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A subset of patients with diffuse gastric cancer harbor deleterious cancer-causing germline mutations in the type 1 E-cadherin (epithelial) gene (CDH1), which predisposes to the autosomal dominantly inherited hereditary diffuse gastric cancer (HDGC) syndrome. These mutations are associated with a 70% life-time risk for diffuse gastric cancer (DGC) and an additional 40% risk for lobular breast cancer in women. Management options for unaffected mutation carriers include prophylactic total gastrectomy.
Four HDGC pedigrees from a cohort of 56 CDH1 mutation-positive families were subjected to further analysis. Cancer diagnoses, whenever possible, were verified with pathology reports and/or slides/tissue block review. Genetic counseling for family members covered the natural history of HDGC, the pros and cons of mutation testing, the lack of effective screening procedures available to CDH1 mutation-positive individuals, and the option for them of prophylactic total gastrectomy.
Within the 4 families, carrier testing for mutations in the CDH1 gene was carried out on 52 individuals, including 25 individuals who were positive for mutation. Prophylactic gastrectomies were performed on a total of 17 individuals from 3 of the families, including 11 first cousins from 1 of the families. Occult DGC was diagnosed in gastrectomy specimens from 13 of 17 individuals (76.5%). During follow-up questioning, each of the 11 cousins stated that the decision for the prophylactic procedure was the “right one” for them.
Gastric cancer is the second most common cause of cancer mortality worldwide.1 The 2 major categories are the intestinal type, which is associated more commonly with environmental perturbations, and diffuse gastric cancer (DGC), which is ascribed etiologically more often to host factor effects.2 The intestinal type has declined in incidence, whereas DGC has remained stable and even may be increasing.3 Hereditary diffuse gastric cancer (HDGC) is an autosomal dominantly inherited disorder caused by mutations of the type 1 E-cadherin (epithelial) gene CDH1 (epithelial cadherin; Online Mendelian Inheritance in Man no. 19,209). The decreased expression of this gene in DGCs appears to account for the pathologic differences between intestinal and diffuse variants of gastric cancer in a subset of families.4–6CDH1 germline mutations have been identified in approximately 40% to 50% of well defined HDGC families from low-incident populations.5, 7, 8 There is also an excess of lobular carcinoma of the breast in women from HDGC families with CDH1 mutations.6, 9, 10 The clinical advantage of identifying a CDH1 mutation carrier is its level of certainty of disease expression, limited only by its penetrance, which, in DGC, is estimated in the range of 70%.5, 11 Unfortunately, it is not possible to determine which CDH1 mutation carriers will develop DGC. Pathology findings indicate that the signet cell cancer phenotype is submucosal, which severely limits the ability of currently available screening procedures to detect early gastric cancer. Mutation carriers can be offered the option of prophylactic total gastrectomy for reducing cancer morbidity and mortality.7, 12 In this report, we discuss our experience with 4 extended HDGC families who are part of a cohort of 56 CDH1 mutation-positive families.
MATERIALS AND METHODS
This study was approved by the authors' institutional review boards. Informed consent was obtained from the individuals who were investigated. Detailed cancer family histories that included the assessment of cancer of all anatomic sites, with particular attention to pathology verification whenever possible, were ascertained at the respective centers. High-risk family members were identified, counseled, and, if appropriate, offered genetic testing for the cancer-predisposing CDH1 mutation. Genetic counseling was provided again at the time results were revealed.
The proband in Family 1 (Fig. 1) contacted us because she was concerned about her cancer family history after the death of her brother from DGC. She had been aware that her mother and 4 of her mother's siblings also had died from DGC. A working pedigree was initiated through the compilation of a genealogic history in concert with medical and pathology documentation. Once permission was granted, this search was extended to as many of the proband's relatives as possible. The family was dispersed geographically, with residences primarily in communities throughout the Midwest and far western United States.
