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Hereditary diffuse gastric cancer: More answers or more questions?
830
SELECTEDSUMMARIES
therapy. Mosse et al. tested the hypothesis that electrical stimulation could propel an endoscope by stimulating muscular contraction. Prototype acrylic ovoid-shaped devices were constructed with 2 stainless steel electrodes mounted on the tapered section. Electro stimulation caused the ovoid to advance rapidly (6 mm/s) up and down the esophagus by inducing circular esophageal muscle contraction. When stimulated at 15 Hz with 30-ms pulses, the threshold for movement in the small intestine was 12 mAr at 20 mA, the device moved reliably in either direction in the small intestine at speeds of up to 4.5 mm/s and negotiated tight curves (Gastrointest Endosc 2001;54:7983). Does this phenomenon have any potential for clinical application in the management of motility disorders of the gut, like a prokinetic, an electric capsule? To jump start the lazy gut! In summary, capsule endoscopy is the visionary end product of the curious minds to fulfill the dream of successfully completing the fantastic voyage through the gut. They made it! Application of advances in robotic technology to capsule endoscopy may provide us an opportunity to understand the pathophysiology of the small bowel disease by allowing us to look, feel, and sense the gut from within and also the ability to gun down the evil. "I have no special talents, I am passionately curious'--Albert Einstein GOTTUMUKKALA S. RAJU, M.D., D.M., MRCP (UK) TONY YUSUF, M.D.
HEREDITARY DIFFUSE GASTRIC CANCER: MORE ANSWERS OR MORE QUESTIONS? Huntsman DG, Carneiro F, Lewis FR, MacLeod PM, Hayashi A, Monaghan KG, Maung R, Seruca R, Jackson CE, Caldas C (Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada; Sections of Medical Genetics, Surgery, and Pathology, Victoria General Hospital, Victoria, British Columbia, Canada; Instituto de Patalogia e Imunologia Molecular and the Faculty of Medicine, University of Porto, Porto, Portugal; Departments of Surgery and Medical Genetics, Henry Ford Hospital, Detroit, Michigan; Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, England). Early gastric cancer in young, asymptomatic carriers of germ-line e-cadherin mutations. N Engl J Med 2 0 0 1 ; 3 4 4 : 1 9 0 4 - 1 9 0 9 .
Chun YS, Lindor NM, Smyrk TC, Petersen BT, Burgart LJ, Guilford PJ, Donohue JH (Departments of Surgery, Medical Genetics, Pathology, and Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Biochemistry Department, Cancer Genetics Laboratory, University of Otago, Dunedin, New Zealand). Germline E-cadherin gene mutations: is prophylactic total gastrectomy indicated? Cancer 2001 ;92:181-187. Although most gastric adenocarcinomas occur sporadically without any evidence of an inherited cancer predisposition, a small fraction of gastric cancers ( 1 % - 3 %) arise as the result of clearly identified inherited gastric cancer predisposition syndromes. These syndromes include 2 recently well-described inherited conditions, hereditary diffuse gastric cancer syndrome and hereditary nonpolyposis colon cancer syndrome, as well as Peutz-Jeghers syndrome, Cowden's syndrome, and
GASTROENTEROLOGYVol. 122, No. 3
some kindreds affected with Li-Fraumeni syndrome and familial adenomatous polyposis (Molecular Genetics of Cancer, 2nd edition 2001; 1 : 115-136). Hereditary diffuse gastric cancer (HDGC) is an autosomal dominantly inherited gastric cancer susceptibility syndrome caused by germline mutations in CDH1, the gene encoding E-cadherin. Despite the discovery of the underlying genetic cause of this syndrome, the optimal management of H D G C family members has been controversial, primarily because of the unproven value of surveillance regimes or prophylactic gastrectomy to affect the clinical outcomes of m u t a t i o n carriers. In 2 nearly simultaneously published studies, H u n t s m a n et al. and Chun et al. have now shown that prophylactically resected stomachs from CDH1 m u t a t i o n carriers that had clinically undetectable disease carry multifocal intramucosal signet ring cancer. These investigators studied 3 different families with highly penetrant phenotypes and found intramucosal gastric cancer in 10 of 10 