|
© Borgis - Postępy Nauk Medycznych 11, 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. Słowa kluczowe: rak żołądka, mutacje genu E-kadheryny (CDH1)
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. Key words: gastric cancer, E-catharin mutations
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
The frequency of hereditary gastric cancer occurrence is several times higher in carriers of BRCA1 and BRCA2gene mutations (24, 25, 26, 27). A high-risk level may not constitute the basis for any effective medical action. However, so far data have been obtained from families with a medical history that consists of a predominant number of breast and ovarian cancer. At our Centre, the BRCA2 gene was studied in families, in which one of the relatives was a person with diagnosed gastric cancer. It was shown that constitutional mutations of the BRCA2 gene in families with the gastric-breast cancer phenotype occur with a 20% genetic frequency; in families with the gastric-ovarian cancer phenotype, the gene occurrence has a frequency of 40% (28, 29). Moreover, it was found that these BRCA2 mutations are located almost exclusively in the gene fragment from exon 2 to exon 11.
Therefore, it appears that there may exist special kinds of BRCA2 gene mutations characterised by a significantly higher risk of developing breast cancer. After these data are verified using a larger material and by perspective studies of mutation carriers, it may turn out that it will be possible to save some subgroups of BRCA2 mutation carriers from death caused by hereditary gastric cancer.
GENE MUTATIONS OF MODERATELY HEIGHTENED GASTRIC CANCER RISK
Preliminary studies conducted at our Centre show that an increased risk of gastric cancer may accompany mutations within the NOD2 (30, 31) and CHK2 genes predisposing to carcinomas of numerous organs (32, 33, 34). The CHK2 gene encoding the human analogue of the Cds1 and Rad53 yeast kinase is activated in response to the DNA damage.
It may be concluded from our research conducted in a group of 117 patients that the CHK2 I157T occurs four times more often (OR=4.38, 95% CI=2.01-9.56) in a group of patients aged less than 50 years and suffering from hereditary gastric cancer.
The NOD2/CARD15 gene encodes the protein taking part in the immunologic response against intracellular pathogens; the 3020insC mutation causes an increased risk of developing chronic inflammatory diseases of the gastrointestinal tract, Crohn's disease, ulcerative colitis and large intestinal cancer secondary to the diseases. It may be concluded from our research conducted at our Centre on a group of 117 patients that the 3020insC NOD2 increases more than twice the risk of hereditary gastric cancer (OR=2.32, 95% CI=1.33-4.07).
The polymorphism of the angiotensin convertase enzyme (ACE) has recently been associated with pathogenesis and the development of human carcinomas. Research by Ebert MP et al. (35) conducted in a group of 88 patients demonstrates that insertion/deletion of the ACE gene may be connected with the development of early gastric cancer.
The XRCC1 gene is part of a complicated protein complex, which also contains DNA ß-polymerase, ligase I and PARP (poly (ADP-ribose) polymerase). This multi-unit complex participates in the DNA repair process. Popławski T. et al. (36) claim that the Gln/Gln variant of the Arg399Gly of the XRCC1 gene occurred more frequently in people with a history of gastric cancer (OR=2, 04; 95%, CI=1.27-3.29) and the results obtained from the research conducted on a group of 152 patients with an occurrence of gastric cancer in their families show that the 399Gln allele of the XRCC1 gene may be regarded as a gastric cancer marker.
The LAPTM4B gene has also been studied recently with respect of predisposal to gastric cancer (37). This gene is connected with genetic predisposal to liver cancer having the LAPTM4B *1 and LAPTM4B *2 alleles. The risk of developing gastric cancer was 1.8 times higher in people with the *1/2 genotype (95% CI=1.27-2.60) and 2.4 times higher in people with the *2/2 LAPTM4B genotype (95% CI=1.19-4.77) as compared to the *1/1 genotype. This research indicates that the *2 LAPTM4B allele may be one of genetic factors predisposing to gastric cancer.