Before his death, a blood sample had been obtained from the proband's affected brother; genetic testing for the CDH1 mutation was performed in the molecular genetic laboratories of 1 of the coauthors (D.G.H.),6, 7 and a CDH1 mutation was identified. Once knowledge that a mutation in CDH1 had been identified in a family member, those relatives at high risk were advised of the availability of genetic counseling and DNA testing. Seventeen relatives were tested, and the results were provided to them during genetic counseling sessions. The 11 relatives who tested positive were advised about the limitations of DGC screening and about the pros and cons of undergoing prophylactic total gastrectomy.
Eleven first cousins harbored the CDH1 mutation (C1003T in exon 7) and underwent prophylactic total gastrectomy. Six of these cousins underwent chromoendoscopy, endoscopic ultrasound, random biopsies, and positron emission-computed tomography (CT) scanning immediately before surgery. All screening tests were negative; however, 10 of the 11 gastrectomy specimens harbored occult carcinomas.13
Subsequently, the family held a reunion, and all 11 individuals who had undergone prophylactic total gastrectomy were in attendance. Three of the authors of this article (H.T.L., J.F.L., and D.G.H.) were invited to attend the reunion, at which time they had an opportunity to review with the attendees all of the ramifications of HDGC. After the reunion, a questionnaire was forwarded to the 11 individuals who underwent gastrectomy to evaluate their emotional and physical well being before and after surgery.
In the second family (Fig. 2), the proband contacted us after the death of 3 of his siblings from DGC over the course of only 18 months. DNA was extracted from their paraffin-embedded tumor tissue blocks, and a CDH1 70G→T mutation was identified.14 Once the pedigree was extended, a Family Information Service (FIS)15 was provided; family members were educated intensively about all facets of the natural history of HDGC, its screening limitations, potential sequelae of prophylactic total gastrectomy, and the pros and cons of DNA testing for the deleterious germline cancer-predisposing CDH1 mutation.
Families 3 (Fig. 3) and 4 (Fig. 4) were evaluated and received essentially the same services and treatments described above for Families 1 and 2. The pedigree of Family 3 recently was published.16
The 11 first cousins in Family 1 (Fig. 1) who underwent prophylactic total gastrectomy reported in their questionnaires that they were satisfied with their decision to have this surgery, especially when 10 of the 11 cousins learned that their postgastrectomy pathology specimens showed microscopic evidence of DGC. The age at which individuals were informed that a member of their family was markedly prone to HDGC ranged between 45 years and 55 years (average age, 48.5 years). Eight of the 11 first cousins were told about the importance of genetic testing by a cousin, 1 was told by a sister-in-law, 1 was told by a sibling, and only 1 was told by a physician. Four of the 11 first cousins decided to be tested immediately, whereas 7 indicated that it took them as long as 6 months to make that decision.
Five of the 11 first cousins who underwent prophylactic total gastrectomy reported that, before their surgery, they had felt frustrated sometimes or often about the finding that there were no cancer screening modalities of proven efficacy available to them. Six cousins thought about how the test results might affect their work or family life, and 6 cousins were concerned about their health insurance status. Ten of the 11 cousins never had difficulty discussing their test results with family members, and they believed that their family had been supportive.
One of these cousins, who had learned at our FIS that mutation carriers also have a high risk of developing lobular carcinoma of the breast, went for breast cancer screening. This resulted in a diagnosis of lobular breast cancer. She stated that “… this (diagnosis) did not come as a big shock. We were looking for it.”
The proband (Fig. 2, individual III-3) contacted the Creighton Center because 3 of his siblings (Fig. 2, individuals III-1, III-2, and III-5) had died of stomach cancer within an 18-month timeframe.14 Family history and pathology reports were gathered. Tumor tissue blocks were retrieved, and all 3 of the siblings were positive for the CDH1 70G→T mutation. We decided that it would be appropriate to have an FIS for the family, and many family members attended. Those high-risk family members who consented were tested for the CDH1 mutation.
