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Khiabany A, Dermanis AA, Liew MS, Ong KR, Kamarajah SK, Griffiths EA. A Systematic Review of Surgical and Pathological Outcomes in Patients With a CDH1 Mutation Undergoing Total Gastrectomy. J Surg Oncol 2024; 130:1539-1550. [PMID: 39257226 DOI: 10.1002/jso.27855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Accepted: 08/10/2024] [Indexed: 09/12/2024]
Abstract
BACKGROUND CDH1 (E-cadherin) genetic mutations are associated with a 30%-70% increased lifetime risk of hereditary diffuse gastric cancer (HDGC). Although prophylactic total gastrectomy (PTG) reduces long-term risk of gastric cancer, the associated morbidity and mortality remain unclear. This systematic review aims to characterise postoperative surgical outcomes in patients undergoing total gastrectomy. METHODS A systematic literature search was performed for studies reporting endoscopic surveillance, surgical and pathological outcomes for patients with CDH1 mutation undergoing a total gastrectomy. RESULTS Thirty-nine studies included 1849 patients, of which 96% had a CDH1 (n = 1777) or CTNNA1 (n = 3) mutation. Endoscopy outcomes were reported for 1640 patients. Cancer foci were identified in 32% (n = 523/1640) and 71% of these patients went on to have a total gastrectomy (n = 369/523). The remaining 78% of patients did not have cancer foci detected on endoscopy (n = 1117/1640). Of these patients, 62% underwent a total gastrectomy (n = 688/1117) and 81% were found to have cancer on surgical histology (n = 556/688). Pathological staging was reported for 790 patients undergoing surgery, of which 68% had pT1 disease (n = 537). Postoperative complications were reported for 430 patients across 23 studies, with the most common complications being anastomotic strictures (25%), anastomotic leaks (13%), wound infections (12%) and pulmonary complications (11%). Only one postoperative death was reported within 30 days. CONCLUSION Rates of early cancers are high in CDH1 patients undergoing PTG, highlighting the need for improvement in reliable endoscopic surveillance. Although postoperative mortality in this surgical cohort remains low, high rates of postoperative complications warrant careful patient counselling.
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Affiliation(s)
- Atousa Khiabany
- Department of Upper Gastrointestinal Surgery, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Trust, Birmingham, UK
| | - Alexander A Dermanis
- Department of Upper Gastrointestinal Surgery, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Trust, Birmingham, UK
| | - Mei Sien Liew
- Department of Upper Gastrointestinal Surgery, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Trust, Birmingham, UK
| | - Kai Ren Ong
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Sivesh K Kamarajah
- Department of Upper Gastrointestinal Surgery, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Trust, Birmingham, UK
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Ewen A Griffiths
- Department of Upper Gastrointestinal Surgery, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Trust, Birmingham, UK
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
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Garitaonaindia Y, Méndez M, Valentín F, Gutiérrez L, de Tejada AH, Sánchez Ruiz A, Provencio M, Romero A. Clinical approach for managing patients with unexpected CDH1 mutations: A case report. Mol Genet Genomic Med 2024; 12:e2496. [PMID: 39056403 PMCID: PMC11273211 DOI: 10.1002/mgg3.2496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 07/05/2024] [Accepted: 07/10/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND Hereditary diffuse gastric cancer (HDGC) (OMIM# 137215) is an autosomal dominant cancer syndrome associated with CDH1 (OMIM# 192090) mutations. Prophylactic total gastrectomy (PTG) is the most recommended preventive treatment when a pathogenic mutation is found. However, the increasing use of genetic testing has led to the identification of incidental CDH1 mutations in individuals without a family history of gastric cancer. It remains unclear whether these patients should undergo prophylactic total gastrectomy. METHODS Germline DNA, obtained from peripheral blood, was analysed by NGS. RESULTS A 47-year-old woman was diagnosed with high-grade serous ovarian carcinoma, FIGO stage IIIC, with a Homologous Recombination Deficiency (HRD) GIS status of 78 (positive, cut-off: 43). She received chemotherapy and niraparib treatment. A multigene panel test revealed no pathogenic mutations in BRCA1 (OMIM# 113705)/BRCA2 (OMIM# 600185) genes, but a de novo deletion of exon 16 in CDH1 was found incidentally. She had no previous family history of gastric or breast cancer. The patient was enrolled in a surveillance program involving periodic endoscopy and was diagnosed with diffuse gastric cancer through biopsies of a pale area in the antrum after 1 year of close endoscopic follow-up. CONCLUSION This case presents supportive evidence for the pathogenic classification of the loss of the last exon of CDH1.