Further studies of newly described mutations of moderately increased risk of developing gastric cancer will enable assessment of the actual gastric cancer risk connected with these mutations in the Polish population.
CONCLUSIONS
Except for the E-cadherin complex, hereditary gastric cancer is currently being diagnosed for research purposes. Nevertheless, keeping registers of these families and their clinical and molecular examinations are very important due to the real prospects for progress in fighting this disease. Piśmiennictwo
1. Zatoński W, Tyczyński J: Nowotwory złośliwe w Polsce w 1996 r. Warszawa, Centrum Onkologii-Inst. im. M. Skłodowskiej-Curie, 1999.
2. Munoz SE, Ferrearoni M, La Vecchia C et al.: Gastric cancer factor in subjects with family history. Cancer Epidemiol Biomerkers Prev 1997; 6: 137-40.
3. Taal BG, van Loon HJ, Kahn N et al.: The role of genetic factors in development of gastric cancer. Ned Tijdschr Geneeskd 1995; 143: 342-6.
4. Caldas C, Carneiro F, Lynch HT et al.: Familial gastric cancer: overview and guidelines for management. J Med Genet 1999; 36: 873-80.
5. Aarnio M, Salovaara R, Aaltonen LA et al.: Features of gastric cancer in hereditary non-polyposis colorectal cancer syndrome. Int J Cancer 1997; 74: 551-5.
6. Varley JM, McGown G, Thorncroft M et al.: An extended Li Fraumeni Kindred with gastric carcinoma and a codon 175 mutation of TP53. J Med Gen 1995; 32: 942-5.
7. Sharma K, Iida M, Mathur P: Familial juvenile polyposis with adenomatouscarcinomatous change. J Gastroenterol Hepatol 1995; 10: 131-4.
8. Hizawa K, Iida M, Matsumoto T et al.: Gastrointestinal manifestation of Cowden.s disease. Report of four cases. J Clin Gastroenterol 1994; 18: 13-8.
9. Westerman AM, Wilson JH: Peutz-Jeghers syndrome: risks of a hereditary condition. Scand J Gastroenterol Suppl 1999; 230: 64-70.
10. Hisada M, Garber JE, Fung CY et al.: Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst 1998; 90: 606-11.
11. Marsh DJ, Coulon V, Lunetta KL et al.: Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet 1998; 7: 507-15.
12. Subramony C, Scott-Conner CEH, Skelton D et al.: Familial juvenile polyposis. Study of a kindred: Evolution of polyps and relationship to gastrointestinal carcinoma. Am J Clin Pathol 1994; 102: 91-7.
13. Gylling A, Abdel-Rahman WM, Juhola M et al.: Is gastric cancer part of the tumour spectrum of hereditary non-polyposis colorectal cancer? A molecular genetic study. Gut 2007; 56: 926-33.
14. Kangelaris KN, Gruber SB: Clinical implications of founder and recurrent CDH1 mutations in hereditary diffuse gastric cancer. JAMA 2007; 297: 2410-1.
15. Kaurah P, MacMillan A, Boyd N et al.: Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA 2007; 297: 2360-72.
16. Guilford P, Hopkins J, Harraway J et al.: E-cadherine germline mutations in familial gastric cancer. Nature 1998; 392: 402-5.
17. Gayther SA, Gorringe KL, Ramus SJ et al.: Identification of germ-line E-cadherin mutations in gastric cancer families of European origin. Cancer Res 1998; 58: 4086-9.
18. Richards FM, McKee SA, Rajpar MH et al.: Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer. Hum Mol Genet 1999; 8: 607-10.
19. Norton JA, Ham CM, Van Dam J et al.: CDH1 truncating mutations in the E-cadherin gene: an indication for total gastrectomy to treat hereditary diffuse gastric cancer. Ann Surg 2007; 245: 873-9.
20. Pharoah PD, Guilford P, Caldas C: Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 2001; 121: 1348-1353.
21. Keller G, Vogelsang H, Becker I et al.: Diffuse type gastric and lobular breast carcinoma in a familial gastric cancer patient with E-cadherin germline mutation. Am J Pathol 1999; 155: 337-42.
