Incidence and prognosis of patients with small intestinal neuroendocrine tumors in a population based nationwide study.

BACKGROUND & AIMS: Small intestinal neuroendocrine tumours (SI-NETs) are the most frequent malignant tumours of the small intestine. Population based studies on SI-NETs are scarce. We aimed to examine the incidence, presentation of disease and prognosis of SI-NET and to determine patient prognosis in those undergoing emergency or elective surgery. METHODS: This was a retrospective population-based study. Information on all patients diagnosed with neuroendocrine tumours of the small intestine (excluding duodenum) from the beginning of the Icelandic Cancer Registry and the pathology departments in the country (1966-2017). Detailed phenotypic information was obtained from medical records on symptoms at diagnosis, treatment, recurrence and survival. RESULTS: A total of 113 patients with SI-NETs were identified, 3 patients were excluded due to lack of data and/or diagnostic error, leaving 110 patients for final analysis. The incidence of SI-NET was 0.78/100,000 and did not increase during the study period. A total of 42 % (n = 46) of patients were diagnosed incidentally. Long-term prognosis, after a landmark of 12 months, was better in patients who were diagnosed incidentally (HR 0.52; p = 0.03). Overall 89 % (n = 98) of cases underwent surgical resection of the primary tumor, 31 % (n = 30) patients acute or semi-acute surgery and 69 % (n = 68) elective surgery. Emergency surgery was associated with a 6-fold risk of death in the first 12 months after surgery (HR: 5.99; p = 0.01) and associated with more severe surgical complications. However, there was no difference in the long-term risk of death after the first 12 months (HR: 1.39; p = 0.27). CONCLUSIONS: The incidence of SI-NETs has not changed significantly in the last decades. Incidentally diagnosed SI-NET was associated with a favorable long-term prognosis. Emergency surgery in patients with SI-NET was associated with a significantly worse short-term risk of mortality compared to those who underwent elective surgery.

Invasive and in situ squamous cell carcinoma of the skin: a nationwide study in Iceland.

BACKGROUND: The worldwide incidence of cutaneous squamous cell carcinoma (cSCC) is increasing. OBJECTIVES: To evaluate the tumour burden of in situ and invasive cSCC in Iceland, where the population is exposed to limited ultraviolet radiation. METHODS: This whole-population study used the Icelandic Cancer Registry, which contains records of all in situ and invasive cSCC cases from 1981 to 2017. Incidence of cSCC was evaluated according to age, anatomical location, residence and multiplicity, and trends were assessed using joinpoint analysis. Age-standardized rates (WSR) and age-specific incidence rates per 100 000 person-years were calculated, along with cumulative and lifetime risks. RESULTS: Between 1981 and 2017, in situ cSCC WSR increased from 1·2 to 19·1 for men and from 2·0 to 22·3 for women. Invasive cSCC WSR rose from 4·6 to 14 for men and from 0·3 to 13·2 for women. The average number of in situ cSCC lesions was 1·71 per woman and 1·39 per man. Women developed more in situ cSCCs than invasive cSCCs in almost all anatomical locations, whereas men developed more invasive cSCCs, mostly on the head and neck. The rates of in situ cSCC were higher in Reykjavik compared with rural areas. Furthermore, women more commonly developed multiple in situ lesions. For lip cSCCs, invasive lesions occurred more frequently than in situ lesions among both sexes. Joinpoint analysis showed that in situ cSCC in women exhibited the most rapid incidence increase. CONCLUSIONS: cSCC has become an increasingly significant public health problem in Iceland. Tanning bed use and travelling abroad may contribute to skin cancer development. Public health efforts are needed to stem the behaviours leading to this rapid rise in cSCC.

Arrest-related death on the basis of a drug-induced excited delirium syndrome.

AIMS: In typical arrest-related death (ARD) scenarios, the victims often show signs of excited delirium syndrome (ExDS), intoxication, exhaustion and/or suffered from a preexisting physical or psychiatrical condition, all of which could have caused or at least triggered the person's death. Since autopsy findings are very rare in such cases, a clear clinicopathologic diagnosis and thus mechanism of death is rarely found. METHODS: We present a case of a 25-year old woman, who died while being arrested by the police. Based on the patient's medical history, autopsy findings, contradicting witness testimonies, and reliable clinical and toxicological blood parameters, the most probable diagnosis is discussed. RESULTS: The cause of death was determined as cardiac arrest subsequent to a combination of excited delirium syndrome, physical exhaustion and respiratory impairment. The manner of death was unnatural and juridically, the charges were dropped. CONCLUSIONS: In cases, where the cause and mechanism of death can only be diagnosed by exclusion, police collaboration, detailed clinical history (past and present) as well as clinical blood parameter analyses are necessary to help evaluating possible contributing factors and the most probable cause of death in ARD.

