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CDH1 Mutation in Two Patients with Hereditary Gastric Cancer

CDH1 Mutation in Two Patients with Hereditary Gastric Cancer 10.2478/chilat-2014-0107 ACTA CHIRURGICA LATVIENSIS • 2014 (14/1) CASE REPORT CDH1 Mutation in Two Patients with Hereditary Gastric Cancer , , , , Jelena Pogodina* **, Roberts Ribenieks*, Dace Berzina* **, Genadijs Trofimovics* **, Edvins Miklasevics* ** *Pauls Stradins Clinical University Hospital, Riga, Latvia **Institute of Oncology, Riga Stradins University, Latvia SUMMARY CDH1 is currently the only gene in which mutations are known to cause hereditary diffuse gastric cancer (HDGC). Hereditary diffuse gastric cancer is defined as a syndrome of inherited predisposition to cancer with autosomal dominant inheritance pattern. Specific criteria are used to identify patients with suspected HDGC and who should be investigated for CDH1 germline mutations. Accurate screening is mandatory for unaffected carriers ofCDH1 mutations and selected high-risk individuals could be considered for prophylactic gastrectomy. Key words: gastric cancer, hereditary diffuse gastric cancer, CDH1 AIM OF THE DEMONSTRATION 58 and died three years later. The paternal grandmother We report two male patients with a history of familial was diagnosed with kidney cancer at age 73 and died gastric cancer and positive CDH1 gene mutation. three years later ( Fig. 2). Endoscopy revealed tumor, which infiltrated the gastric wall with penetrating the TWO CASE REPORTS serosa. Biopsies confirmed adenocarcinoma and a total Both patients were admitted to our hospital with gastrectomy with Braun esophagojejunostomy was diagnosis of gastric adenocarcinoma and underwent perfomed. Intraoperative finding revealed a tumor total gastrectomy. Their family history was significant extending along the lesser curvatura of the stomach for gastric cancer and patients fulfilled the hereditary from cardia to the pyloric region with the tumor diffuse gastric cancer criteria. invasion extending out of the stomach wall and adjacent Patient 1 on presentation was a 54-year-old male with a to the great omentum. Histopathological examination family history of gastric cancer. The patient’s father was revealed moderately differentiated adenocarcinoma, 8 diagnosed with gastric cancer and died of the disease at lymph nodes metastases and great omentum metastases, the age of 56 years. The father’s brother was diagnosed witch was classified as pT4AN3AM1G2Ro, stage IV. The with gastric cancer at age 51 and died two years later. The patient received palliative chemotherapy (Epirubicin 75 mother’s brother was diagnosed and died of oesofageal mg; Cisplatin 90 mg; Tegafur 400 mg twice a day during cancer and mother’s sister was diagnosed and died of two week.) colorectal cancer at 82 years ( Fig. 1). DNA sequencing was performed in both patients and The patient had epigastric pain, fatigue and weakness results showed CDH1 gene mutation 3’UTR+54 C>T for approximately three month. Endoscopy revealed (Fig.3). tumor, located in the gastric cardia. Biopsies confirmed adenocarcinoma and a total gastrectomy with Braun DISCUSSION esophagojejunostomy was perfomed. The postoperative The first description of hereditary diffuse gastric cancer period was uneventful and he was discharged on the was in three Maori families in New Zealand and the first 7th day. Histopathological examination revealed poorly evidence supporting the role of CDH1 as a major gastric differentiated adenocarcinoma and 9 lymph nodes cancer susceptibility gene came from genetic linkage metastases, which was classified as pT3N3AM0G3Ro, studies in these Maori families (6). stage IIIB. The patient received 45 Grays of radiotherapy Hereditary diffuse gastric cancer (HDGC) is an autosomal and 2 courses of adjuvant chemotherapy according to dominant genetic predisposition syndrome caused ECF scheme (5- fluorouracil 1000 mg, Farmorubicin by germine mutation in the CDH1 gene (3,7). HDGC 90 mg, Cisplatin 100mg). Eleven month after total account for 1-3% of all gastric cancer (7,8). gastrectomy computed tomography revealed liver The CDH1 gene is located on chromosome 16 and metastasis. encodes E-cadherin. E-cadherin is a calcium-dependent Patient 2 a 44-year-old man presented with abdominal cell-cell adhesion protein