CDH1 germline variants are enriched in patients with colorectal cancer, gastric cancer, and breast cancer.

BACKGROUND AND AIMS: CDH1 germline variants have been linked to heritability in diffuse gastric (DGC) and lobular breast cancer (LBC). Studies have not yet assessed whether CDH1 is a cancer-susceptibility gene in other cancers. Herein, we mapped the landscape of pathogenic and likely pathogenic (P/LP) germline variants in CDH1 across various cancers and ethnicities. METHODS: We evaluated CDH1 germline P/LP variants in 212,944 patients at one CLIA-certified laboratory (Invitae) and described their frequency in 7 cancer types. We screened for CDH1 variant enrichment in each cancer relative to a cancer-free population from The Genome Aggregation Database version 3 (gnomADv3). RESULTS: CDH1 P/LP variants were identified in 141 patients, most commonly in patients with DGC (27/408, 6.6%) followed by colorectal signet-ring cell cancer (CSRCC; 3/79, 3.8%), gastric cancer (56/2756, 2%), and LBC (22/6809, 0.3%). CDH1 P/LP variants were enriched in specific ethnic populations with breast cancer, gastric cancer, CRC, LBC, DGC, and CSRCC compared to matched ethnicities from gnomADv3. CONCLUSION: We report for the first time the prevalence of P/LP CDH1 variants across several cancers and show significant enrichment in CDH1 P/LP variants for patients with CSRCC, DGC, and LBC across various ethnicities. Future prospective studies are warranted to validate these findings.

Mucin expression in gastric- and gastro-oesophageal signet-ring cell cancer: results from a comprehensive literature review and a large cohort study of Caucasian and Asian gastric cancer.

BACKGROUND: The literature on the prognostic relevance of signet-ring cell (SRC) histology in gastric cancer (GC) is controversial which is most likely related to inconsistent SRC classification based on haematoxylin-eosin staining. We hypothesised that mucin stains can consistently identify SRC-GC and predict GC patient outcome. METHODS: We performed a comprehensive literature review on mucin stains in SRC-GC and characterised the mucin expression in 851 Caucasian GC and 410 Asian GC using Alcian Blue (AB)-Periodic Acid-Schiff (PAS), MUC2 (intestinal-type mucin), and MUC5AC (gastric-type mucin). The relationship between mucin expression and histological phenotype [poorly cohesive (PC) including proportion of SRCs, non-poorly cohesive (non-PC), or mucinous (MC)], clinicopathological variables, and patient outcome was analysed. RESULTS: Depending on mucin expression and cut-offs, the positivity rates of SRC-GC reported in the literature varied from 6 to 100%. Patients with MUC2 positive SRC-GC or SRC-GC with (gastro)intestinal phenotype had poorest outcome. In our cohort study, PC with ≥ 10% SRCs expressed more frequently MUC2, MUC5AC, and ABPAS (p < 0.001, p = 0.004 and p < 0.001, respectively). Caucasians with AB positive GC or combined ABPAS-MUC2 positive and MUC5AC negative had poorest outcome (all p = 0.002). This association was not seen in Asian patients. CONCLUSIONS: This is the first study to suggest that mucin stains do not help to differentiate between SRC-GC and non-SRC-GC. However, mucin stains appear to be able to identify GC patients with different outcome. To our surprise, the relationship between outcome and mucin expression seems to differ between Caucasian and Asian GC patients which warrants further investigations.

The Yield of Staging Laparoscopy in Gastric Cancer is Affected by Racial and Ethnic Differences in Disease Presentation.