Basal cell carcinoma: an emerging epidemic in women in Iceland.

BACKGROUND: An epidemic of basal cell carcinoma (BCC) has led to a significant healthcare burden in white populations. OBJECTIVES: To provide an update on incidence rates and tumour burden in an unselected, geographically isolated population that is exposed to a low level of ultraviolet radiation. METHODS: This was a whole-population study using a cancer registry containing records of all cases of BCC in 1981-2017. We assessed BCC incidence according to age, residence and multiplicity and assessed trends using join-point analysis. Age-standardized and age-specific incidence rates were calculated along with cumulative and lifetime risks. RESULTS: During the study period, the age-standardized incidence rates increased from 25·7 to 59·9 for men, and from 22·2 to 83·1 for women (per 100 000). Compared with the single-tumour burden, the total tumour burden in the population was 1·72 times higher when accounting for multiplicity. At the beginning of the study period, the world-standardized rates in men and women were similar, but by the end of the study period the rates were 39% higher in women (83·1 per 100 000, 95% confidence interval 77·9-88·3) than in men (59·9 per 100 000, 95% confidence interval 55·6-64·2). This increase was most prominent in women on sites that are normally not exposed to ultraviolet radiation in Iceland: the trunk and legs. CONCLUSIONS: This is the only reported population in which the incidence of BCC is significantly higher in women than in men. The period of notable increase in BCC lesions correlates with the period of an increase in tanning beds and travel popularity. The high multiplicity rates suggest that the total tumour burden worldwide might be higher than previously thought. What is already known about this topic? Basal cell carcinoma (BCC) is becoming an increasing healthcare burden worldwide, especially in white populations. Recent population studies have reported a rapid increase in incidence among younger individuals, especially women. What does this study add? Iceland is the only reported population in which the incidence of BCC is significantly higher in women than in men, and there does not seem to be a clear relationship between latitude and BCC incidence in Europe. Men might be comparatively protected in the northern low-ultraviolet environment, with tanning beds and travel abroad likely playing important roles in the observed incidence increase, especially in women. The high multiplicity rates suggest that the total tumour burden worldwide might be higher than previously thought. Linked Comment: Pandeya. Br J Dermatol 2020; 183:799-800.

Autopsy rates in Iceland.

A clinical as well as forensic autopsy is a uniform medical investigation of the deceased, which mainly serves to verify the plausibility of information on the cause, mode and mechanism of death provided by the police and/or medical personnel. Despite its importance in the context of a conclusive assessment of a person's medical history and in detecting any criminal correlation or malpractice, a significant decline in autopsies is evident in Iceland. This article gives an overview on autopsy rates in Iceland and compares the situation with European countries.

Peri- and post mortem hemorrhages in the anterior neck after chin-collar application.

Intense blunt compression trauma to the neck can result in subcutaneous, intramuscular or laryngeal mucosa bleedings of different intensity. While these findings can easily be detected through a layer-wise dissection of the neck muscles and soft tissue during autopsy, it can be difficult to distinguish between peri-/post- and ante mortem hemorrhages solely based on macroscopic findings. Especially when an initial preliminary diagnosis is required, possible artifacts have to be excluded. The study at hand examines possible peri- and post mortem hemorrhages in the anterior neck after NorMors™ chin-collar application. In routine clinical and forensic autopsy cases, where such a chin-collar has been placed around the neck of the deceased in close proximity after death, focus was directed to the soft tissue and muscles of the neck. The results of our analysis could prove that the use of chin-collar shortly within the first 1 ½ hours after death applies just enough pressure to the neck to be able to cause superficial hemorrhages within the surface of the sternocleidomastoid muscles, which can mimic vital compression trauma injuries. Based on location, morphological outlines and intensity of the injuries, it is possible to correlate them with the position of the applied collar. Together with histological analyses, asphyxia by a second party involvement can be excluded. However, the application of chin-collars should be prohibited in any case, where an autopsy might be performed.