that plays a role in the pain for two month. The patient’s history included two maintenance of cell differentiation and the normal family members diagnosed with gastric carcinoma. The architecture of epithelial cells, thereby functioning as a patient’s father was diagnosed with gastric cancer at tumor suppression protein. Mutation in the gene results age 48 and died of the disease at the age of 49 years. A in decreased gene expression and loss of function of father’s brother was diagnosed with gastric cancer at age E-cadherin. This leads to abnormal morphogenesis and 35 ACTA CHIRURGICA LATVIENSIS • 2014 (14/1) architecture of epithelial tissue, loss of cellular polarity In conclusion, HDGC is a rare inherited cancer, with and contact inhibition, unregulated growth, and one-third to one- half of cases due to a mutation in the invasion of adjacent tissue (5,8). CDH1 gene. Carries of the mutation have approximate Between 25% and 50% of families that fit the 80% lifetime risk of developing HDGC. These cases International Gastric Cancer Linkage Consortium highlights the importance of recognition of the HDGC (IGCLC) criteria for HDGC will have autosomal syndrome and of testing for CDH1 germline mutations in dominant inherited germline CDH1 mutations and about other family members and probands’ offsprings. 39% of HDGC patients carry a CDH1 gene mutation. The penetrance is approximately 80%, so the lifetime chance Conflict of interest: None of an individual with a CDH1 mutation developing gastric cancer is high, and the risk increases with age REFERENCES (4,8). Diffuse gastric cancer is poorly-differentiated due 1. Bevan S, Houlston RS. Genetic predisposition of to defective intracellular adhesion molecules caused by gastric cancer // Q J Med 1999;92:5-10 mutations in E-cadherin that are common in this type 2. Blair V, Martin I, Shaw D, Winship I, Kerr D, of gastric cancer. These defective intracellular adhesion Arnold J, Harawira P, McLeod M, Parry S, Charlton molecules allow individual tumor cells to grow A, Findlay M, Cox B, Humar B, More H, Guilford and invade neighboring structures without distinct P. Hereditary diffuse gastric cancer: diagnosis formations. Early detection and diagnosis of HDGC are and management // Clin Gastroenterol Hepatol difficult because it is mostly located submucosally, and 2006;4:262-275 distributed as discrete foci along the entire length of 3. Caldas C, Carneiro F, Lynch HT, Yokota J, Wiesner the stomach. Currently, there are no reliable screening GL, Powell SM, Lewis FR, Huntsman DG, Pharoah methods for early detection. Prognosis is generally poor, PD, Jankowski JA, MacLeod P, Vogelsang H, Keller because this type of cancer is often found at a later stage, G, Park KG, Richards FM, Maher ER, Gayther SA, is more aggressive, and more difficult to treat (1). Oliveira C, Grehan N, Wight D, Seruca R, Roviello Due to the high risk of individuals with a CDH1 gene F, Ponder BA, Jackson CE. Familial gastric cancer: mutation developing HDGC, the difficulty in early overview and guidelines for management // J Med detection, and the relatively early age of cancer Genet 1999;36:873-880 onset, genetic testing availability can greatly impact a 4. Fitzgerald RC, Hardwick R, Huntsman D, Carneiro patient’s family members. Recommendations regarding F, Guilford P, Blair V, Chung DC, Norton J, Ragunath mutational analysis screening were made in 1999 by the K, Van Krieken JH, Dwerryhouse S, Caldas C; IGCLC and are for those individuals with a minimum of International Gastric Cancer Linkage Consortium. two cases of diffuse gastric cancer in first and/or second Hereditary diffuse gastric cancer: updated consensus degree relatives, with one diagnosis before age 50, or guidelines for clinical management and directions three or more confirmed cases with onset at any age (3). for future research // J Med Genet 2010;47:436- These guidelines were updated to include individuals with diffuse gastric cancer diagnosed before age 40 and 5. Graziano F, Humar B, Guilford P. The role of the individuals or family members diagnosed with HDGC E-cadherin gene (CDH1) in diffuse gastric cancer and LBC or signet ring colon carcinoma before age 50 susceptibility: from the laboratory to clinical (4). The genetic testing is typically accomplished by practice // Ann Oncol 2003; 14:1705-1713 denaturing high-performance liquid chromatography 6. Guilford P, Hopkins J, Harraway J, McLeod M, and automated DNA sequencing. It should be followed McLeod N, Harawira Pet al. E-cadherin germline by genetic counseling to discuss the results, any risks mutations in familial gastric cancer // Nature based on the results, and options for cancer surveillance. 