22. Fitzgerald RC, Caldas C: E-cadherin mutations and hereditary gastric cancer: prevention by resection? Dig Dis 2002; 20: 23-31.
23. Huntsman DG, Carneiro F, Lewis FR et al.: Early gastric cancer in young, asymptomatic carriers o germ-line E-cadherin mutations. N Engl J Med 2001; 344: 1904-9.
24. Thompson D, Easton D: Breast Cancer Linkage Consortium. Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 2001; 68: 410-9.
25. Gayther SA, Mangion J, Russell P et al.: Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet 1997; 15: 103-5.
26. BCLC – The Breast Cancer Linkage Consortium. Cancer risk in BRCA2 mutation carriers. J Natl Cancer Inst 1999; 91: 1310-6.
27. Johannsson O, Loman N, Möller T et al.: Incidence of malignant tumours in relatives of BRCA1 and BRCA2 germline mutation carriers. Eur J Cancer 1999; 35: 1248-57.
28. Jakubowska A, Nej K, Huzarski T et al.: BRCA2 gene mutations in families with aggregations of breast and stomach cancers. Br J Cancer 2002; 87: 888-91.
29. Jakubowska A, Scott R, Menkiszak J et al.: A high frequency of BRCA2 gene mutations in Polish families with ovarian and stomach cancer. Eur J Hum Genet 2003; 11: 955-8.
30. Teodorczyk U et al.: The NOD2 gene mutations and the risk of familial gastric cancer. Konferencja: Nowotwory dziedziczne – profilaktyka, diagnostyka, leczenie. Szczecin, 21-22.10.2004 r. Streszczenia.
31. Teodorczyk U et al.: The NOD2 gene mutations and the risk of gastric cancer.13th United European Gastroenterology Week „UEGW 2005”, Copenhagen, Denmark, 15-19 October 2005; Abstracts, OP-G-303.
32. Cybulski C, Górski B, Huzarski T et al.: CHK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet 2004; 75: 1131-1135.
33. Kurzawski G, Suchy J, Cybulski C et al.: Testy DNA umiarkowanie zwiększonego ryzyka zachorowania na nowotwory złośliwe. Genetyka Kliniczna Nowotworów 2008. Monografia pod redakcją J. Lubińskiego, Print Group Sp z o.o. Szczecin 2008.
34. Lubiński J, Huzarski T, Kurzawski G et al: The 3020insC allele of NOD2 predisposes to cancers of multiple organs. Hereditary Cancer in Clinical Practice 2005; 3: 59-63.
35. Ebert MP, Lendeckel U, Westphal S et al.: The angiotensin I-converting enzyme gene insertion/deletion polymorphism is linked to early gastric cancer. Cancer Epidemiol Biomarkers Prev 2005; 14: 2987-2989.
36. Popławski T et al.: Związek między polimorfizmami genu XRCC1 a rodzinnym występowaniem raka żołądka.Gastroenterologia Polska 2008; 15: 225-228.
37. Liu Y, Zhang QY, Qian N et al.: Relationship between LAPTM4B gene polymorphism and susceptibility of gastric cancer. Annals of Oncology 2007; 18: 311-316.
otrzymano/received: 2010-10-01 zaakceptowano/accepted: 2010-10-29 Adres/address: *Anna Jakubowska International Hereditary Cancer Centre Department of Genetics and Pathology Pomeranian Medical University ul. Połabska 4, 70-115 Szczecin tel.: (91) 466-15-32 e-mail: aniaj@sci.pam.szczecin.pl Artykuł Clinical genetics of stomach cancer w Czytelni Medycznej Borgis. |
  Proszę kliknąć w wybraną okładkę aby przejść na stronę czasopisma
 |
Chcesz być na bieżąco? Polub nas na Facebooku: strona Wydawnictwa na Facebooku |