The incidence and outcome of ischemic colitis in a population-based setting.

OBJECTIVE: Population-based studies on patients with ischemic colitis (IC) are limited. We aimed to determine the incidence, risk factors and outcome of patients with IC. METHODS: A retrospective nationwide study was conducted on adult patients with histologically confirmed IC in 2009-2013 in Iceland. IC patients were matched for age and gender with patients hospitalized with lower gastrointestinal bleeding. Data were collected on clinical presentation, comorbidities, smoking habits, management and outcome. RESULTS: Eighty-nine patients, 61 (69%) females and mean age of 65 years (±17), fulfilled the predetermined criteria. Females were older than males, 68 years (±14) vs. 59 years (±20) (p = .0170). The mean cumulative incidence was 7.3 cases per 100,000 inhabitants. A total of 57 (64%) patients presented with abdominal pain, hematochezia and diarrhea. IC was localized in the left colon in 78 (88%) patients. Overall, 62 (70%) patients had cardiovascular disease vs. 53 (60%) of control group (NS) and 55 (62%) had a history of smoking vs. 53 (60%) in control group (NS). Ten (11%) patients required surgery and/or died within 30-days from hospital admission. At the end of follow-up, 7 (9%) patients had experienced recurrence of IC with an estimated 3-year recurrence rate of 15%. CONCLUSIONS: IC is a common clinical phenomenon that affects a wide range of age groups, but is most prominent among elderly women. It typically presents with a clinical triad of abdominal pain, hematochezia and diarrhea. Most cases are mild and self-limiting with a good prognosis.

Cutaneous melanoma in Iceland: changing Breslow's tumour thickness.

BACKGROUND: The incidence of cutaneous melanoma increased dramatically in Iceland during the last two decades of the 20th century. OBJECTIVE: The aim of this study was to investigate the trend in Breslow's tumour thickness during the years 1980-2009. METHODS: The population-based Icelandic Cancer Registry provided information on all cutaneous melanomas diagnosed in the country during the study period, a total of 854 cases. Incidence rates were stratified according to gender, age at diagnosis, year of diagnosis and Breslow's tumour thickness. RESULTS: When stratified by gender and age, the incidence of thin (≤1.0 mm) melanomas increased dramatically in all subgroups. The increase in thin (≤1.0 mm) melanomas was more apparent in women or 2.6 per 100,000 in 1980-1989 to 13.3 in 2000-2009 and especially in young (<50 years) women or from 1.6 to 12.2 per 100,000 during the same period compared to an increase from 0.2 to 3.4 per 100,000 for young (<50 years) men (P < 0.05). In intermediate thickness (1.01-4.0 mm) tumours, the incidence increased only in men over the age of 50 from 2.1 in 1980-1989 to 11.3 per 100,000 in 2000-2009 (P < 0.05). The incidence of thick melanomas (>4 mm) did not increase. The median Breslow's thickness declined from 2.15 mm in 1980-1989 to 0.9 mm in 2000-2009 in males and from 1.0 to 0.6 mm in females for the same period (P < 0.001). CONCLUSION: The rise in melanoma incidence in individuals under 50 years and in women over 50 years was confined to thin tumours. However, among older males there was also an increased incidence of tumours of an intermediate thickness. This could indicate that future melanoma educational campaigns in Iceland should be directed at older individuals, and that older men may need special attention regarding suspicious nevi.

Bleeding-related symptoms in colorectal cancer: a 4-year nationwide population-based study.

BACKGROUND: Little is known about the major presenting features of patients with colorectal cancer (CRC) in a population-based setting, especially regarding bleeding-related symptoms. AIM: To determine the proportion of CRC patients presenting with bleeding-related symptoms, to compare bleeders and nonbleeders and to explore the role of anticoagulants in bleeders. METHODS: This was a nationwide, population-based, retrospective study, investigating all patients diagnosed with CRC in Iceland from 2008 to 2011. Bleeding-related symptoms were defined as overt bleeding, iron deficiency anaemia or a positive faecal occult blood test. Obstructive symptoms were defined as a confirmed diagnosis of ileus or dilated intestines on imaging. RESULTS: Data were available for 472/496 (95%) patients, males 51%, mean age 69 (±13) years. In all, 348 (74%) patients had bleeding-related symptoms; of these 348 patients, 61% had overt bleeding. Bleeders were less likely than nonbleeders to have metastases at diagnosis, 19% vs. 34% (P < 0.001). Overt bleeders were less likely than nonbleeders to have obstructive symptoms, 2% vs. 16% respectively (P < 0.0001). Occult bleeders were more likely to have proximal cancer (69%) than both overt (17%) and nonbleeders (44%) (P < 0.0001); however, they were less likely than nonbleeders to have metastases (22% vs. 35%, P < 0.05). Bleeders were more likely to use warfarin than nonbleeders (9% vs. 3%, P < 0.05); the use of low-dose aspirin was the same (24%). CONCLUSIONS: The majority of patients with CRC present with bleeding-related symptoms. Bleeders with CRC present earlier than nonbleeders. Warfarin use may induce bleeding in some patients, resulting in an earlier diagnosis.

