© Borgis - Postępy Nauk Medycznych 11/2010, s. 877-880
*Anna Jakubowska, Beata Wojnarska, Urszula Teodorczyk, Jan Lubiński
Clinical genetics of stomach cancer
Genetyka kliniczna raka żołądka
International Hereditary Cancer Centre, Department of Genetics and Pathology, Pomeranian Medical University
Head of the Genetics and Pathology Unit: prof. dr hab. med. Jan Lubiński
Streszczenie
Rak żołądka jest jednym z najczęściej diagnozowanych nowotworów złośliwych przewodu pokarmowego. W około 20% wszystkich diagnozowanych przypadków raka żołądka stwierdza się rodzinną agregację nowotworów, co sugeruje, że przyczyną zachorowania na raka żołądka w tych rodzinach może być predyspozycja genetyczna. Opisany został szereg zespołów dziedzicznej predyspozycji do nowotworów w przebiegu których rak żołądka występuje ze zwiększoną częstością, są to zespoły: dziedzicznego niezwiązanego z polipowatością raka jelita grubego (zespół Lyncha), dziedzicznego raka piersi lub/i jajnika, rodzinnej polipowatości gruczolakowatej jelita grubego oraz Cowden'a, Peutz-Jeghers'a, Li-Fraumeni i Bloom'a (4-13). Jedynym opisanym jak dotychczas zespołem predysponującym do dziedzicznego raka żołądka specyficznego narządowo o ustalonym podłożu genetycznym jest zespół spowodowany nosicielstwem mutacji genu E-kadheryny (CDH1) (14, 15), charakteryzujący się występowaniem „rozlanego” raka żołądka w bardzo wczesnym wieku. Oprócz raka żołądka, u nosicieli mutacji w CDH1, opisano również występowanie raka piersi typu zrazikowatego, raka jelita grubego oraz raka prostaty. W przypadku osób z konstytucyjną mutacją genu E-kadheryny jest w pełni uzasadnione i zalecane wykonanie operacji profilaktycznego usunięcia żołądka.
Z wyjątkiem opisanego poniżej zespołu E-kadheryny, brak dotychczas zweryfikowanych, co do skuteczności zasad postępowania w rodzinach z dziedzicznym rakiem żołądka. Wiele ośrodków zaleca wykonywanie gastroskopii raz w roku rozpoczynając je od wieku 5-10 lat niższego od najmłodszego zachorowania na raka żołądka wśród krewnych. Jednakże optymalne postępowanie profilaktyczno-lecznicze może zostać określone dopiero na podstawie badań przeprowadzonych na dużych grupach pacjentów.
Summary
Gastric cancer (GC) is one of the most frequently diagnosed malignancies of the gastrointestinal tract. Familial aggregation of stomach cancer in about 20% of all diagnosed cases suggests that in these families stomach cancer is caused by genetic predisposition. Stomach cancer has been shown to be part of the tumour spectrum in other inherited complexes, including hereditary non-polyposis colon cancer (HNPCC), familial adenomatous polyposis (FAP), Cowden's complex, Peutz-Jeghers complex, Li-Fraumeni complex and Bloom's complex.
The only complex of genetic predisposition to familial gastric cancer is characterized by detection of E-cadherin (CDH1) gene mutations in early onset cases diagnosed with diffuse gastric cancer. Along with substantially increased risk of diffuse gastric cancer, in families with detected CDH1 mutation, lobular breast cancer, colon cancer and prostate cancer have been reported. Because of the very high penetrance of CDH1 mutations and lack of effective methods in detection of early gastric cancer, prophylactic gastrectomy is recommended to all CDH1 carriers.
Up to now it is not known have to deal with patients from families with gastric cancer aggregation. Except of families with detected CDH1 mutations there is a lack of surveillance protocols for patients with recognized hereditary gastric cancer. In most centres is recommended annual gastroscopy in all relatives starting 5-10 years earlier than the youngest age of diagnosis of family with aggregation of GCs. However, the most appropriate prophylactic and medical treatment for GC patients from families with recognized genetic predisposition can be determined after extended analyses on large patients group.
FAMILIAL AND CLINICAL CRITERIA FOR HEREDITARY GASTRIC CANCER
In 1999, an international group of experts (International Gastric Cancer Linkage Consortium – IGCLC) at Cambridge proposed familial and clinical criteria for diagnosing hereditary gastric cancer (4) based on the results of research of families with aggregations of GCs, especially families with constitutional E-cadherin mutations.