prophylactic gastrectomy specimens. Importantly, surveillance using upper endoscopy and mucosal biopsy, chromoendoscopy, and/or endoscopic ultrasonography failed to identify intramucosal gastric cancer found at the time of gastrectomy in 7 of 7 cases. The remarkable and independent findings in both studies are that all the operations were performed as prophylactic interventions, but in each case, they were presumably therapeutic and curative. Although limited by small numbers and limited follow-up, these 2 studies have reinvigorated the discussion of the role of prophylactic gastrectomy in the management of H D G C . Comment. In 1998, Guilford et al. discovered germline mutations
in CDH1 in 3 Maori families predisposed to diffuse gastric cancer (Nature 1998;392:402-405). Since that initial discovery, several gastric cancer families from a variety of ethnic backgrounds, including Caucasian, Japanese, Korean, and African American, have been found to also carry CDHI mutations, which has led to the recognition of a distinct family gastric cancer syndrome designated HDGC (Nature 1998;392:402-405; Hum Mutat 1999;14:249-255). Preliminary analysis of these families has shown that HDGC seems to have 70% penetrance and that family members may also be at increased risk for breast and colon cancer (Hum Mutat 1999;14:249-255, Hum Mol Genet 1999;8:607-610). To appreciate the significance of the findings of Huntsman et al. and Chun et al., it is helpful to understand the role of E-cadherin in gastric epithelial cell biology and gastric carcinogenesis. E-cadherin is a 120-kilodalton calcium-dependent adhesion molecule that is a member of the cadherin family of proteins, a class of Cell surface proteins that establish intercellular connections through homophilic interactions and maintain the organization of epithelial tissues. Ecadherin also regulates the normal cellular localization and function of the catenins (c~, [3, and ~/). Consistent with the concept that loss of normal cell:cell contact and dysregulation of catenins promotes cancer, CDH1 is frequently mutated or inactivated in a variety of cancers including breast, thyroid, prostate, colon, and gastric cancer (Biochim Biophys Acta 1994;1198:11-26). In fact, CDHI was initially implicated in gastric carcinogenesis in 1994 when Becker et al. identified somatic CDH1 mutations in specimens of diffuse gastric cancer (Cancer Res 1994;54:3845-3852). Interestingly and relevant to HDGC, somatic mutations in CDH1 have been identified in 40%83% of sporadic diffuse-type gastric cancers but in no sporadic intestinal-type gastric cancers (J Natl Cancer Inst 1995;87:1082-
March 2 0 0 2
1084, Lab Invest 1999;79:459-465, J p n J Cancer Res 1996;87:843848, Proc Natl Acad Sci U S A 1994;91:1858-1862, Jpn J Cancer Res 1996;87:1153-1159). Because CDH1 is a tumor suppressor gene, inactivation of this protein is believed to promote tumor formation. Although biallelic inactivation can occur through somatic mutations or allelic imbalance events (loss of heterozygosity), aberrant CpG dinucleotide methylation of the CDH1 promoter has also been shown to inactivate E-cadherin in both sporadic and inherited diffuse gastric cancer (Nat Genet 2000;26:16-17, Oncogene 2001;20:1525-1528). However, despite our understanding of the molecular biology of E-cadherin and our recognition of CDH1 germline mutations as the underlying cause of HDGC, the optimal clinical management of HDGC family members is still unclear. The studies by Huntsman et al. and Chun et al. have shed light on this subject and have provided support for the role of prophylactic gastrectomy in the management of at least some of these families. Similar to the debate surrounding the role of prophylactic organ removal for other hereditary cancer predisposition syndromes such as hereditary breast ovary cancer syndrome, which is caused by BRCA1 and BRCA2 germline mutations, the role of prophylactic gastrectomy in the management of HDGC families has been controversial (Cancer Genet Cytogenet 2000;122: 1-6, J Med Genet 1999;36:873-880). As in HDGC, prophylactically removed breast and ovary specimens from BRCA mutation carriers have been shown to contain occult foci of malignant cells, even in the setting of negative mammographic