BACKGROUND: Gastric cancer is a heterogeneous disease with variable presentation between racial and ethnic groups. Staging laparoscopy (SL) detects occult metastases not visible on cross-sectional imaging and therefore improves staging. It remains unclear how differences in race and ethnicity affect disease presentation and the yield of SL. METHODS: We performed a retrospective review of a prospectively maintained database to identify patients with gastric cancer treated with curative intent at our institutions from 2008 to 2015. RESULTS: Hispanic patients presented at an earlier mean age (55.5 ± 11.9 years) compared with Asian (59.8 ± 13.9 years), African American (61.0 ± 10.0 years), and white patients (61.7 ± 12.5 years; p = 0.046) and with more locally advanced disease (clinical stage T3/T4 or node positive; Hispanic 87%; African American 79%; white 68%, Asian 55%; p = 0.03). SL identified 42 patients (34%) with occult metastatic disease. Hispanics were more likely to have a positive SL (44%) than white patients (21%; p = 0.04). On univariate analysis, Hispanic ethnicity, clinical T3/T4, positive nodal disease, signet ring cells, and poor differentiation were predictors of a positive SL. On multivariable analysis, clinical T3/T4, signet ring cells, and poor differentiation independently predicted radiographically occult disease. CONCLUSIONS: Hispanic patients presented with more locally advanced disease and were more likely to have occult disease found on SL compared with white patients. Laparoscopy should be used routinely as part of the pretreatment staging evaluation for patients with locally advanced disease as it alters the management in a significant proportion of patients.

Prognostic significance of signet ring gastric cancer.

PURPOSE: Studies in Asia have questioned the dictum that signet ring cell carcinoma (SRC) has a worse prognosis than other forms of gastric cancer. Our study determined differences in presentation and outcomes between SRC and gastric adenocarcinoma (AC) in the United States. PATIENTS AND METHODS: The National Cancer Institute Surveillance, Epidemiology, and End Results database was reviewed for SRC and AC from 2004 to 2007. RESULTS: We reviewed 10,246 cases of patients with gastric cancer, including 2,666 of SRC and 7,580 of AC. SRC presented in younger patients (61.9 v 68.7 years; P < .001) and less often in men (52.7% v 68.7%; P < .001). SRC patients were more frequently black (11.3% v 10.9%), Asian (16.4% v 13.2%), American Indian/Alaska Native (0.9% v 0.8%), or Hispanic (23.3% v 14.0%; P < .001). SRC was more likely to be stage T3-4 (45.8% v 33.3%), have lymph node spread (59.7% v 51.8%), and distant metastases (40.2% v 37.6%; P < .001). SRC was more likely to be found in the lower (30.7% v 24.2%) and middle stomach (30.6% v 20.7%; P < .001). Median survival was not different between the two (AC, 14.0 months v SRC, 13.0 months; P = .073). Multivariable analyses demonstrated SRC was not associated with mortality (hazard ratio [HR], 1.05; 95% CI, 0.96 to 1.11; P = .150). Mortality was associated with age (HR, 1.01; 95% CI, 1.01 to 1.02; P < .001), black race (HR, 1.10; 95% CI, 1.01 to 1.20; P = .026), and tumor grade. Variables associated with lower mortality risk included Asian race (HR, 0.83; 95% CI, 0.77 to 0.91; P < .001) and surgery (HR, 0.37; 95% CI, 0.34 to 0.39; P < .001). CONCLUSION: In the United States, SRC significantly differs from AC in extent of disease at presentation. However, when adjusted for stage, SRC does not portend a worse prognosis.

Disparities in gastric cancer outcomes among Asian ethnicities in the USA.

BACKGROUND: Survival for gastric cancer is reportedly higher in Asians than for other races. It is unclear whether differences in outcome exist among Asian ethnicities. Our objective was to assess gastric cancer survival in Asian ethnic groups in a large heterogeneous population. METHODS: Asian-Americans treated for gastric adenocarcinoma between 1988 and 2006 were identified from the Los Angeles County Cancer Surveillance Program. Patients were stratified and compared by ethnicity (Korean, Japanese, Chinese, Vietnamese or Filipino). RESULTS: Of the 1,817 Asian-Americans in the study cohort, 45% (n = 810) were Korean, 25% (n = 462) were Chinese, 11% (n = 193) were Japanese, 10% (n = 188) were Filipino, and 9% (n = 164) were Vietnamese. For the entire cohort Koreans and Filipinos had the longest and shortest median survival (MS), respectively (22.4 and 10.3 months, respectively; P < 0.001). Multivariate analysis demonstrated that Japanese and Filipino ethnicity independently predicted worse survival compared with Korean ethnicity [hazard ratio (HR) 1.37, 95% confidence interval (CI) 1.08-1.73, P = 0.008; and HR 1.71, 95% CI 1.37-2.13, P < 0.001, respectively]. In the surgical cohort, Koreans and Filipinos had the longest and shortest survival, respectively (MS of 57.8 and 21.7 months, respectively; P < 0.001). Multivariate analysis of the surgical cohort also demonstrated that Japanese and Filipino ethnicity independently predicted worse survival compared with Korean ethnicity (HR 1.61, 95% CI 1.22-2.13, P < 0.001; and HR 1.66, 95% CI 1.24-2.22, P < 0.001, respectively). CONCLUSION: There are differences in gastric cancer survival among Asian ethnicities. Future studies addressing varying environmental exposures and molecular expression patterns in gastric cancer are warranted to better understand these disparities in outcome.