The proband initially was reluctant to consider prophylactic total gastrectomy, although he was positive for the germline mutation. Part of this reluctance was attributed to the finding that his mother (Fig. 2, individual II-2), age 78 years, was positive for the mutation but had never manifested DGC. Furthermore, he was undergoing periodic upper gastric endoscopy with biopsies and felt confident that this would be protective, although we repeatedly had discussed the finding that this screening was ineffective. We kept in contact with him for 3 years with annual telephone calls to provide him with information about screening limitations. He finally agreed that his best prospect would be prophylactic gastrectomy. He underwent that procedure and, although his stomach showed no visible abnormalities (Fig. 5), microscopic foci of early DGC were identified (Fig. 6). He became a spokesman for getting better education for the rest of his family. Consequently, we held a second FIS. That accounted in part for individual IV-1 being tested and having the CDH1 mutation identified. He chose to undergo prophylactic gastrectomy, and 2 foci of intramucosal signet cell carcinoma were identified in the gastric body mucosa.
Also noteworthy in the pedigree is individual II-3, who had lobular carcinoma of the breast at age 40 years, developed DGC at age 49 years and died at age 55 years. Her daughter (individual III-7) also had lobular carcinoma of the breast. Another individual of interest is II-7, who is completely asymptomatic at age 80 years of age and is positive for the CDH1 mutation; she has not undergone gastric screening. Her daughter is positive for the mutation and has had breast cancer (pathology unavailable).
The proband of Family 3 (Fig. 3, individual III-1) was diagnosed with infiltrating lobular carcinoma of the breast at age 58 years followed by contralateral infiltrating ductal carcinoma at age 66 years. On the basis of her personal history of breast cancer, coupled with breast and ovarian cancer confirmed by death certificate in her family, she was tested for the breast cancer genes BRCA1 and BRCA2 and was identified with a previously unreported BRCA2 variant of uncertain significance (E2175Q). While she was being treated for her breast cancer, she began to complain of epigastric pain. Gastric duodenoscopy identified a stage IV DGC. During palliative surgery for the DGC, she had a metastatic pancreatic islet cell tumor identified. CDH1 genetic testing was performed on a research protocol, and a CDH1 mutation (2195G > A) was revealed and subsequently confirmed in a clinical laboratory.8 Although this mutation originally was reported as a missense mutation (R372Q), its likely pathogenic effect is through the activation of a cryptic splice site in exon 14, leading to a truncated protein.8, 17
The discovery of a CDH1 mutation in the family led several of the proband's high-risk relatives to undergo genetic testing, many of whom were troubled with the decision of whether to pursue prophylactic total gastrectomy. The varied age of onset of DGC in the family and the 3 long-lived, unaffected, mutation-positive women (individuals III-2, III-3, and III-4) were reasons given to delay or decline prophylactic surgery. Because of her concern for her children, the daughter, aged 39 years (individual IV-6), of a woman who had died from gastric cancer at age 33 years (individual III-5) elected to undergo surgery. Her clinical course and personal sentiments are documented in a case report.16 A 2-mm focus of signet cell cancer was discovered in her stomach (Fig. 7), and a Brenner tumor of the ovary also was discovered and removed. The finding of the occult gastric cancer reinforced her belief that she made the right surgical decision; in addition, it sparked 3 other women in the family to stop endoscopic screening and pursue preventive surgery. Her sister (individual IV-7) had a fundic gland polyp removed from her stomach during a screening endoscopy before prophylactic gastrectomy; no cancer was identified in her surgical specimen.
In Family 4 (Fig. 4), the proband (individual IV-1) is an unaffected man aged 42 years who consulted with a gastroenterologist regarding a 6-month history of abdominal pain and a striking family history of gastric cancer. Esophageal gastroduodenoscopy (EGD) and a CT scan of the abdomen were performed with normal findings. A consultation to the genetics clinic was initiated by his gastroenterologist, who recognized the likely hereditary nature of gastric cancer in this family. This referral enabled our initial contact with the family.
It was recognized that individual III-6, an unaffected woman aged 69 years, would be the most informative family member for genetic testing, because her mother and 2 sons (individuals IV-5 and IV-6) from different partners died of DGC. Genetic testing for the CDH1 mutation was performed in the molecular genetic laboratories of 1 of the coauthors (D.G.H.) using previously described methods, and the CDH1 1792C→T mutation was identified.8 Individual III-6 has been cooperative and has participated actively in this research as a way to help her family. Although physicians have told her that gastric cancer is not hereditary, she has always believed that it is in her family, and she was not surprised to learn of the CDH1 mutation. She does not undergo regular cancer screening but recently has become interested in gastric cancer screening. She is aware that members of other families with HDGC have undergone prophylactic total gastrectomy; but, for her, this seems too extreme.