and pelvic ultrasound examinations (J Clin Oncol 2000;18:2728-2732, Arch Pathol Lab Med 2000;124:378-381). Furthermore, prophylactic bilateral mastectomy reduces the risk of breast cancer by 90% in at-risk individuals but is also associated with negative effects on self-esteem and sexual relationships (Nat Med 2000;6:1024-1028). The effect of prophylactic gastrectomy on reducing the risk of gastric cancer in CDH1 mutation carriers is unknown at this time, but the results from Huntsman et al. and Chun et al. suggest it may provide a significant reduction in risk. Nonetheless, the morbidity of gastrectomy, which includes weight loss, lactose intolerance (50% of patients), fat malabsorption and steatorrhea (66%-100% of patients), dumping syndrome (20%-30% of patients), bacterial overgrowth, postprandial fullness, and iron and B12 vitamin deficiencies, presents a significant disincentive to embracing this as a universal management strategy (Acta Chir Scand 1988;154:37-41, Surgery 1990;108:488-494, Ann Surg 1975;182:415-429). Furthermore, the families who participated in the studies by Huntsman et al. and Chun et al. all had highly penetrant cancer-susceptibility phenotypes, which shifted the balance in favor of prophylactic gastrectomy. Indeed, because HDGC is believed to be only 70% penetrant in most families, a universal policy of prophylactic gastrectomy would result in 30% of HDGC mutation carriers receiving a nontherapeutic gastrectomy (Hum Murat 1999;14:249-255). Yet, despite these concerns, the low success rates of curing even early stage diffuse gastric cancer combined with the unproven value of any current surveillance techniques to identify preclinical gastric cancers is a strong argument that prophylactic gastrectomy may be a viable option for some HDGC family members. In the future, identification of families that could potentially benefit from prophylactic gastrectomy will require a careful determination of the family history in addition to CDH1 mutation analysis of the at-risk individuals. There are several issues raised by these studies that will only be resolved with more extended follow-up. Although it is easily accepted that prophylactic gastrectomies should prolong the life expectancy of individuals undergoing this procedure, that outcome is, at present, not proven. In addition, studies have identified breast and colon cancer in mutation carriers in at least some HDGC families, and it is
SELECTED SUMMARIES
831
possible that individuals who undergo prophylactic gastrectomy may still be at increased risk for cancers at distant sites (Hum Mutat 1999;14:249-255, Hum Mol Genet 1999;8:607-610). Another currently unresolved issue surrounding the use of prophylactic gastrectomy in CDHI mutation carriers is the quality of life after gastrectomy, which may improve because of the reduction of anxiety about developing stomach cancer or worsen because of the side effects associated with the procedure. An additional major issue is whether surveillance modalities or preventive strategies can be identified that will obviate the need for prophylactic gastrectomy in the future. Possible strategies that may serve such a purpose include endoscopic surveillance with optical coherent tomography or molecular marker analysis of body fluids, such as gastric lavage fluid. In regard to prevention, it has been shown in a small study of 2 HDGC families that half of the tumors demonstrated methylation of the CDH1 promoter as the "second hit," and it is tempting to consider the potential value of prophylactic treatment of these mutation carriers with demethylaring agents, such as 5-azadeoxycytidine (Nat Genet 2000;26:16-17). Although outstanding issues remain regarding the management of CDH1 mutation carriers in HDGC families, several recommendations can be made at this time. First, familial gastric cancer patients should be referred to a health care provider who can provide genetic counseling and testing to best identify individuals who are at enhanced risk for gastric cancer in these families. Second, the ability of surveillance regimens including upper endoscopy with biopsy, endoscopic ultrasonography, and/or chromoendoscopy is not proven and possibly of no value in identifying early and potentially