In accordance with the proposed criteria, hereditary diffuse gastric cancer (HDGC) can be diagnosed if:
1) there are at least two histopathologically verified cases of HDGC in families of first- or second-degree relatives and at least one of the GCs was diagnosed before reaching the age of 50.
2) there have been at least three histopathologically verified cases of HDGC in families of first- or second-degree relatives, regardless of their age.
The IGCLC decided to take into consideration whether the familial intestinal Gastric Cancer (FIGC) is dependent on the incidence of gastric cancer in a given population.
Countries with high gastric cancer incidence, such as Japan, China, Korea, and Portugal, should apply the following criteria:
1) histopathologically verified gastric cancer of the intestinal type has been diagnosed in at least 3 members of a given family, one of whom is a first-degree relative for the other two;
2) at least two of these people are first-degree relatives from two different generations;
3) intestinal gastric cancer was diagnosed in at least one of these people before the age of 50.
In countries with low gastric cancer incidence (such as the United States, Great Britain, Norway, and Poland), FIGC can be diagnosed if the following criteria are met:
1) there are at least two histopathologically verified cases of intestinal gastric cancer in first- or second-degree relatives and at least one of them was diagnosed with GC before reaching the age of 50.
2) there have been at least three cases of GC in first- or second-degree relatives, regardless of their age.
FAMILIAL AND CLINICAL CRITERIA FOR HEREDITARY GASTRIC CANCER DIAGNOSIS WITH A HIGH PROBABILITY
On the basis of research conducted at our Centre, we were able to define criteria for identifying families suspected of hereditary gastric cancer. It may be concluded that hereditary gastric cancer may be diagnosed with a high probability in the following cases:
1) 2 cases of GC have been diagnosed in first-degree relatives above the age of 50;
2) gastric cancer was diagnosed at the age of 45 or less;
3) 1 case of gastric cancer and an extragastric carcinoma have been diagnosed in first-degree relatives, regardless of their age.
PROCEDURES APPLIED TO FAMILIES WITH HEREDITARY GASTRIC CANCER
Except for the E-cadherin complex described below, there are no procedures verified in terms of their effectiveness, to be applied to families with hereditary gastric cancer. In practice, gastroscopies are performed on an annual basis at numerous centres, starting at the age of 5-10 years less than the youngest age, at which relatives were diagnosed with gastric cancer. However, it is an action that will most probably enable early diagnosis of intestinal-type carcinomas.
Epidemiological and clinical data imply that it will probably be the prevention of hereditary gastric cancer by Helicobacterpylor eradication and diet optimisation that will play a significant role in the future. Experience with carriers of E-cadherin mutations shows that preventive gastrectomy will, unfortunately, be the only alternative in some cases of hereditary gastric cancer (19).
E-CADHERIN COMPLEX
Diffuse gastric cancer is diagnosed in approx. 30% of these carcinomas cases. Among patients with histopathological diagnosis of this cancer, the total cure rate and the survival rate are very low.
Some cases of hereditary diffuse gastric cancer are caused by E-cadherin gene mutations (9, 16, 17, 18). CDH1 mutations are inherited in an autosomal dominant way and the carrier of the mutations is at approx. 40-80% risk of developing diffuse gastric cancer (15, 20).
In addition to gastric cancer, cases of lobular breast cancer (39% risk of occurrence of this cancer in women), large intestine cancer and prostate cancer have also been described in carriers of CDH1 mutations (15, 20, 21). Various types of mutations are detected within the CDH1, both small point mutations of the nucleotide substitution type (approx. 70% of all mutations) and insertions as well as deletions. In the case of people with a constitutional E-cadherin gene mutation, preventive stomach removal is fully justified and recommended (22, 23).
Recent publications report that mutations within the CDH1 gene are detected in 30-40% families with hereditary diffuse gastric cancer (HDCG) and in 50% of families with gastric cancer diagnosed in two relatives before the age of 50 (15, 19, 20). At our Centre, no mutation of this gene was detected among patients from 100 families with the aggregation of diffuse gastric cancer. Therefore, it appears that E-cadherin gene mutations are not the main cause of hereditary gastric cancer.
HEREDITARY GASTRIC CANCER CAUSED BY BRCA2 GENE MUTATIONS
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