Hereditary Diffuse Gastric Cancer: Updated Guidelines
Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patient's perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.
Worldwide, gastric cancer (GC) is the fifth leading cause of cancer and the third most common cause of death from cancer, with an estimated number of 723 000 deaths annually. The vast majority of GCs are sporadic, but it has now been established that 1–3% of GCs arise as a result of inherited cancer predisposition syndromes. These syndromes include Li-Fraumeni syndrome, Lynch syndrome, Peutz-Jeghers syndrome, hereditary breast and ovarian cancer,MUTYH-associated adenomatous polyposis (MAP), familial adenomatous polyposis, juvenile polyposis syndrome and PTEN hamartoma tumour syndrome (Cowden syndrome). The lifetime risk of GC in these syndromes varies substantially between populations studied, but is generally low.
Over 15 years ago, linkage analysis implicated germline mutations in the CDH1 gene, encoding the tumour-suppressor protein E-cadherin, as the genetic cause of hereditary diffuse GC (HDGC). Heterozygous germline CDH1 mutations increase lifetime risk of developing diffuse GC (DGC) and lobular breast cancer (LBC). Criteria have been set to select families eligible for screening of germline CDH1 mutations, and they were updated in 2010. Not all families fulfilling these criteria have mutations in CDH1, indicating that other genes may also be involved in DGC predisposition. Germline mutations in CTNNA1 were described in three families that presented with DGC, one of them fulfilled the 2010 HDGC criteria.
Increasing awareness of HDGC and the rapid advances in genetic diagnostic tools, endoscopic modalities and the increasing use of laparoscopic surgery led a group of clinical geneticists, gastroenterologists, surgeons, oncologists, pathologists, molecular biologists, dieticians and patients' representatives from nine different countries to convene a workshop in order to update the management guidelines for this condition set in 2010 and to propose directions for future research. The workshop discussions were focused on five major topics: (1) genetic counselling and mutation analysis; (2) endoscopic surveillance and screening of cancer; (3) risk-reduction surgery of the stomach and breasts; (4) pathological specimen processing and diagnosis; and (5) patients' and dieticians' perspective.
Abstract and Introduction
Abstract
Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patient's perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.
Introduction
Worldwide, gastric cancer (GC) is the fifth leading cause of cancer and the third most common cause of death from cancer, with an estimated number of 723 000 deaths annually. The vast majority of GCs are sporadic, but it has now been established that 1–3% of GCs arise as a result of inherited cancer predisposition syndromes. These syndromes include Li-Fraumeni syndrome, Lynch syndrome, Peutz-Jeghers syndrome, hereditary breast and ovarian cancer,MUTYH-associated adenomatous polyposis (MAP), familial adenomatous polyposis, juvenile polyposis syndrome and PTEN hamartoma tumour syndrome (Cowden syndrome). The lifetime risk of GC in these syndromes varies substantially between populations studied, but is generally low.
Over 15 years ago, linkage analysis implicated germline mutations in the CDH1 gene, encoding the tumour-suppressor protein E-cadherin, as the genetic cause of hereditary diffuse GC (HDGC). Heterozygous germline CDH1 mutations increase lifetime risk of developing diffuse GC (DGC) and lobular breast cancer (LBC). Criteria have been set to select families eligible for screening of germline CDH1 mutations, and they were updated in 2010. Not all families fulfilling these criteria have mutations in CDH1, indicating that other genes may also be involved in DGC predisposition. Germline mutations in CTNNA1 were described in three families that presented with DGC, one of them fulfilled the 2010 HDGC criteria.
Increasing awareness of HDGC and the rapid advances in genetic diagnostic tools, endoscopic modalities and the increasing use of laparoscopic surgery led a group of clinical geneticists, gastroenterologists, surgeons, oncologists, pathologists, molecular biologists, dieticians and patients' representatives from nine different countries to convene a workshop in order to update the management guidelines for this condition set in 2010 and to propose directions for future research. The workshop discussions were focused on five major topics: (1) genetic counselling and mutation analysis; (2) endoscopic surveillance and screening of cancer; (3) risk-reduction surgery of the stomach and breasts; (4) pathological specimen processing and diagnosis; and (5) patients' and dieticians' perspective.
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