curable gastric cancer. Third and final, prophylactic gastrectomy is a viable management strategy but should be reserved for those individuals who have undergone extensive genetic assessment and preoperative counseling. The rapidly unfolding story about HDGC that has transpired in the last 2 years has shown that the power of genetics can alter our understanding and management of this disease, however, additional questions have now been raised that need to be answered in turn. WILLIAM M. GRADY, M.D. RICHARD M. PEEK, JR., M.D. Reply. Germline CDH1 mutations occur only in families with diffuse gastric cancer and not in families where index cases have the more common intestinal type gastric cancer (Cancer Res 1998;58:40864089). The importance of including careful histopathologic review when ascertaining families for genetic testing (J Med Genet 1999; 36:873-880) is highlighted by our accumulated experience. A total of 57 families have been analyzed to date: CDH1 mutations were found in 7 of 21 (33%) HDGC kindred and in none of the others. Recent publications may be of assistance in the management of these families. First, through the International Gastric Cancer Linkage Consortium (IGCLC), data from several pedigrees with HDGC caused by germline CDH1 mutation has been combined to estimate the penetrance of gastric and breast cancer in gene carriers (Gastroenterology 2001;121;1348-1353). The lifetime accumulated risk for women with a germline truncating CDH1 mutation was calculated to be 83% (95% confidence interval [CI], 58%-100%) and 67% for men (95% CI, 39%-99%). Women have a lifetime risk of breast cancer of 39% (95% CI, 12%-84%). Although all 10 prophylactic gastrectomy specimens reported had microscopic foci of diffuse gastric cancer, and no proven screening technology exists, a decision to undergo prophylactic surgery does not need to be rushed because the biological behavior of these early lesions is not known (N Engl J Med 2001;344:1904-1909, Cancer 2001; 92:181-187). This is particularly true for female CDH1 mutation
SELECTEDSUMMARIES
therapy. Mosse et al. tested the hypothesis that electrical stimulation could propel an endoscope by stimulating muscular contraction. Prototype acrylic ovoid-shaped devices were constructed with 2 stainless steel electrodes mounted on the tapered section. Electro stimulation caused the ovoid to advance rapidly (6 mm/s) up and down the esophagus by inducing circular esophageal muscle contraction. When stimulated at 15 Hz with 30-ms pulses, the threshold for movement in the small intestine was 12 mAr at 20 mA, the device moved reliably in either direction in the small intestine at speeds of up to 4.5 mm/s and negotiated tight curves (Gastrointest Endosc 2001;54:7983). Does this phenomenon have any potential for clinical application in the management of motility disorders of the gut, like a prokinetic, an electric capsule? To jump start the lazy gut! In summary, capsule endoscopy is the visionary end product of the curious minds to fulfill the dream of successfully completing the fantastic voyage through the gut. They made it! Application of advances in robotic technology to capsule endoscopy may provide us an opportunity to understand the pathophysiology of the small bowel disease by allowing us to look, feel, and sense the gut from within and also the ability to gun down the evil. "I have no special talents, I am passionately curious'--Albert Einstein GOTTUMUKKALA S. RAJU, M.D., D.M., MRCP (UK) TONY YUSUF, M.D.
HEREDITARY DIFFUSE GASTRIC CANCER: MORE ANSWERS OR MORE QUESTIONS? Huntsman DG, Carneiro F, Lewis FR, MacLeod PM, Hayashi A, Monaghan KG, Maung R, Seruca R, Jackson CE, Caldas C (Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada; Sections of Medical Genetics, Surgery, and Pathology, Victoria General Hospital, Victoria, British Columbia, Canada; Instituto de Patalogia e Imunologia Molecular and the Faculty of Medicine, University of Porto, Porto, Portugal; Departments of Surgery and Medical Genetics, Henry Ford Hospital, Detroit, Michigan; Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, England). Early gastric cancer in young, asymptomatic carriers of germ-line e-cadherin mutations. N Engl J Med 2 0 0 1 ; 3 4 4 : 1 9 0 4 - 1 9 0 9 .