1998;392:402-405 It may be distressing for family members who test 7. Lynch HT, Grady W, Suriano G, Huntsman D. positive for a CDH1 gene mutation, but they should be Gastric cancer: new genetic developments // J Surg encouraged to share their results with family members, Oncol. 2005;90:114-133 since genetic testing is available, and there are also 8. Oliveira C, Seruca R, Carneiro F. Genetics, pathology IGCLC guidelines for the management of unaffected and clinics of familial gastric cancer // Int J Surg individuals. These include endoscopic examinations Pathol 2006;14:21-33 with screening biopsies every six months starting at age 20 (3). Annual screening (mammogram and breast magnetic resonance imaging) for LBC beginning at age 35 is advised for female CDH1 mutation carriers (2). Our reported cases had family histories with multiple family members diagnosed with gastric cancer. This shows the importance of informing family members about positive mutation results, since a thorough, informative family history can potentially lead to faster testing, diagnosis, and treatment. 36 ACTA CHIRURGICA LATVIENSIS • 2014 (14/1) Ki 73 d 76 St 56 St 51 CRC82 Oe St 48 St 58 d56 d 53 d 82 d49 d 61 St 51 St 44 Fig. 1. Patients 1 Fig. 2. Patients 2 Pedigree of families with germline CDH1mutation. Squares indicate males; circles indicate females. Solid symbols indicate the cancer patient. Symbols with a slash indicate deceased individuals. An arrow points to the proband. Fig. 3. CDH1 gene mutation - 3’UTR+54 C>T Address: Jelena Pogodina Pauls Stradins Clinical University Hospital, Pilsonu street 13, LV-1002, Riga, Latvia E-mail: raisone@inbox.lv http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Chirurgica Latviensis de Gruyter

CDH1 Mutation in Two Patients with Hereditary Gastric Cancer

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10.2478/chilat-2014-0107
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10.2478/chilat-2014-0107 ACTA CHIRURGICA LATVIENSIS • 2014 (14/1) CASE REPORT CDH1 Mutation in Two Patients with Hereditary Gastric Cancer , , , , Jelena Pogodina* **, Roberts Ribenieks*, Dace Berzina* **, Genadijs Trofimovics* **, Edvins Miklasevics* ** *Pauls Stradins Clinical University Hospital, Riga, Latvia **Institute of Oncology, Riga Stradins University, Latvia SUMMARY CDH1 is currently the only gene in which mutations are known to cause hereditary diffuse gastric cancer (HDGC). Hereditary diffuse gastric cancer is defined as a syndrome of inherited predisposition to cancer with autosomal dominant inheritance pattern. Specific criteria are used to identify patients with suspected HDGC and who should be investigated for CDH1 germline mutations. Accurate screening is mandatory for unaffected carriers ofCDH1 mutations and selected high-risk individuals could be considered for prophylactic gastrectomy. Key words: gastric cancer, hereditary diffuse gastric cancer, CDH1 AIM OF THE DEMONSTRATION 58 and died three years later. The paternal grandmother We report two male patients with a history of familial was diagnosed with kidney cancer at age 73 and died gastric cancer and positive CDH1 gene mutation. three years later ( Fig. 2). Endoscopy revealed tumor, which infiltrated the gastric wall with penetrating the TWO CASE REPORTS serosa. Biopsies confirmed adenocarcinoma and a total Both patients were admitted to our hospital with gastrectomy with Braun esophagojejunostomy was diagnosis of gastric adenocarcinoma and underwent perfomed. Intraoperative finding revealed a tumor total gastrectomy. Their family history was significant extending along the lesser curvatura of the stomach for gastric cancer and patients fulfilled the hereditary from cardia to the pyloric region with the tumor diffuse gastric cancer criteria. invasion extending out of the stomach wall and adjacent Patient 1 on presentation was a 54-year-old male with a to the great omentum. Histopathological examination family history of gastric