From gene to disease; E-cadherin and hereditary diffuse gastric cancer

Hereditary diffuse gastric cancer (HDGC) is a rare autosomal dominant syndrome associated with an early-onset, histologically diffuse, signet ring cell type gastric cancer and the occurrence of cancer at other anatomical sites, i.e. breast, colon, prostate and ovary. Inactivating germline mutations in the CDH1 gene, encoding the cell to cell adhesion protein E-cadherin, predispose to HDGC. About 30% of HDGC families have a proven pathogenic CDH1 mutation. Lifetime penetrance of HDGC is about 70%. In HDGC families the recommendation for prophylactic total gastrectomy is restricted to carriers of an inactivating CDH1 mutation.     

Preventive resection of hereditary diffuse gastric cancer

Hereditary diffuse gastric cancers are rare, accounting for at most 1-3% of gastric cancers. It can be caused by a mutation in the tumour-suppressor gene CDH1. A healthy person carrying a CDH1 mutation has a cumulative risk of developing gastric cancer of 70-80%. In most cases, gastric cancer is detected before the age of 40 years. The effectiveness of screening for hereditary diffuse gastric cancer or early detection with twice-yearly upper GI endoscopy with blind biopsies is highly questionable. Given the poor prognosis of patients with hereditary diffuse gastric cancer, prophylactic gastrectomy can be considered an option for patients with a CDH1 mutation. It is recommended that the supervision, screening and possible preventative gastrectomy for hereditary diffuse gastric cancers are handled by a multidisciplinary team in a specialised centre.     

Genetic background and clinical features of hereditary diffuse gastric cancer

With the development of the molecular biology more pathological condition have been identified (p53 mutation and breast cancer, Ret protooncogene point mutation and medullary thyroid cancer), which could lead to malignant disease. The recent advances in the molecular genetics lead to the recognition of the hereditary diffuse gastric cancer that inherited in a dominant autosomal manner with incomplete penetrance. About 25-30% of families fulfilling the criteria have germline mutation of the CDH1 gene coding the calcium-dependent E-cadherin protein. In confirmed cases, prophylactic gastrectomy suggested in the early adolescent age.     

Carcinoma of the fallopian tube after prophylactic laparoscopic ovariectomy in a patient with a BRCAI mutation

A 48-year-old woman with a distended abdomen appeared to have ascites and was admitted to the gynaecological ward. At the age of 31 years she had been diagnosed with breast cancer and had undergone surgical breast conservation of the right breast. There was a history of both ovarian cancer and breast cancer in her family. Genetic evaluation showed that she was carrying a BRCAI germline mutation. At the age of 42 years she underwent a prophylactic bilateral laparoscopic ovariectomy and 5 years later she underwent a complete mastectomy due to breast carcinoma of the left breast. Two months later she developed ascites, a raised CA125 level and on a CT scan carcinoma of the peritoneum. During the laparotomy a fallopian tube carcinoma was found. After the uterus, fallopian tubes and omentum had been surgically removed, chemotherapy took place. The patient tolerated this well and the CA125 value decreased. Recently, the first molecular evidence was found that linked fallopian tube cancer to germline mutations in BRCAI patients. Patients harbouring a BRCA germline mutation not only have an increased risk of ovarian carcinoma but also of fallopian tube carcinoma. Therefore, in patients with a BRCA mutation, prophylactic surgery should take the form of an adnexectomy, not an oophorectomy.     

Familial ovarian cancer

Women with mutations in the BRCA1 or BRCA2 genes are at increased risk for the development not only of breast, but of ovarian cancer. The estimated lifetime risk of contracting ovarian cancer for women bearing the mutation is 16% for Ashkenazi Jews and up to 60% for high-risk populations. If a woman is at high familial risk of getting ovarian cancer, an intense screening with transvaginal ultrasound or determination of CA 125 can be done, although these methods have not proved beneficial so far. It is thought by some that the use of the contraceptive pill can prevent up to 50% of family-associated ovarian cancers, but the few existing studies have yielded contradictory results. That prophylactic oophorectomy can prolong the lives of healthy women with a family history or who bear a germline BRCA mutation is quite sure, but it is not helpful in preventing peritoneal carcinoma. The clinicopathologic behavior of mutation-associated ovarian cancer differs from the growth pattern of sporadic ovarian cancer. The hope is to develop suitable therapies for both types.     