pT4 stage II and III colon cancers carry the worst prognosis in a nationwide survival analysis. Shepherd's local peritoneal involvement revisited.

The aim of this study is to clarify the prognostic importance of several well-known but still debated pathological variables related to the survival of colon cancer patients. The study focuses on the definition and survival carried by the pT4 category and stage II where the presence of high-risk variables may determine whether or not adjuvant chemotherapy is administered. A retrospective nationwide study was carried out including all colon cancer patients that underwent resection in Iceland between 1990 and 2004 (n = 889). All histopathology was reassessed. Cancer-specific survival (CSS) and overall survival were analysed using Kaplan-Meier and Cox regression analysis. In stage II, the five-year CSS for pT4 was 50% (95% CI, 32-69%), which was the lowest survival observed in that stage. In stage III the five-year CSS was 30% (95% CI, 18-41%) and 37% (95% CI, 26-48%) for pT4 and pN2 tumors, respectively. Lymphatic invasion and differentiation had no prognostic value in stage II. The survival associated with pT4a versus pT4b depends on how these categories are defined with regard to Shepherd's local peritoneal involvement (LPI). In the present series, pT4 is a major indicator of poor prognosis in patients with stage II and III colon carcinoma. Four-tiered TNM or Dukes staging systems are insufficient by not taking this variable into account. Only Shepherd's LPI4 and a subgroup of LPI3 (i.e., borderline LPI3/LPI4) should qualify for the pT4a subcategory. The results do not support lymphatic invasion or poor differentiation as high-risk stage II variables.

The frequency of advanced adenoma in consulting patients: a nationwide survey in Iceland (2003-2006).

AIM: To assess the frequency of advanced colorectal adenomas in consulting patients in Iceland. METHOD: The histological configuration of colorectal adenomas (CRA) found in 3603 patients was classified into tubular (TA), villous (VA) and serrated (SA) and the degree of neoplastic severity into low-grade dysplasia (LGD), high-grade dysplasia (HGD), carcinoma in situ (CIS), intramucosal carcinoma (IMC) and submucosal carcinoma (SMC). Advanced CRA were those showing HGD, CIS, IMC and/or SMCs. In patients with two or more adenomas, the adenoma with the highest degree of epithelial neoplasia was selected to record cases. RESULTS: Between 2003 and 2006 a total of 19424 endoscopic examinations (13572 colonoscopies and 5852 sigmoidoscopies) were performed in Iceland (mean, 4856 endoscopies per year). At histology a mean of 759.3 CRA per year were found. Thus, CRA were found in 15.6% of the colorectal endoscopies performed per year. Out of the 3037 CRA studied, 67% were TA, 29% VA and the remaining 4% SA. LGD was present in 79%, HGD in 15%, CIS in 2.4%, IMC in 1.9% and SMC in 1.9%. Consequently, out of 3037 CRA investigated, 652 (21.5%) were advanced CRA; 71% of these showed HGD, 11% CIS, 9% IMC and 9% SMC. Two-thirds of the 652 advanced CRA were advanced VA, and more than three-quarters of 58 advanced CRA with SMC, were advanced VA. CONCLUSION: Advanced VA displaying intraepithelial neoplasia (HGD and CIS) showed a propensity to evolve into invasive carcinoma. Accordingly, VA displaying HGD and CIS might be regarded as biological markers for predicting colorectal cancer risk. This is the first study in which the frequency of CRA and advanced CRA detected in consulting patients is reported on a nationwide basis.

Risks of second primary cancer among patients with major histological types of lung cancers in both men and women.

