 1,026 cancer-free controls. We found multiple SNPs with P < 0.01 and performed validation studies for 18 putative functional SNPs in PSMB9 in other two GWAS datasets. Two SNPs (rs1351383 and rs2127675) were associated with melanoma risk in the GenoMEL dataset (P = 0.013 and 0.004, respectively), but failed validation in the Australia dataset. Genotype-phenotype analysis revealed these two SNPs were significantly correlated with mRNA expression levels of PSMB9. Further experiments revealed that the promoter SNP rs2071480, which is in high LD with rs1351383 and rs2127675, involved in influencing transcription factor binding and gene expression. Taken together, our data suggested that functional variants in PSMB9 may contribute to melanoma susceptibility.
GWAS; Cell cycle; PSMB9; Polymorphism; melanoma
Several grading schemes for the extent of residual tumor in post-treatment pancreaticoduodenectomy (PD) specimens have been proposed. However, the prognostic significance of these grading schemes is unknown.
Histopathologic slides of 223 cases who received neoadjuvant chemoradiation and PD were reviewed. The extent of residual tumor was graded using both the College of American Pathologists (CAP) and the Evans grading systems. The grading results were correlated with clinicopathological parameters and survival.
Among the 223 patients, 6 patients (2.7%) showed pathologic complete response (pCR, CAP Grade 0 or Evans grade IV), 36 cases (16.1%) with minimal residual tumor (CAP Grade 1 or Evans grade III), 124 cases (55.6%) with moderate response (CAP Grade 2 or Evans grade IIb) and 57 cases (25.6%) with poor response (CAP grade 3, 18 with Evans Grade I and 39 with Evans Grade IIa response). Patients with pCR or minimal residual tumor (response group 1) had better survivals than those with moderate and poor response (response group 2). Response group 1 patients had lower post-therapy tumor and AJCC stages, lower rates of lymph node metastasis, positive resection margin, and recurrence/metastasis. Grading the extent of residual tumor is an independent prognostic factor for OS in multivariate analysis.
pCR or minimal residual tumor in post-treatment PD specimens correlate with better survival in patients with PDAC who received neoadjuvant therapy and PD. Histologic grading of the extent of residual tumor in PD specimen is an important prognostic factor in patients with PDAC who received neoadjuvant therapies.
Pancreatic cancer; Pathologic response; Survival; Prognosis
Lymphovascular invasion (LVI) is a prognostic factor in many types of human malignancies including pancreatic ductal adenocarcinoma (PDAC). However, the prognostic significance of LVI in patients with PDAC who received neoadjuvant therapy and pancreaticoduodenectomy (PD) is unclear. In this study, we analyzed LVI in 212 patients who received neoadjuvant chemoradiation and subsequent PD at our institution between January 1999 and December 2007. LVI was present in 61.8 % (131/212) of the patients. Of the 131 cases that were positive for LVI, 67 (31.6%) patients had tumor invasion into lymphovascular spaces without muscle layer (non-muscular LVS) and 64 (30.2%) had tumor invasion into muscular vessels. The presence of tumor invasion into muscular vessels correlated with higher frequencies of positive resection margin, lymph node metastasis, and locoregional/distant recurrence. Patients with tumor invasion into muscular vessels had significantly shorter disease-free survival (DFS) and overall survival (OS) than those patients who had no LVI or who had tumor invasion of non-muscular LVS (p<0.01). Tumor invasion into muscular vessels is an independent prognostic factor in patients with PDAC who received neoadjuvant therapies. Our results showed tumor invasion into muscular vessels plays an important role in the progression of PDAC and in predicting the prognosis in this group of patients.
pancreatic cancer; muscular vessel invasion; lymphovascular invasion; survival; prognosis
DNA repair pathway genes play an important role in maintaining genomic integrity and protecting against cancer development. This study aimed to identify novel SNPs in the DNA repair–related genes associated with melanoma risk from a genome-wide association study (GWAS).
A total of 8,422 SNPs from the 165 DNA repair–related genes were extracted from a GWAS of melanoma risk, including 494 cases and 5,628 controls from the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). We further replicated the top SNPs in a GWAS of melanoma risk from the MD Anderson Cancer Center (1,804 cases and 1,026 controls).
A total of 3 SNPs with P value < 0.001 were selected for in silico replication. One SNP was replicated: rs3902093 [A] in EXO1 promoter region (Pdiscovery = 6.6×10-4, Preplication = 0.039, Pjoint = 2.5×10-4; ORjoint = 0.80, 95% CI: 0.71, 0.90). This SNP was associated with the expression of the EXO1; carriers of the A allele showed lower expression (P = 0.002).
Our study found that a promoter region SNP in the editing and processing nucleases gene EXO1 was associated with decreased expression of EXO1 and decreased melanoma risk. Further studies are warranted to validate this association and to investigate the potential mechanisms.
Perineural invasion (PNI) is one of the established prognostic factors in pancreatic ductal adenocarcinoma (PDAC). However, the prognostic significance of PNI in patients with PDAC who received neoadjuvant therapy and pancreaticoduodenectomy (PD) is not clear. In this study, we performed detailed examination of neural invasion in PD specimens from 212 patients with PDAC who received neoadjuvant chemoradiation (treated group) and 60 untreated patients at our institution between January 1999 and December 2007. The frequency of PNI was higher in untreated group (80%, 48/60) than the treated group (58%, 123/212). For the 123 treated cases that were positive for PNI, extra-tumoral PNI, intra-tumoral PNI, intra-pancreatic PNI only, extra-pancreatic PNI, and intra-neural invasion were identified in 86 (69.9%), 37 (30.1%), 11 (8.9%), 112 (91.1%), and 35 (28.5%) respectively. Presence of PNI correlated with tumor size, margin status, lymph node metastasis, pathologic tumor and AJCC stages in the treated group. Tumor involvement of nerves >0.8 mm correlated with higher frequency of positive margin compared to those with PNI involving nerves ≤0.8 mm, but not with other clinicopathologic parameters and survival. In treated group, the presence of PNI or intra-neural invasion correlated significantly with shorter disease-free survival (DFS) and overall survival (OS) compared to those with no PNI or PNI only respectively. PNI was an independent prognostic factor for both DFS and OS in multivariate analysis. Our results showed that PNI plays an important role in the progression of PDAC and in predicting the prognosis in this group of patients.
pancreatic cancer; perineural invasion; intra-neural invasion; survival; prognosis