Recommendations for the management of women with an increased genetic risk of gynaecological cancer

About 5% of all ovarian-cancer cases are caused by a genetic predisposition, in particular as a component of the autosomal dominant hereditary breast-ovarian-cancer syndrome. This syndrome is usually due to germline mutations in the BRCA1- or BRCA2-gene. Ovarian and endometrial cancer also occur in families with hereditary non-polyposis colorectal cancer (HNPCC). This syndrome is caused by germline mutations in DNA mismatch-repair genes. Women at high risk of gynaecological cancer based upon familial clustering of disease or a demonstrated pathogenic germ-line mutation are candidates for surveillance: annual gynaecological examinations, including vaginal echoscopy and serum carcinoma antigen CA125 testing. Prophylactic surgery in the form of adnexectomy leads to a marked, but not complete, reduction of ovarian-cancer risk in high-risk cases. There is insufficient evidence to advise against the use of oral contraceptives or hormonal substitution after adnexectomy for healthy women with a genetic predisposition to breast cancer. Recommendations for surveillance and prevention should only be given after genetic-risk counselling, based on a detailed family study and DNA-based diagnosis.     

Breast cancer risk in Ashkenazi BRCA1/2 mutation carriers: effects of reproductive history

BACKGROUND: Younger age at first birth and greater parity generally reduce the risk of developing breast cancer, but whether this reduced risk holds in women with a mutation in the BRCA1 or BRCA2 gene is unknown. METHODS: In a Washington DC community-based study conducted in 1996, we tested 5318 Ashkenazi Jews for three BRCA1/2 founder mutations and identified 120 mutation carriers. Applying an extension of the "kin-cohort" analysis, we compared the effects of reproduction on breast cancer risk in carriers and noncarriers. We also used a case-case analysis among 288 participants who had been diagnosed with breast cancer. RESULTS: In noncarriers, the estimated relative risk (RR) of breast cancer rose 5% with each 5-year increment in age at first birth (RR = 1.05; 95% confidence interval [CI] = 0.97-1.15). By contrast, the estimated risk in mutation carriers fell with each 5-year increment in age (RR = 0.65; 95% CI = 0.37-1.16). Among the 288 participants who were breast cancer survivors themselves, the comparison of carriers with noncarriers also showed no protection associated with early birth in the presence of a mutation in BRCA1 or BRCA2. CONCLUSIONS: It is not yet clear whether the recognized breast cancer risk factors operate in the same way in women who carry a mutation in the BRCA1 or BRCA2 genes.     

The role of genetic factors in the development of gastric cancer

In general, a genetic predisposition to a tumour disease such as gastric cancer is postulated in patients with cancer at an unusually early age or when several relatives are affected. A clear definition of hereditary gastric cancer is lacking. Two types of families may be distinguished: kindreds with gastric cancer only (site-specific), and kindreds with gastric as well as colorectal cancer, representing the hereditary non-polyposis colon cancer (HNPCC) syndrome. A genetic predisposition is presumed in young patients with a diffuse type of gastric cancer, in contrast to the intestinal type which is associated with atrophic gastritis and older age. A variety of genetic abnormalities in tumour tissue have been described, e.g. mutations in genes involved in DNA repair. Helicobacter pylori plays an important role in the aetiology, but the interaction with genetic factors is unknown.     

Multiple endocrine neoplasia type 1: recent developments and guidelines for DNA diagnosis and periodic clinical monitoring

Multiple endocrine neoplasia type 1 (MEN-1) is an autosomal dominantly inherited disorder, characterised by the occurrence of multiple tumours, particularly in the parathyroid glands, the pancreatic islets, the pituitary gland, the adrenal glands, as well as neuroendocrine carcinoid tumours. Since the identification of the responsible gene in 1997, the diagnosis MEN-1 can be assessed easily, and even presymptomatically, by DNA analysis. An early diagnosis is of importance because through periodic clinical monitoring of (putative) MEN1 gene germline mutation carriers, tumour development can be detected and treated at an early stage. Eligible for DNA analysis are MEN-1 patients and their family members, as well as patients with seemingly sporadic MEN-1 related tumours in whom on clinical grounds carriership of a MEN1 gene germline mutation is suspected. Eligible for periodic clinical monitoring are putative and confirmed carriers of a MEN1 germline mutation from the age of 5.     