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Affiliation(s)
| | - Miriam Méndez
- Medical Oncology DepartmentPuerta de Hierro University HospitalMadridSpain
| | - Fátima Valentín
- Gastroenterology and Hepatology DepartmentEndoscopy Unit Puerta de Hierro University HospitalMadridSpain
| | - Lourdes Gutiérrez
- Medical Oncology DepartmentPuerta de Hierro University HospitalMadridSpain
| | - Alberto Herreros de Tejada
- Gastroenterology and Hepatology DepartmentEndoscopy Unit Puerta de Hierro University HospitalMadridSpain
| | | | - Mariano Provencio
- Medical Oncology DepartmentPuerta de Hierro University HospitalMadridSpain
| | - Atocha Romero
- Medical Oncology DepartmentPuerta de Hierro University HospitalMadridSpain
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Welton ML. Jeff Norton and the Definition of 'Un'. Ann Surg Oncol 2024; 31:3618-3621. [PMID: 38472676 DOI: 10.1245/s10434-024-15080-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 02/08/2024] [Indexed: 03/14/2024]
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Gallanis AF, Gamble LA, Samaranayake SG, Lopez R, Rhodes A, Rajasimhan S, Fasaye GA, Juma O, Connolly M, Joyce S, Berger A, Heller T, Blakely AM, Hernandez JM, Davis JL. Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy. J Clin Oncol 2024; 42:421-430. [PMID: 37903316 PMCID: PMC10824374 DOI: 10.1200/jco.23.01238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/01/2023] [Accepted: 09/13/2023] [Indexed: 11/01/2023] Open
Abstract
PURPOSE Risk-reducing surgery for cancer prevention in solid tumors is a pressing clinical topic because of the increasing availability of germline genetic testing. We examined the short- and long-term outcomes of risk-reducing total gastrectomy (RRTG) and its lesser-known impacts on health-related quality of life (QOL) in individuals with hereditary diffuse gastric cancer syndrome. METHODS Individuals who underwent RRTG as part of a single-institution natural history study of hereditary gastric cancers were examined. Clinicopathologic details, acute and chronic operative morbidity, and health-related QOL were assessed. Validated questionnaires were used to determine QOL scores and psycho-social-spiritual measures of healing. RESULTS One hundred twenty-six individuals underwent RRTG because of a pathogenic or likely pathogenic germline CDH1 variant between October 2017 and December 2021. Most patients (87.3%; 110/126) had pT1aN0 gastric carcinoma with signet ring cell features on final pathology. Acute (<30 days) postoperative major morbidity was low (5.6%; 7/126) and nearly all patients (98.4%) lost weight after total gastrectomy. At 2 years after gastrectomy, 94% (64/68) of patients exhibited at least one chronic complication (ie, bile reflux, dysphagia, and micronutrient deficiency). Occupation change (23.5%), divorce (3%), and alcohol dependence (1.5%) were life-altering consequences attributed to total gastrectomy by some patients. In patients with a median follow-up of 24 months, QOL scores decreased at 1 month after gastrectomy and returned to baseline by 6-12 months. CONCLUSION RRTG is associated with life-changing adverse events that should be discussed when counseling patients with CDH1 variants about gastric cancer prevention. The risks of cancer-prevention surgery should not only be judged in the context of likelihood of death due to disease if left untreated, but also based on the real consequences of organ removal.