Chun YS, Lindor NM, Smyrk TC, Petersen BT, Burgart LJ, Guilford PJ, Donohue JH (Departments of Surgery, Medical Genetics, Pathology, and Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Biochemistry Department, Cancer Genetics Laboratory, University of Otago, Dunedin, New Zealand). Germline E-cadherin gene mutations: is prophylactic total gastrectomy indicated? Cancer 2001 ;92:181-187. Although most gastric adenocarcinomas occur sporadically without any evidence of an inherited cancer predisposition, a small fraction of gastric cancers ( 1 % - 3 %) arise as the result of clearly identified inherited gastric cancer predisposition syndromes. These syndromes include 2 recently well-described inherited conditions, hereditary diffuse gastric cancer syndrome and hereditary nonpolyposis colon cancer syndrome, as well as Peutz-Jeghers syndrome, Cowden's syndrome, and
GASTROENTEROLOGYVol. 122, No. 3
some kindreds affected with Li-Fraumeni syndrome and familial adenomatous polyposis (Molecular Genetics of Cancer, 2nd edition 2001; 1 : 115-136). Hereditary diffuse gastric cancer (HDGC) is an autosomal dominantly inherited gastric cancer susceptibility syndrome caused by germline mutations in CDH1, the gene encoding E-cadherin. Despite the discovery of the underlying genetic cause of this syndrome, the optimal management of H D G C family members has been controversial, primarily because of the unproven value of surveillance regimes or prophylactic gastrectomy to affect the clinical outcomes of m u t a t i o n carriers. In 2 nearly simultaneously published studies, H u n t s m a n et al. and Chun et al. have now shown that prophylactically resected stomachs from CDH1 m u t a t i o n carriers that had clinically undetectable disease carry multifocal intramucosal signet ring cancer. These investigators studied 3 different families with highly penetrant phenotypes and found intramucosal gastric cancer in 10 of 10 prophylactic gastrectomy specimens. Importantly, surveillance using upper endoscopy and mucosal biopsy, chromoendoscopy, and/or endoscopic ultrasonography failed to identify intramucosal gastric cancer found at the time of gastrectomy in 7 of 7 cases. The remarkable and independent findings in both studies are that all the operations were performed as prophylactic interventions, but in each case, they were presumably therapeutic and curative. Although limited by small numbers and limited follow-up, these 2 studies have reinvigorated the discussion of the role of prophylactic gastrectomy in the management of H D G C . Comment. In 1998, Guilford et al. discovered germline mutations
in CDH1 in 3 Maori families predisposed to diffuse gastric cancer (Nature 1998;392:402-405). Since that initial discovery, several gastric cancer families from a variety of ethnic backgrounds, including Caucasian, Japanese, Korean, and African American, have been found to also carry CDHI mutations, which has led to the recognition of a distinct family gastric cancer syndrome designated HDGC (Nature 1998;392:402-405; Hum Mutat 1999;14:249-255). Preliminary analysis of these families has shown that HDGC seems to have 70% penetrance and that family members may also be at increased risk for breast and colon cancer (Hum Mutat 1999;14:249-255, Hum Mol Genet 1999;8:607-610). To appreciate the significance of the findings of Huntsman et al. and Chun et al., it is helpful to understand the role of E-cadherin in gastric epithelial cell biology and gastric carcinogenesis. E-cadherin is a 120-kilodalton calcium-dependent adhesion molecule that is a member of the cadherin family of proteins, a class of Cell surface proteins that establish intercellular connections through homophilic interactions and maintain the organization of epithelial tissues. Ecadherin also regulates the normal cellular localization and function of the catenins (c~, [3, and ~/). Consistent with the concept that loss of normal cell:cell contact and dysregulation of catenins promotes cancer, CDH1 is frequently mutated or inactivated in a variety of cancers including breast, thyroid, prostate, colon, and gastric cancer (Biochim Biophys Acta 1994;1198:11-26). In fact, CDHI was initially implicated in gastric carcinogenesis in 1994 when Becker et al. identified somatic CDH1 mutations in specimens of diffuse gastric cancer (Cancer Res 1994;54:3845-3852). Interestingly and relevant to HDGC, somatic mutations in CDH1 have been identified in 40%83% of sporadic diffuse-type gastric cancers but in no sporadic intestinal-type gastric cancers (J Natl Cancer Inst 1995;87:1082-