A case of primary adenosquamous carcinoma of the stomach showing Borrmann 4 type

Adenosquamous carcinoma is a rare histological type of gastric cancer. We reported a 61-year-old man with primary adenosquamous carcinoma of the stomach showing Borrmann 4 type. Gastrofibroscopic biopsy and lymph node biopsy showed squamous and adenosquamous carcinoma respectively. Operated specimen revealed a adenosquamous carcinoma with diffuse infiltration.     

胃癌及癌前病变胃黏膜和胃腺瘤中APC基因表达及其意义

目的 探讨结肠腺瘤性息肉病（APC）基因在胃癌及胃腺瘤发生、发展中的重要作用以及其在胃癌早期诊断中的意义。方法 运用免疫组化技术检测APC基因蛋白在30例胃癌，30例不典型增生，30例肠上皮化生（肠化）和10例胃腺瘤，30例正常胃黏膜组织中的表达。结果 APC基因蛋白阳性表达率在胃腺瘤（50％），肠化（66．7％），不典型增生胃黏膜组织（53．3％）及胃癌（60％）中比正常胃黏膜（90％）明显降低（P〈0．05）。在中重度不典型增生胃黏膜组织中APC基因表达率（30．8％）比在轻度不典型增生中（70．6％）低（P〈0．05）。APC基因在中分化腺癌组表达率与低分化组比较差异有统计学意义（38．5％vs 83．3％，P=0．0287）。肠型胃癌中APC基因的表达率比在弥漫型胃癌低（47．6％vs 88．9％，P=0．0401）。结论 APC基因的失活在胃腺瘤的发生中起重要作用。APC基因的失活是胃癌发生的早期事件，APC基因蛋白表达产物的检测对早期胃癌的诊断可能是一项比较有价值的指标。     

Chronic atrophic gastritis and Helicobacter pylori infection among Japanese Americans in Seattle

Gastric cancer is still a major cause of mortality due to cancer worldwide. The most common type of gastric cancer is intestinal type carcinoma, which usually occurs in stomachs containing chronic atrophic gastritis. Individuals with chronic atrophic gastritis are considered to be at increased risk for developing intestinal type carcinoma of the stomach. To examine the association between chronic atrophic gastritis and other gastric cancer risk factors, a cross-sectional study was conducted using serum samples and questionnaire information collected from 776 persons of full Japanese ancestry in the greater Seattle area in 1994. The presence of chronic atrophic gastritis and Helicobacter pylori infection was determined by measurement of serum pepsinogen levels and H. pylori antibodies, respectively. Based on multiple logistic regression, the significant predictors of chronic atrophic gastritis were age over 50 years, H. pylori infection, and 20 years or more lived in Japan. Alcohol consumption, smoking, prior peptic ulcer, and history of gastric cancer in parents were not significantly associated with chronic atrophic gastritis. The results imply that H. pylori infection since earlier life and other unknown exposure factors in Japan might have played an important role in the development of chronic atrophic gastritis.     

21例早期胃癌患者的临床病理特点

目的分析早期胃癌的临床病理特点。方法选择本院21例经内镜活检及病理诊断为胃癌、手术后病理确诊为早期胃癌的患者,分析并总结其内镜下的特点、部位及病理类型。结果21例患者中,病灶位于胃窦12例,胃体4例,胃角4例,胃底1例。早期胃癌镜下分型中,Ⅰ型1例,Ⅱ型12例,Ⅲ型8例。黏膜内癌13例,黏膜下层癌8例,其中黏膜内癌淋巴结转移2例,黏膜下层癌淋巴结转移1例;高、中低分化管状腺癌10例,腺癌6例,印戒细胞癌4例及乳头状腺癌1例。结论内镜检查是诊断早期胃癌的首选方法,增强对内镜表现及病理认识,有助于提高早期胃癌检出率。     

Gastric cancer in Tasmania (1978-1992)