Signal transduction proteins in tumors from Puerto Rican and Caucasian gastric adenocarcinoma patients: expression differences with potential for specific targeted therapies.

Overexpression of the HER2/NEU gene is associated with aggressive behavior and poor prognosis in breast cancer, making the Her2/neu protein a directed-therapy target. Tumors of two Puerto Rican (PR) patients overexpressed Her2/neu and resulting partial clinical responses motivated us to compare Her2/neu expression in PR (n = 101) and Caucasian non-Hispanic (n = 95) patients. Immunohistochemistry of tumors showed overexpression of p-Stat3, Cyclin D1, and Her2/neu, compared to non-neoplastic mucosa. Her2/neu and EGF-R protein levels were statistically significantly different with higher levels of both proteins in the PR group. Importantly, Her2/neu expression was strong and diffuse in tumors with signet-ring morphology, while other histo-pathological subtypes showed higher intra-tumoral Her2/neu heterogeneity than typically observed in breast cancer. Targeted therapies in gastric cancer directed at EGF-R and Hers-2/neu pathways warrant further investigation. These therapies may be especially effective in PR patients and in patients with signet-ring cell morphologies with a dismal prognosis.

Epstein-Barr virus-associated gastric carcinoma in Kazakhstan.

AIM: To investigate the incidence of Epstein-Barr virus-associated gastric cancer (EBV-GC) in Kazakhstan and to compare it with that in Russia, Western and Asian countries in order to evaluate the significance of epidemiopathologic and ethnic factors. METHODS: In situ hybridization (ISH) of EBV-encoded small RNA-1 (EBER-1) was used to identify the presence of EBER-1 signal in 139 formalin-fixed and paraffin-embedded GC tissues from Kazakhstan. RESULTS: EBER-1 expression was observed in the nuclei of 10% of the cases of GC (14/139), but not in the surrounding normal mucosa. The incidence of the diffuse type of EBV-GC was significantly higher in Kazakhstan (14%, 13/91) than that of the intestinal type (2%, 1/48). Furthermore, the incidence was significantly higher in males (14%, 12/89) than in females (3.7%, 2/53) from all countries. The overall incidence of EBV-GC increased from 6.7% in Asian countries to 8.7% in Russia, 10.1% in Kazakhstan and 16% in Western countries. CONCLUSION: Geographical differences in the incidence of EBV-GC may reflect the epidemiologic factors and/or dietary habits independent of histological type and sex.

Differential trends in the intestinal and diffuse types of gastric carcinoma in the United States, 1973-2000: increase in the signet ring cell type.