March 2 0 0 2
1084, Lab Invest 1999;79:459-465, J p n J Cancer Res 1996;87:843848, Proc Natl Acad Sci U S A 1994;91:1858-1862, Jpn J Cancer Res 1996;87:1153-1159). Because CDH1 is a tumor suppressor gene, inactivation of this protein is believed to promote tumor formation. Although biallelic inactivation can occur through somatic mutations or allelic imbalance events (loss of heterozygosity), aberrant CpG dinucleotide methylation of the CDH1 promoter has also been shown to inactivate E-cadherin in both sporadic and inherited diffuse gastric cancer (Nat Genet 2000;26:16-17, Oncogene 2001;20:1525-1528). However, despite our understanding of the molecular biology of E-cadherin and our recognition of CDH1 germline mutations as the underlying cause of HDGC, the optimal clinical management of HDGC family members is still unclear. The studies by Huntsman et al. and Chun et al. have shed light on this subject and have provided support for the role of prophylactic gastrectomy in the management of at least some of these families. Similar to the debate surrounding the role of prophylactic organ removal for other hereditary cancer predisposition syndromes such as hereditary breast ovary cancer syndrome, which is caused by BRCA1 and BRCA2 germline mutations, the role of prophylactic gastrectomy in the management of HDGC families has been controversial (Cancer Genet Cytogenet 2000;122: 1-6, J Med Genet 1999;36:873-880). As in HDGC, prophylactically removed breast and ovary specimens from BRCA mutation carriers have been shown to contain occult foci of malignant cells, even in the setting of negative mammographic and pelvic ultrasound examinations (J Clin Oncol 2000;18:2728-2732, Arch Pathol Lab Med 2000;124:378-381). Furthermore, prophylactic bilateral mastectomy reduces the risk of breast cancer by 90% in at-risk individuals but is also associated with negative effects on self-esteem and sexual relationships (Nat Med 2000;6:1024-1028). The effect of prophylactic gastrectomy on reducing the risk of gastric cancer in CDH1 mutation carriers is unknown at this time, but the results from Huntsman et al. and Chun et al. suggest it may provide a significant reduction in risk. Nonetheless, the morbidity of gastrectomy, which includes weight loss, lactose intolerance (50% of patients), fat malabsorption and steatorrhea (66%-100% of patients), dumping syndrome (20%-30% of patients), bacterial overgrowth, postprandial fullness, and iron and B12 vitamin deficiencies, presents a significant disincentive to embracing this as a universal management strategy (Acta Chir Scand 1988;154:37-41, Surgery 1990;108:488-494, Ann Surg 1975;182:415-429). Furthermore, the families who participated in the studies by Huntsman et al. and Chun et al. all had highly penetrant cancer-susceptibility phenotypes, which shifted the balance in favor of prophylactic gastrectomy. Indeed, because HDGC is believed to be only 70% penetrant in most families, a universal policy of prophylactic gastrectomy would result in 30% of HDGC mutation carriers receiving a nontherapeutic gastrectomy (Hum Murat 1999;14:249-255). Yet, despite these concerns, the low success rates of curing even early stage diffuse gastric cancer combined with the unproven value of any current surveillance techniques to identify preclinical gastric cancers is a strong argument that prophylactic gastrectomy may be a viable option for some HDGC family members. In the future, identification of families that could potentially benefit from prophylactic gastrectomy will require a careful determination of the family history in addition to CDH1 mutation analysis of the at-risk individuals. There are several issues raised by these studies that will only be resolved with more extended follow-up. Although it is easily accepted that prophylactic gastrectomies should prolong the life expectancy of individuals undergoing this procedure, that outcome is, at present, not proven. In addition, studies have identified breast and colon cancer in mutation carriers in at least some HDGC families, and it is