cancer. The patient’s father was revealed moderately differentiated adenocarcinoma, 8 diagnosed with gastric cancer and died of the disease at lymph nodes metastases and great omentum metastases, the age of 56 years. The father’s brother was diagnosed witch was classified as pT4AN3AM1G2Ro, stage IV. The with gastric cancer at age 51 and died two years later. The patient received palliative chemotherapy (Epirubicin 75 mother’s brother was diagnosed and died of oesofageal mg; Cisplatin 90 mg; Tegafur 400 mg twice a day during cancer and mother’s sister was diagnosed and died of two week.) colorectal cancer at 82 years ( Fig. 1). DNA sequencing was performed in both patients and The patient had epigastric pain, fatigue and weakness results showed CDH1 gene mutation 3’UTR+54 C>T for approximately three month. Endoscopy revealed (Fig.3). tumor, located in the gastric cardia. Biopsies confirmed adenocarcinoma and a total gastrectomy with Braun DISCUSSION esophagojejunostomy was perfomed. The postoperative The first description of hereditary diffuse gastric cancer period was uneventful and he was discharged on the was in three Maori families in New Zealand and the first 7th day. Histopathological examination revealed poorly evidence supporting the role of CDH1 as a major gastric differentiated adenocarcinoma and 9 lymph nodes cancer susceptibility gene came from genetic linkage metastases, which was classified as pT3N3AM0G3Ro, studies in these Maori families (6). stage IIIB. The patient received 45 Grays of radiotherapy Hereditary diffuse gastric cancer (HDGC) is an autosomal and 2 courses of adjuvant chemotherapy according to dominant genetic predisposition syndrome caused ECF scheme (5- fluorouracil 1000 mg, Farmorubicin by germine mutation in the CDH1 gene (3,7). HDGC 90 mg, Cisplatin 100mg). Eleven month after total account for 1-3% of all gastric cancer (7,8). gastrectomy computed tomography revealed liver The CDH1 gene is located on chromosome 16 and metastasis. encodes E-cadherin. E-cadherin is a calcium-dependent Patient 2 a 44-year-old man presented with abdominal cell-cell adhesion protein that plays a role in the pain for two month. The patient’s history included two maintenance of cell differentiation and the normal family members diagnosed with gastric carcinoma. The architecture of epithelial cells, thereby functioning as a patient’s father was diagnosed with gastric cancer at tumor suppression protein. Mutation in the gene results age 48 and died of the disease at the age of 49 years. A in decreased gene expression and loss of function of father’s brother was diagnosed with gastric cancer at age E-cadherin. This leads to abnormal morphogenesis and 35 ACTA CHIRURGICA LATVIENSIS • 2014 (14/1) architecture of epithelial tissue, loss of cellular polarity In conclusion, HDGC is a rare inherited cancer, with and contact inhibition, unregulated growth, and one-third to one- half of cases due to a mutation in the invasion of adjacent tissue (5,8). CDH1 gene. Carries of the mutation have approximate Between 25% and 50% of families that fit the 80% lifetime risk of developing HDGC. These cases International Gastric Cancer Linkage Consortium highlights the importance of recognition of the HDGC (IGCLC) criteria for HDGC will have autosomal syndrome and of testing for CDH1 germline mutations in dominant inherited germline CDH1 mutations and about other family members and probands’ offsprings. 39% of HDGC patients carry a CDH1 gene mutation. The penetrance is approximately 80%, so the lifetime chance Conflict of interest: None of an individual with a CDH1 mutation developing gastric cancer is high, and the risk increases with age REFERENCES (4,8). Diffuse gastric cancer is poorly-differentiated due 1. Bevan S, Houlston RS. Genetic predisposition of to defective intracellular adhesion molecules caused by gastric cancer // Q J Med 1999;92:5-10 mutations in E-cadherin that are common in this type 2. Blair V, Martin I, Shaw D, Winship I, Kerr D, of gastric cancer. These defective intracellular adhesion Arnold J, Harawira P, McLeod M, Parry S, Charlton molecules allow individual tumor cells to grow A, Findlay M, Cox B, Humar B, More H, Guilford and invade neighboring structures without distinct P. Hereditary diffuse gastric cancer: diagnosis formations. Early detection and