A detailed analyses of gastric cancer incidence and mortality rates in Tasmania was done using fifteen years (1978-1992) of population based Tasmanian Cancer Registry data. The age standardised incidence rates for the period were 12.5 per 100,000 men (95% CI 11.4-13.6) and 5.2 per 100,000 women (95% CI 4.6-5.8). The age standardised mortality rates were 10.6 per 100,000 men (95% CI 9.6-11.6) and 4.1 per 100,000 women (95% CI 3.5-4.6). Male:Female ratio of mortality rates was 2.6. Gastric cancer mortality rates have now significantly declined among males (p = .03) and females (p = .02). No significant decline was observed for incidence rates among males (p = .1) and females (p = .3). For cases overall, there was a preponderance of intestinal type of gastric cancer (76.5%). No significant trend over time was observed in the mean rate of occurrence of intestinal or diffuse type of gastric cancer. The ratio of intestinal: diffuse was 6.5 for all ages. Among males, a significant (p = .03) upward trend in the incidence was observed for proximal tumours, while no such trend (p = .07) was observed among women. A significant decline in incidence of distal tumours was observed for males (p = .000) and females (p.007). Male:Female ratio for proximal tumour was 4.7:1. The results suggests that Tasmanians may have been a population at high risk of gastric cancer.     

ARCAD: A method for estimating age-dependent disease risk associated with mutation carrier status from family data

We present ARCAD, a method to estimate the disease risk associated with mutation carrier status using data on families ascertained by affected individuals, in which a germline mutation has been detected. Because the event of interest, the age of onset, is a censored variable, the method uses the survival analysis approach to formulate the likelihood. Provided that selection criteria are clearly defined, the ascertainment bias is removed by including a correction term in the likelihood computation. We simulated family data and selected those with a proband affected before age 17, and at least one or at least two relatives affected before age 46. We show that including the correction for the ascertainment provides reliable estimates of the risk, even when many individuals are not tested for the mutation. An application to cancer risk and germline p53 mutations is presented. We routinely investigate the p53 status for all the children treated in the Department of Pediatric Oncology at the Institute Gustave Roussy, whose family displays at least one relative affected by cancer before age 46. We identified 5 families with an inherited germline p53 mutation. The risk for any cancer for a mutation carrier estimated by ARCAD was 42% within the age class 0–16 years, 38% within the age class 17–45 years, and 63% after 45 years, with a lifetime risk of 85%. These risks are almost entirely explained by the occurrence of the six most frequent cancers encountered in the Li-Fraumeni syndrome. © Wiley-Liss, Inc.     

胃癌亚甲基四氢叶酸还原酶基因多态性及其与微卫星不稳的关系

目的探讨胃癌亚甲基四氢叶酸还原酶（MTHFR）基因多态性与微卫星不稳的关系。方法采用聚合酶链反应一限制性片段长度多态性技术检测122例胃癌和101名正常对照的MTHFR基因C677T和A1298C多态性；采用PCR为基础的方法检测微卫星不稳定性（MSI）。结果MTHFR C677T多态性可分为677CC、677CT和677TT三种类型。胃癌组3种基因型频率分别为47．5％、39．3％和13．1％；对照组分别为48．5％、42．6％和8．9％，两组相比差异无统计学意义（P〉0．05）。以677CC基因型做为参考，胃贲门癌677CT基因型OR值为0．38，95％CI：0．15～0．98；TT基因型OR值为0．26，95％CI：0．03～2．18；677CT＋TT基因型OR值为0．36，95％CI：0．07～0．98。胃体癌677TT基因型OR值为3．03，95％CI：1．07～8．65。MTHFR A1298C多态性可分为1298AA、1298AC和1298CC3种类型。胃癌组3种基因型频率分别为59．8％、36．1％和4．1％；对照组分别为57．4％，37．6％和5．0％，两组相比差异无统计学意义（P〉0．05）。以1298AA基因型的OR值为1．00，胃窦癌AC基因型的OR值为0．87，95％CI：0．42～1．82，CC基因型的OR值为0．41，95％CI：0．05～3．72。MTHFR 677TT基因型胃癌与微卫星不稳显著相关（P〈0．05），而MTHFR A1298C多态性与微卫星不稳无关（P〉0．05）。结论重庆地区人群中MTHFR C677T多态性是胃贲门癌的保护因素，是胃体癌的危险因素；MTHFR A1298C多态性可能是胃窦癌的保护因素；677TT基因型胃癌的发生可能涉及到MSI途径。     

Gastric cancer in Africa: what do we know about incidence and risk factors?