SELECTED SUMMARIES
831
possible that individuals who undergo prophylactic gastrectomy may still be at increased risk for cancers at distant sites (Hum Mutat 1999;14:249-255, Hum Mol Genet 1999;8:607-610). Another currently unresolved issue surrounding the use of prophylactic gastrectomy in CDHI mutation carriers is the quality of life after gastrectomy, which may improve because of the reduction of anxiety about developing stomach cancer or worsen because of the side effects associated with the procedure. An additional major issue is whether surveillance modalities or preventive strategies can be identified that will obviate the need for prophylactic gastrectomy in the future. Possible strategies that may serve such a purpose include endoscopic surveillance with optical coherent tomography or molecular marker analysis of body fluids, such as gastric lavage fluid. In regard to prevention, it has been shown in a small study of 2 HDGC families that half of the tumors demonstrated methylation of the CDH1 promoter as the "second hit," and it is tempting to consider the potential value of prophylactic treatment of these mutation carriers with demethylaring agents, such as 5-azadeoxycytidine (Nat Genet 2000;26:16-17). Although outstanding issues remain regarding the management of CDH1 mutation carriers in HDGC families, several recommendations can be made at this time. First, familial gastric cancer patients should be referred to a health care provider who can provide genetic counseling and testing to best identify individuals who are at enhanced risk for gastric cancer in these families. Second, the ability of surveillance regimens including upper endoscopy with biopsy, endoscopic ultrasonography, and/or chromoendoscopy is not proven and possibly of no value in identifying early and potentially curable gastric cancer. Third and final, prophylactic gastrectomy is a viable management strategy but should be reserved for those individuals who have undergone extensive genetic assessment and preoperative counseling. The rapidly unfolding story about HDGC that has transpired in the last 2 years has shown that the power of genetics can alter our understanding and management of this disease, however, additional questions have now been raised that need to be answered in turn. WILLIAM M. GRADY, M.D. RICHARD M. PEEK, JR., M.D. Reply. Germline CDH1 mutations occur only in families with diffuse gastric cancer and not in families where index cases have the more common intestinal type gastric cancer (Cancer Res 1998;58:40864089). The importance of including careful histopathologic review when ascertaining families for genetic testing (J Med Genet 1999; 36:873-880) is highlighted by our accumulated experience. A total of 57 families have been analyzed to date: CDH1 mutations were found in 7 of 21 (33%) HDGC kindred and in none of the others. Recent publications may be of assistance in the management of these families. First, through the International Gastric Cancer Linkage Consortium (IGCLC), data from several pedigrees with HDGC caused by germline CDH1 mutation has been combined to estimate the penetrance of gastric and breast cancer in gene carriers (Gastroenterology 2001;121;1348-1353). The lifetime accumulated risk for women with a germline truncating CDH1 mutation was calculated to be 83% (95% confidence interval [CI], 58%-100%) and 67% for men (95% CI, 39%-99%). Women have a lifetime risk of breast cancer of 39% (95% CI, 12%-84%). Although all 10 prophylactic gastrectomy specimens reported had microscopic foci of diffuse gastric cancer, and no proven screening technology exists, a decision to undergo prophylactic surgery does not need to be rushed because the biological behavior of these early lesions is not known (N Engl J Med 2001;344:1904-1909, Cancer 2001; 92:181-187). This is particularly true for female CDH1 mutation