The proband's mother (individual III-2), age 59 years, had been having yearly EGD screening for approximately 20 years and recently was diagnosed with Barrett esophagus. She had been seriously considering prophylactic total gastrectomy for the past 2 or 3 years. She chose to have predictive genetic testing and had the CDH1 gene mutation identified. She has stated that she will undergo total gastrectomy in the very near future. Because she has early satiety and epigastric pain, she believes that she already may have DGC and hopes that it will be caught early. Now that his mother's results are known, the proband would like to have predictive genetic testing, and he is getting his insurance in place before testing.
Individual III-4 is a woman aged 68 years who is a sister of the proband's mother. She was diagnosed with lobular breast cancer at age 58 years. Two of 29 lymph nodes were positive. She declined chemotherapy and has not undergone regular mammograms because she was diagnosed with breast cancer. Initially, she was reluctant to participate in a family meeting but decided to do so when her family physician said it was a good thing to do. She tested positive for the CDH1 mutation. She also feels that prophylactic total gastrectomy is too extreme. Before an FIS, none of the family members knew of the association of lobular breast cancer and HDGC.
Individual IV-13 is an unaffected man aged 48 years. He has never had EGD. He tested positive for the CDH1 mutation. He received some information about screening and prevention of gastric cancer at the FIS and met with 1 of the coauthors (W.G.) for more detailed information about these options. He felt that prophylactic total gastrectomy would have a negative impact on his employment. He will undergo screening for gastric cancer and hopes that having a positive attitude about cancer and eating a healthy diet will have a positive impact.
Identification of the CDH1 mutation confirmed many family members' beliefs about the hereditary nature of gastric cancer in their family. Six of 8 family members (75%) who were in direct contact with 1 of the coauthors (S.W.) already had received some form of gastric cancer screening. Six of 7 family members (86%) who attended the FIS chose to have predictive genetic testing, and they all valued the opportunity to participate in CDH1 research.
Several challenges are presented when counseling and clinically managing family members who carry a deleterious CDH1 mutation. For example, the age of onset of DGC in HDGC families with a CDH1 mutation may be extremely variable, even within families. Thus, whereas the average age of onset of DGC in HDGC families is approximately 38 years, it can range from 16 years to 82 years.8 The marked intrafamilial variability in age of onset in Family 3 was a factor in the family's general reluctance to undergo prophylactic gastrectomy. This wide variability in age of onset also poses a serious challenge for clinical geneticists and genetic counselors when discussing predictive genetic testing for family members who are in their teens. Given the young ages of onset that have been reported, it is not unreasonable to offer genetic testing to individuals in their late teens. It is important to realize that predictive testing in these at-risk teens will raise complex medical, ethical, psychosocial, and legal implications.18 Therefore, it is imperative to offer sensitive counseling over several sessions by genetic counselors and clinical geneticists who are dealing with the family.
There remains a large number of progeny of the mutation-positive and/or HDGC cancer-affected parents (Figs. 1–4) who are at increased cancer risk and who clearly need special attention. Our primary concern is to continue this work in counseling and educating those individuals who are at inordinately high risk for DGC so that they can make their own decisions about testing; and, if they are positive for a CDH1 mutation, then they may consider the option of prophylactic total gastrectomy. Some individuals who tested positive for the CDH1 mutation indicated that they may elect to delay prophylactic surgery, considering the disease's incomplete penetrance, and hope that a diagnostic measure will be discovered that is of acceptable sensitivity and specificity so that their decision about surgical prophylaxis can be reconciled. Those who test negative can be relieved that the life-threatening burden of DGC has been reduced to a population-based risk of much less than 1%.