BACKGROUND: Patterns of second primary cancers (SPCs) following first primary lung cancers (FPLCs) may provide aetiological insights into FPLC. METHODS: Cases of FPLCs in 13 cancer registries in Europe, Australia, Canada, and Singapore were followed up from the date of FPLC diagnosis to the date of SPC diagnosis, date of death, or end of follow-up. Standardised incidence ratios (SIRs) were calculated to estimate the magnitude of SPC development following squamous cell carcinoma (SCC), small cell lung carcinoma (SCLC), and adenocarcinoma (ADC). RESULTS: Among SCC patients, male SIR=1.58 (95% confidence interval (CI)=1.50-1.66) and female SIR=2.31 (1.94-2.72) for smoking-related SPC. Among SCLC patients, the respective ratios were 1.39 (1.20-1.60) and 2.28 (1.73-2.95), and among ADC patients, they were 1.73 (1.57-1.90) and 2.24 (1.91-2.61). We also observed associations between first primary lung ADC and second primary breast cancer in women (SIR=1.25, 95% CI=1.05-1.48) and prostate cancer (1.56, 1.39-1.79) in men. CONCLUSION: The FPLC patients carried excess risks of smoking-related SPCs. An association between first primary lung ADC and second primary breast and ovarian cancer in women at younger age and prostate cancers in men may reflect an aetiological role of hormones in lung ADC.

Risk of second malignant neoplasms after childhood central nervous system malignant tumours: an international study.

PURPOSE: The aim of this study was to assess the risk of second malignant neoplasms (SMNs) other than central nervous system (CNS) neoplasms after childhood CNS cancer in an international multicentre study. METHODS: Individual data on cases of CNS cancer in children (0-14 years) and on subsequent SMNs were obtained from 13 population-based cancer registries contributing data for different time periods in 1943-2000. Standardised incidence ratios (SIRs) with 95% confidence intervals (CI), absolute excess risk and cumulative incidence of SMNs were computed. RESULTS: We observed 43 SMNs in 8431 CNS cancer survivors. The SIR was 10.6 (4.85-20.1) for thyroid cancer (nine cases), 2.75 (1.01-5.99) for leukaemia (six cases) and 2.47 (0.90-5.37) for lymphoma (six cases). The SIRs were highest in the first 10 years after CNS cancer diagnosis. The cumulative incidence of non-CNS SMNs was 3.30% (0.95-5.65%) within 45 years after a CNS cancer diagnosis. Within 15 years, the cumulative incidence was highest for cases diagnosed after 1980 (0.56%, 95% CI: 0.29-0.82%). CONCLUSION: This population-based study indicates that about one every 180 survivors of a childhood CNS cancer will develop a non-CNS SMN within the following 15 years. The excess is higher after glioma and embryonal malignant tumour than after another CNS tumour.

Adenocarcinoma of the prostate in Iceland: a population-based study of stage, Gleason grade, treatment and long-term survival in males diagnosed between 1983 and 1987.

OBJECTIVE: To investigate adenocarcinoma of the prostate in a single population with an extended follow-up period. MATERIAL AND METHODS: Using the Icelandic Cancer Registry, we identified all Icelandic men diagnosed with prostate cancer between 1983 and 1987. Disease stage, initial treatment and follow-up information were obtained from hospital records and death certificates. A critical evaluation was made of the accuracy of the death certificates regarding prostate cancer. All available histology information was reviewed and graded according to the Gleason grading system. RESULTS: A total of 414 men were diagnosed with adenocarcinoma of the prostate. Of these, 370 were alive at the time of diagnosis and stage could be determined. Four stage groups were defined: focal incidental (n=50); localized (n=164); local advanced (n=32); and metastatic disease (n=124). The mean age at diagnosis was 74.4 years (range 53-94 years). The combined Gleason score was 2-5 in 89, 6-7 in 117, 8-10 in 117 and unknown in 47 cases. The median follow-up period for the group was 6.15 years (range 0.3-19.8 years). Thirty men received treatment with curative intent: radiation therapy, n=20; and radical prostatectomy, n=10. A total of 334 patients died during the follow-up period, of whom 168 (50%) died of prostate cancer. Prostate cancer-specific survival at 10 and 15 years was 100% and 90.6%, respectively for focal incidental cancer; 73.1% and 60.8% for men with localized disease; 23.4% and 11.7% for local advanced disease; and 6.81% and 5.45% for metastatic disease. A Cox multivariate analysis showed age, stage and Gleason score to be independent predictors of prostate cancer death. A total of 104 patients with localized disease and a Gleason score of

Second primary cancers among 109 000 cases of non-Hodgkin's lymphoma.