diagnosis of HDGC are and management // Clin Gastroenterol Hepatol difficult because it is mostly located submucosally, and 2006;4:262-275 distributed as discrete foci along the entire length of 3. Caldas C, Carneiro F, Lynch HT, Yokota J, Wiesner the stomach. Currently, there are no reliable screening GL, Powell SM, Lewis FR, Huntsman DG, Pharoah methods for early detection. Prognosis is generally poor, PD, Jankowski JA, MacLeod P, Vogelsang H, Keller because this type of cancer is often found at a later stage, G, Park KG, Richards FM, Maher ER, Gayther SA, is more aggressive, and more difficult to treat (1). Oliveira C, Grehan N, Wight D, Seruca R, Roviello Due to the high risk of individuals with a CDH1 gene F, Ponder BA, Jackson CE. Familial gastric cancer: mutation developing HDGC, the difficulty in early overview and guidelines for management // J Med detection, and the relatively early age of cancer Genet 1999;36:873-880 onset, genetic testing availability can greatly impact a 4. Fitzgerald RC, Hardwick R, Huntsman D, Carneiro patient’s family members. Recommendations regarding F, Guilford P, Blair V, Chung DC, Norton J, Ragunath mutational analysis screening were made in 1999 by the K, Van Krieken JH, Dwerryhouse S, Caldas C; IGCLC and are for those individuals with a minimum of International Gastric Cancer Linkage Consortium. two cases of diffuse gastric cancer in first and/or second Hereditary diffuse gastric cancer: updated consensus degree relatives, with one diagnosis before age 50, or guidelines for clinical management and directions three or more confirmed cases with onset at any age (3). for future research // J Med Genet 2010;47:436- These guidelines were updated to include individuals with diffuse gastric cancer diagnosed before age 40 and 5. Graziano F, Humar B, Guilford P. The role of the individuals or family members diagnosed with HDGC E-cadherin gene (CDH1) in diffuse gastric cancer and LBC or signet ring colon carcinoma before age 50 susceptibility: from the laboratory to clinical (4). The genetic testing is typically accomplished by practice // Ann Oncol 2003; 14:1705-1713 denaturing high-performance liquid chromatography 6. Guilford P, Hopkins J, Harraway J, McLeod M, and automated DNA sequencing. It should be followed McLeod N, Harawira Pet al. E-cadherin germline by genetic counseling to discuss the results, any risks mutations in familial gastric cancer // Nature based on the results, and options for cancer surveillance. 1998;392:402-405 It may be distressing for family members who test 7. Lynch HT, Grady W, Suriano G, Huntsman D. positive for a CDH1 gene mutation, but they should be Gastric cancer: new genetic developments // J Surg encouraged to share their results with family members, Oncol. 2005;90:114-133 since genetic testing is available, and there are also 8. Oliveira C, Seruca R, Carneiro F. Genetics, pathology IGCLC guidelines for the management of unaffected and clinics of familial gastric cancer // Int J Surg individuals. These include endoscopic examinations Pathol 2006;14:21-33 with screening biopsies every six months starting at age 20 (3). Annual screening (mammogram and breast magnetic resonance imaging) for LBC beginning at age 35 is advised for female CDH1 mutation carriers (2). Our reported cases had family histories with multiple family members diagnosed with gastric cancer. This shows the importance of informing family members about positive mutation results, since a thorough, informative family history can potentially lead to faster testing, diagnosis, and treatment. 36 ACTA CHIRURGICA LATVIENSIS • 2014 (14/1) Ki 73 d 76 St 56 St 51 CRC82 Oe St 48 St 58 d56 d 53 d 82 d49 d 61 St 51 St 44 Fig. 1. Patients 1 Fig. 2. Patients 2 Pedigree of families with germline CDH1mutation. Squares indicate males; circles indicate females. Solid symbols indicate the cancer patient. Symbols with a slash indicate deceased individuals. An arrow points to the proband. Fig. 3. CDH1 gene mutation - 3’UTR+54 C>T Address: Jelena Pogodina Pauls Stradins Clinical University Hospital, Pilsonu street 13, LV-1002, Riga, Latvia E-mail: raisone@inbox.lv

Journal

Acta Chirurgica Latviensis – de Gruyter

Published: Nov 24, 2014

Keywords: Medicine; Clinical Medicine; Surgery; Surgery, other

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