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Affiliation(s)
- Amber F. Gallanis
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Lauren A. Gamble
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Sarah G. Samaranayake
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Rachael Lopez
- Clinical Center Nutrition Department, National Institutes of Health, Bethesda, MD
| | - Amanda Rhodes
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Suraj Rajasimhan
- Pharmacy Department, National Institutes of Health Clinical Center, Bethesda, MD
| | - Grace-Ann Fasaye
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | | | - Maureen Connolly
- Clincal Center Nursing Department, National Institutes of Health, Bethesda, MD
| | - Stacy Joyce
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Ann Berger
- Pain and Palliative Care Service, Clinical Center, National Institutes of Health, Bethesda, MD
| | - Theo Heller
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Andrew M. Blakely
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Jonathan M. Hernandez
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Jeremy L. Davis
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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Lim HJ, di Pietro M, O’Neill JR. A Systematic Review on Clinical and Health-Related Quality of Life Outcomes following Total Gastrectomy in Patients with Hereditary Diffuse Gastric Cancer. Cancers (Basel) 2024; 16:473. [PMID: 38339225 PMCID: PMC10854827 DOI: 10.3390/cancers16030473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 12/23/2023] [Accepted: 12/25/2023] [Indexed: 02/12/2024] Open
Abstract
Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominant syndrome associated with early onset diffuse gastric cancer. Definitive treatment is prophylactic total gastrectomy (PTG) associated with significant morbidity. Studies published from January 2000 to December 2022 reporting clinical, histopathological or health-related quality of life outcomes in HDGC patients undergoing PTG were identified. The study quality was assessed by the "Newcastle-Ottawa scale". Of the 257 articles screened, 21 were selected. A total of 353 patients were examined in 15 studies that reported surgical outcomes. The median age was 42 years old. The median major complication and mortality rates were 19.2% and 0.3%, respectively. The most common complications were wound infection at 4.8% followed by anastomotic leak and pulmonary complications at 4.5% each. Following PTG, 88.6% of patients had early lesions amongst 414 patients. The mean/median number of signet ring cell carcinoma foci in the gastrectomy specimens was from 2 to 78. All cases were stage 1 with no lymph node involvement. There was a wide range of psychosocial effects following PTG closely related to the physical symptoms. It is imperative for patients to receive comprehensive preoperative counselling to make an informed decision and be followed up under the care of a multidisciplinary team.
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Affiliation(s)
- Hui Jun Lim
- Early Cancer Institute, University of Cambridge, Cambridge CB2 0XZ, UK or (H.J.L.); (M.d.P.)
- Department of Sarcoma, Peritoneal and Rare Tumours (SPRinT), Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore 168583, Singapore
| | - Massimiliano di Pietro
- Early Cancer Institute, University of Cambridge, Cambridge CB2 0XZ, UK or (H.J.L.); (M.d.P.)
| | - J. Robert O’Neill
- Early Cancer Institute, University of Cambridge, Cambridge CB2 0XZ, UK or (H.J.L.); (M.d.P.)
- Cambridge Oesophagogastric Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
- Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XR, UK
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Bryant MK, Sillcox R, Grady WM, Oelschlager BK. Laparoscopic prophylactic total gastrectomy with limited lymphadenectomy for CDH1 gene carriers. Surg Endosc 2023; 37:9373-9380. [PMID: 37644154 DOI: 10.1007/s00464-023-10303-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 07/12/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND CDH1 gene mutations are the leading etiology of hereditary diffuse gastric cancer with cumulative lifetime risk ranging up to 83%. Prophylactic total gastrectomy (PTG) is, therefore, recommended for CDH1 carriers. A laparoscopic approach may reduce operative risk versus an open operation, thus leading more patients with CDH1 mutations to pursue PTG prior to cancer development. However, more experience and oncologic outcome data are needed for a laparoscopic approach and indicated lymphadenectomy. METHODS A retrospective descriptive cohort study of adult patients with CDH1 mutations who underwent laparoscopic PTG with D1 lymphadenectomy between 2012 and 2022 was conducted at a single institution. All patients had preoperative EGD screening, and those with visible tumor lesions on surveillance EGD were excluded and not considered prophylactic. Demographics, family history, pathology, and operative course were obtained. Outcomes included complications, readmission, and postoperative weight change. RESULTS Among 23 patients, median age was 48 years (IQR 37, 53) and 15 (65%) were female. Family history for gastric and/or lobular breast cancer was present in 22 (96%) patients. The median [IQR] time from positive genetic testing to PTG was 347 days [140, 625]. Pathologic evaluation showed five (22%) patients with foci of gastric cancer on pre-operative EGD biopsies, 10 (44%) in resected stomach specimens. All lymph nodes were negative. To address early postoperative complications, EJ anastomotic technique changed from EEA to GIA over the course of the study and feeding jejunostomy was no longer placed during PTG with minimal change in postoperative weight loss. CONCLUSIONS This is the largest series, spanning 10 years at a single institution, dedicated solely to a laparoscopic approach for risk-reducing PTG. A laparoscopic approach with limited lymphadenectomy resulted in acceptable surgical and oncologic outcomes. Despite no visible cancer, over half of our patients had foci of early gastric cancer. Therefore, CDH1 carriers should consider laparoscopic PTG.