The choices for unaffected mutation carriers are screening programs that lack acceptable sensitivity versus the option of prophylactic total gastrectomy.14 The decision to undergo gastric surgical prophylaxis in a CDH1 mutation carrier must be made relatively early in life, because the average age of onset of DGC in members of HDGC families, as discussed above, is approximately 38 years.5, 11 This decision may be heightened by patients' knowledge that diagnostic procedures capable of providing early diagnosis are limited given the submucosal presence of DGC. Further support in the decision-making process is the extremely poor prognosis when there is DGC with regional or distal spread.14 The high fatality rate among members of HDGC families provides a further stimulus to preventive surgery.
A patient's decision to undergo prophylactic total gastrectomy is often an extremely difficult one, because the entire stomach must be sacrificed. For some, it may be equally difficult to accept that one can live a reasonably normal life in the absence of this organ. However, the surgical decision was eased in a major way for the 11 first cousins described above (Fig. 1), because the majority of those individuals had witnessed a parent die as a result of the progressive course of DGC. When told that there was an approximate 30% chance that they would not develop DGC because of its reduced penetrance, this clearly factored into some of their decision making. However, because they knew that they had the deleterious mutation, they had to resolve the cancer probabilities, which they clearly knew favored the development of DGC. They knew through our educational program that available DGC screening procedures were wholly inadequate.14 Perhaps foremost on the positive side of their decision-making process was the psychological support provided to each other in the sense of a “group therapy” family commitment to help each other, as strongly evidenced in Family 1.15 There was very strong solidarity among these cousins about the importance of prophylactic gastrectomy, and this influence of camaraderie was pervasive throughout our genetic counseling sessions dealing with these high-risk individuals.
Once individuals were armed with facts about the natural history of DGC, many told us that, in essence, the only decision left was when the prophylactic gastrectomy should be performed. Knowing that their prognosis would become extremely grave once DGC symptoms became manifest, all 11 first cousins in Family 1 decided to undergo prophylactic surgery, most within a couple of years of receiving their CDH1 mutation results.
Prophylactic Gastrectomy and Reconstruction
Preoperative multidisciplinary evaluation includes genetic counseling, gastroenterology, dietary consultation, and surgical consultation. In our protocol, which was established for a group of families with a recently described founder CDH1 mutation, patients are evaluated by the surgeon on at least 3 separate occasions so that they understand the potential short- and long-term complications of prophylactic gastrectomy, the estimated predicted weight loss, and potential metabolic consequences.8 They are advised of the possible need for reoperation, the possibility of anastomotic leak, and potential death. They are familiarized with a postgastrectomy diet and informed that it may take up to 1 year for weight stabilization and accommodation to dietary modifications to take place. They also are advised that the estimated lifetime risk of gastric cancer may decline somewhat over time as more families are evaluated and that medical-genetic therapy eventually may become available for this condition.
Endoscopic evaluation is undertaken by the surgeon who will perform the surgery, and at least 15 random gastric mucosal biopsies are provided for pathology. Delineation of the gastroesophageal junction and the presence or absence of hiatal herniation is noted. If the latter is present, then discussion of a possible thoracoabdominal approach to gastrectomy is undertaken. Colonoscopy is performed, and an abdominal CT scan is used to delineate possible extragastric extension or lymph node involvement. Although a variety of approaches to prophylactic gastrectomy have been described, including laparoscopic gastrectomy and the provision of a Hunt-Lawrence pouch reconstruction, we have performed gastrectomy successfully with end-to-side esophagojejunal reconstruction and feeding jejunostomy in 17 patients with the 2398delC founder mutation (D.W., unpublished data). Currently, we are in the process of evaluation, including quality-of-life assessment, of a cohort of patients undergoing this procedure.
An important limitation of our study was because of the lack of formal psychological evaluation. This may have provided a more complete assessment of the emotional concerns and how these may have been ameliorated through psychological/psychiatric consultation. This limitation becomes of particular importance when the at-risk patient receives a positive CDH1 mutation result, knows the gravity of DGC, and must wrestle with the decision to undergo prophylactic total gastrectomy. It will be important to conduct formal behavioral studies in HDGC families to better understand the determinants of their medical decision making and to help them cope with the arduous decisions at hand.
Trudy Shaw, MA, provided technical assistance throughout the development of this article. We gratefully acknowledge the dedication, help, and inspiration provided by the hereditary diffuse gastric cancer family members who participated in this study.