An analysis of other primary cancers in individuals with non-Hodgkin's lymphoma (NHL) can help to elucidate this cancer aetiology. In all, 109 451 first primary NHL were included in a pooled analysis of 13 cancer registries. The observed numbers of second cancers were compared to the expected numbers derived from the age-, sex-, calendar period- and registry-specific incidence rates. We also calculated the standardised incidence ratios for NHL as a second primary after other cancers. There was a 47% (95% confidence interval 43-51%) overall increase in the risk of a primary cancer after NHL. A strongly significant (P<0.001) increase was observed for cancers of the lip, tongue, oropharynx*, stomach, small intestine, colon*, liver, nasal cavity*, lung, soft tissues*, skin melanoma*, nonmelanoma skin*, bladder*, kidney*, thyroid*, Hodgkin's lymphoma*, lymphoid leukaemia* and myeloid leukaemia. Non-Hodgkin's lymphoma as a second primary was increased after cancers marked with an asterisk. Patterns of risk indicate a treatment effect for lung, bladder, stomach, Hodgkin's lymphoma and myeloid leukaemia. Common risk factors may be involved for cancers of the lung, bladder, nasal cavity and for soft tissues, such as pesticides. Bidirectional effects for several cancer sites of potential viral origin argue strongly for a role for immune suppression in NHL.

Second primary malignancies in patients with male breast cancer.

An international multicentre study of first and second primary neoplasms associated with male breast cancer was carried out by pooling data from 13 cancer registries. Among a total of 3409 men with primary breast cancer, 426 (12.5%) developed a second neoplasia; other than breast cancer, a 34% overall excess risk of second primary neoplasia, affecting the small intestine (standardised incidence ratio, 4.95, 95% confidence interval, 1.35-12.7), rectum (1.78, 1.20-2.54), pancreas (1.93, 1.14-3.05), skin (nonmelanoma, 1.65, 1.16-2.29), prostate (1.61, 1.34-1.93) and lymphohaematopoietic system (1.63, 1.12-2.29). A total of 225 male breast cancers was recorded after cancers other than breast cancer, but an increase was found only after lymphohaematopoietic neoplasms. BRCA2 (and to some extent BRCA1) mutations may explain the findings for pancreatic and prostate cancers. Increases at other sites may be related to unknown factors or to chance. This large study shows that the risks for second discordant tumours after male breast cancer pose only a moderate excess risk.

Gastric glassy cells: a study of 3202 gastrectomy specimens from dwellers of the Atlantic and Pacific basins.

Fifteen years ago we detected gastric cells with glassy cytoplasm (GCs) in the human pyloric antrum. The frequency of these cells was subsequently investigated in sections from gastrectomies carried on in populations dwelling on the rim of the Atlantic and Pacific basins. In this work we compared the results obtained in these disparate geographic regions. We reviewed sections from 3203 gastrectomies (1942 in the Atlantic basin and 1261 in the Pacific basin). In the Atlantic basin 12/1942 (0.6%) of the gastrectomies had GCs, whereas in the Pacific basin 26/1261 (2.1%) of the gastrectomies had GCs. The difference was significant (p<0.05). The proportion of gastrectomies with GCs was higher in patients in Vancouver, Canada, than in New York, and higher in Santiago de Chile than in Buenos Aires, despite the fact that these populations reside at approximately the same geographic latitude. Previous studies with the same material indicated that both the extension of intestinal metaplasia and the frequency of ciliated metaplasia were significantly higher in the Pacific than in the Atlantic basin. Hence, the difference in the frequencies of GCs appears to be a new indication that dissimilar environmental exposures in the two basins might have influenced the histological make-up of the gastric mucosa.

CYP17 promoter polymorphism and breast cancer risk in males and females in relation to BRCA2 status.