Gastric cancer is a major contributor to mortality worldwide, yet its incidence varies widely around the world in a way which our current understanding of aetiology cannot fully explain. Incidence data from Africa are weak, reflecting poor diagnostic resources, but there are firm data on intestinal metaplasia and gastric atrophy which are important steps in the carcinogenesis pathway. The available registry data suggest that incidence is unlikely to be dramatically different from Europe or North America. Helicobacter pylori infection is an important permissive factor in the development of cancer, but H. pylori seroprevalence is high all over Africa and cannot clearly be correlated with cancer. However, there is evidence that specific bacterial virulence genes, particularly vacA and iceA allele1, do contribute to cancer risk. Intestinal metaplasia and gastric atrophy have been the focus of twelve studies and are common in Africa. Epstein-Barr virus, which causes 10% of cancer worldwide, is the focus of only one African study. Work in other continents demonstrates that other risk factors apply only to one or other of the two major histological types, intestinal and diffuse. Diet, smoking, alcohol and salt intake predispose to the intestinal type of cancer, but genetic factors predispose to the diffuse type. There is a pressing need for information on the histological types occurring in Africa, and their associated risk factors. Most urgently, information on dietary predisposition to cancer is required to inform public health policy with respect to the demographic transition (urbanisation and lifestyle changes) which is occurring all over the continent.     

Recognition of congenital endometrial carcinoma: the importance of family history and investigation of microsatellite instability in the tumour

Endometrial cancer diagnosed at a relatively young age or in a patient with a medical history of colorectal cancer may be indicative of Lynch syndrome. Four women, aged 43, 60, 41 and 54 respectively, with a family history of endometrial or colorectal neoplasm were examined for microsatellite instability (MSI) in tumour tissue with positive results. Subsequently, a mutation was found in one of the DNA mismatch repair genes. Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), is caused by a germline mutation in a mismatch repair gene and is an autosomal dominant disorder that is characterized by the development of carcinoma of the endometrium and colorectum at a relatively young age. Until recently, recognition of Lynch syndrome was mainly based on an, often incomplete, family history, but today the presence of MSI in tumour tissue can be used to identify patients at risk for Lynch syndrome. A pathologist can contribute to identifying a patient at risk for Lynch syndrome by initiating MSI testing when: (a) endometrial cancer is diagnosed under the age of 50, (b) a combination of endometrial cancer and colorectal cancer is diagnosed under the age of 70.     

Hystological types and mortality for gastric cancer in São Paulo, Brazil

The objective of this study was to analyze, according to Lauren's classification, the prevalence of a hystological type - intestinal or diffuse -, among gastric carcinomas. The authors reviewed 650 hystological sections from a Hospital in the City of S?o Paulo during a 30-year period, following the definitions of the above classification. After the 50's the intestinal type proved to be prevalent, reaching 62.74% of all cases of gastric cancer in the 80's, and showing a ratio of intestinal/diffuse type of 1.71. Other large series of cases whose diagnoses followed the nomenclature of WHO Hystological Classification showed to be inadequate for this study. The prevalence of the intestinal type of gastric carcinoma seems to disagree with the decreasing rates of mortality due to this disease in the State of S?o Paulo, in the same period. Further studies, such as the analysis of incidence rates and prevalence of Helicobacter pylori, among others, are necessary for a better understanding of these data.     

Clinicopathological and histochemical studies of linitis plastica type gastric cancer with special reference to early gastric cancer in the region of the fundic gland

In this study, early gastric cancer in the region of the fundic gland was found to occur predominantly in women. Many lesions of this type were identified in the posterior wall of the middle portion of the stomach. Histologically, the lesions were classified as poorly differentiated carcinomas in all cases of early cancer. On the other hand, in 9 patients with cancer of linitis plastica type having IIc lesions (less than 2.0 cm in diameter) located in the region of the fundic gland, the tumor focus was also in the posterior wall of the middle portion of the stomach. Giant folds were present diffusely in all other portions of the gastric mucosa in these latter cases. These cases also had diffuse infiltration of cancer cells into the submucosa, muscle layer and extraserosal regions. Histologically, the lesions were classified, in all cases of linitis plastica type, as poorly differentiated carcinomas including signet ring cells. Acid mucopolysaccharides (AMPS) and sialic acid were histochemically detected in the interstitial tissues of early gastric carcinomas and linitis plastica type gastric cancers. The AMPS digestion rates were higher for early cancer tissue. The present results support the hypothesis that early gastric cancer in the region of the fundic gland may occur in conditions favorable to tumor growth and may develop into cancer of linitis plastica type.