CONTEXT: During the last 50 years, the incidence and mortality of gastric cancer has declined in many countries. This decline has primarily included the intestinal type (Lauren classification). However, there is an impression among pathologists that the diffuse type, especially the signet ring cell subtype, has become more prevalent. OBJECTIVES: Using data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute, we analyzed the trends of the 2 primary types (intestinal and diffuse) of gastric carcinomas from 1973 through 2000. DESIGN: Trends in age-adjusted rates were determined for gastric carcinomas through the SEER statistical program (SEER*Stat), which is available on the Internet to the public. RESULTS: During the period studied, the intestinal type continued to decline in males, females, African Americans, and whites. The intestinal type was more common in males than in females and more common in African Americans than in whites. In contrast, a consistent increase in the rate of the diffuse type of gastric carcinoma was seen during this period. The rate increased from 0.3 cases per 100 000 persons in 1973 to 1.8 cases per 100 000 persons in 2000. This increase was seen in males, females, African Americans, and whites. The predominant increase occurred in the signet ring type. CONCLUSIONS: The results indicate a progressive decrease in the incidence of the intestinal type of gastric cancer and an increase in the diffuse type of gastric carcinoma, especially the signet ring cell type. The clinical implications of the increase are considered.

Asian ethnicity-related differences in gastric cancer presentation and outcome among patients treated at a canadian cancer center.

PURPOSE: Differences in stage-stratified survival have been reported between Asian and Western populations with gastric cancer. This study examines differences in presentation and outcomes among Asian and non-Asian patients evaluated and treated at a Canadian institution. PATIENTS AND METHODS: We reviewed 2,043 patients (159 Asians and 1,884 non-Asians) with gastric adenocarcinoma treated between 1978 and 1997. Overall survival was examined by the Kaplan-Meier method, and multivariable analysis by Cox proportional hazards was used to identify whether Asian ethnicity had independent prognostic significance for survival. RESULTS: Median survival was 13.1 months for Asians and 11.1 months for non-Asians (P =.0016). Asian patients were younger and had a greater proportion of signet ring cell histology but were less likely to have proximal disease. Signet ring cell histology did not adversely affect survival. By multivariable analysis, proximal location, poor differentiation, and extent of disease were independently associated with worse survival. Survival was improved with curative resection, palliative resection, and palliative chemotherapy. Asian ethnicity was not independently associated with survival (hazard ratio, 0.89; 95% confidence interval, 0.74 to 1.08). Although a similar proportion of patients underwent curative resection, an interaction was observed between Asian ethnicity and efficacy of resection, with Asians achieving a greater benefit as compared with non-Asians even when adjusted for age and location. CONCLUSION: The disparity between Eastern and Western gastric cancer survival is not explained by the hypothesis of ethnicity-related differences in tumor biology. Although it is not an independent predictor of survival, Asian ethnicity is associated with distinct characteristics at presentation and more favorable outcomes after curative surgery.

Surgical pathology of colorectal cancer in Filipinos: implications for clinical practice.

BACKGROUND: A number of studies published in the Philippine literature have demonstrated certain peculiar clinicopathologic characteristics of colorectal cancer among Filipinos. This study presents the latest data and analyzes their implications for clinical practice. STUDY DESIGN: The pathology reports of all patients who underwent operation for colorectal cancer at the Philippine General Hospital over a period of 7 years were reviewed. RESULTS: One thousand two hundred seventy-seven patients were included. The male to female ratio was almost 1:1. The majority of patients were in the sixth and seventh decades of life, with a mean age of 55.3 years. Patients 40 years of age and younger made up 17% of the total. The site of cancer in order of frequency was rectum (49.8%), left colon (27.9%), and right colon (21.4%). Cancers of the right colon were more common in women, and rectal cancers were more frequent in men. Seventy-six percent of the tumors were well to moderately differentiated adenocarcinomas, and 6.7% were poorly differentiated. Mucinous and signet ring carcinomas were found in 11% and 1% of cases, respectively. Forty-four percent of patients had localized disease at the time of operation, 54% had regional disease, and 2% had disseminated disease. Associated predisposing conditions noted were polyps (4.7%), schistosomiasis (3%), and tuberculosis (1.5%). CONCLUSIONS: Colorectal cancer in Filipinos exhibits a number of unique clinicopathologic features, such as a higher proportion of early age of onset tumors, more advanced stage at presentation, an association with chronic granulomatous diseases, and relatively rare occurrence with polyps. This might suggest the possibility of a different pathway for tumor development of colorectal cancer in this population of patients. Also, current screening guidelines advocated for the Western population might not be appropriate for Filipinos.