A T-C polymorphism in the promoter region of the CYP17 gene has been associated with male and female breast cancer risk as well as early-onset familial breast cancer. The potential role of this polymorphism was investigated in relation to breast cancer risk in Icelandic male and female carriers and noncarriers of a BRCA2 mutation. The study population consisted of 39 male and 523 female breast cancer cases and 309 male and 395 female controls. Of the cases, 15 males and 55 females carried a BRCA2 mutation. We did not find a significant association between male breast cancer risk and CYP17 genotypes. Among male breast cancer cases, the frequency of the CC genotype was higher among carriers of the 999del5 mutation (33.3%) than noncarriers (16.7%), although this difference also did not reach a statistical significance. No association was observed with breast cancer risk among females irrespective of menopausal status, stage of the disease or BRCA2 status. Our findings do not indicate a role for the CYP17 T-C polymorphism in female breast cancer, but a role in male carriers of a BRCA2 mutation could not be excluded because of the small sample size.

High frequency of LOH, MSI and abnormal expression of FHIT in gastric cancer.

The FHIT gene is a putative tumour suppressor gene. In this study, we analysed a set of 50 gastric tumours for alterations of FHIT, and found 38 of 45 tumours (84%) exhibiting loss of heterozygosity (LOH) within the FHIT gene. We used both nested Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) and single step RT-PCR to analyse the FHIT transcripts and found 34 of 39 (87%) tumours and seven of the 11 (64%) corresponding non-cancerous tissues showed low or aberrant expression of FHIT mRNA and the appearance of the aberrant FHIT transcripts depended on the conditions of the RT-PCR. In these aberrant transcripts, frequent deletions and/or insertions were detected by direct sequencing. All breakpoints for deletions and insertions were at splicing sites. All insertions came from the adjacent introns, whose appearance was completely in accordance with the 'GU-AG' rule for pre-mRNA splicing. It may be suggested that an alternative splicing mechanism functions in the formation of these aberrant transcripts. The fragile nature of FRA3B within the FHIT gene could be responsible for the formation of the aberrant mRNA. Negative or reduced Fhit expression was detected in 39 of 50 tumours (78%). Moreover, an association was found between abnormal Fhit expression and positive node status (P=0.012). Thirteen of 48 tumours (27%) displayed microsatellite instability (MSI), among which 10 tumours also showed MSI within the FHIT gene. Furthermore, we detected an association between MSI and negative node status (P=0.02). We conclude that the abnormalities of FHIT, presumably associated with the unstable nature of FRA3B within the FHIT gene, are involved in the carcinogenesis of gastric cancer, and lack of mismatch repair (MMR) could possibly promote its alteration in a subset of gastric tumours.

Alterations of E-cadherin and beta-catenin in gastric cancer.

BACKGROUND: The E-cadherin-catenin complex plays a crucial role in epithelial cell-cell adhesion and in the maintenance of tissue architecture. Perturbation in the expression or function of this complex results in loss of intercellular adhesion, with possible consequent cell transformation and tumour progression. METHODS: We studied the alterations of E-cadherin and beta-catenin in a set of 50 primary gastric tumours by using loss of heterozygosity (LOH) analysis, gene mutation screening, detection of aberrant transcripts and immunohistochemistry (IHC). RESULTS: A high frequency (75%) of LOH was detected at 16q22.1 containing E-cadherin locus. Three cases (6%) showed the identical missense mutation, A592T. This mutation is not likely to contribute strongly to the carcinogenesis of gastric cancer, because a low frequency (1.6%) of this mutation was also found in 187 normal individuals. We also detected a low frequency (0.36%, 0%) of this mutation in 280 breast tumours and 444 other tumours, including colon and rectum, lung, endometrium, ovary, testis, kidney, thyroid carcinomas and sarcomas, respectively. We also analyzed the aberrant E-cadherin mRNAs in the gastric tumours and found that 7 tumours (18%) had aberrant mRNAs in addition to the normal mRNA. These aberrant mRNAs may produce abnormal E-cadherin molecules, resulting in weak cell-cell adhesion and invasive behaviour of carcinoma cells. Reduced expression of E-cadherin and beta-catenin was identified at the frequency of 42% and 28%, respectively. Specially, 11 tumours (22%) exhibited positive cytoplasmic staining for beta-catenin IHC. An association was found between reduced expression of E-cadherin and beta-catenin. Moreover, an association was detected between reduced expression of E-cadherin and diffuse histotype. CONCLUSION: Our results support the hypothesis that alterations of E-cadherin and beta-catenin play a role in the initiation and progression of gastric cancer.