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Affiliation(s)
- Mary K Bryant
- Department of Surgery, University of Washington, 1959 NE Pacific St, Box 3564101, Seattle, WA, 98195, USA
| | - Rachel Sillcox
- Department of Surgery, University of Washington, 1959 NE Pacific St, Box 3564101, Seattle, WA, 98195, USA
| | - William M Grady
- Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Brant K Oelschlager
- Department of Surgery, University of Washington, 1959 NE Pacific St, Box 3564101, Seattle, WA, 98195, USA.
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Mokhtari-Esbuie F, Szeglin B, Ravari MR, Duncan M, Harmon JW. Pioneering use of genetic analysis for CDH1 to identify candidates for prophylactic total gastrectomy to prevent hereditary diffuse gastric cancer. EGASTROENTEROLOGY 2023; 1:e100017. [PMID: 38188186 PMCID: PMC10769461 DOI: 10.1136/egastro-2023-100017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
Worldwide, gastric cancer results in significant morbidity and mortality. Ten per cent of patients with gastric cancer have a strong family history of the disease. CDH1 (E-cadherin) has been identified as a key gene whose mutation leads to hereditary diffuse gastric cancer. We overviewed 33 articles with prophylactic total gastrectomy and assessed the outcomes and benefits. Families with mutations in CDH1 may benefit from early prophylactic total gastrectomy. Dr Mark Duncan has applied his experience as a high-volume gastric cancer surgeon to treat not only individual patients, but several generations of patients within a family. This use of prophylactic total gastrectomy is well tolerated by patients and prevents the future development of gastric cancer.
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Affiliation(s)
| | - Bryan Szeglin
- Department of Surgery, Johns Hopkins Medicine, Baltimore, Maryland, USA
| | | | - Mark Duncan
- Department of Surgery, Johns Hopkins University, Baltimore, Maryland, USA
- Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA
| | - John W Harmon
- Department of Surgery, Johns Hopkins University, Baltimore, Maryland, USA
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Gallanis AF, Davis JL. Unique challenges of risk-reducing surgery for hereditary diffuse gastric cancer syndrome: a narrative review. Eur J Cancer Prev 2023; 32:391-395. [PMID: 36977191 PMCID: PMC10249595 DOI: 10.1097/cej.0000000000000798] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 03/04/2023] [Indexed: 03/30/2023]
Abstract
The common use of genetic testing has reinvigorated discussions surrounding enhanced cancer surveillance, chemoprevention, and preventive surgery strategies due to increasing recognition of pathogenic germline genetic variants. Prophylactic surgery for hereditary cancer syndromes can significantly reduce the risk of developing cancer. Hereditary diffuse gastric cancer (HDGC), characterized by high penetrance and an autosomal dominant inheritance pattern, is causally linked to germline mutations in the CDH1 tumor suppressor gene. Risk-reducing total gastrectomy is currently recommended in patients with pathogenic and likely pathogenic CDH1 variants; however, the physical and psychosocial sequelae of complete stomach removal are substantial and need to be investigated further. In this review, we address the risks and benefits of prophylactic total gastrectomy for HDGC in the context of prophylactic surgery for other highly penetrant cancer syndromes.
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Affiliation(s)
- Amber F. Gallanis
- Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Jeremy L. Davis
- Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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Asif B, Sarvestani AL, Gamble LA, Samaranayake SG, Famiglietti AL, Fasaye GA, Quezado M, Miettinen M, Korman L, Koh C, Heller T, Davis JL. Cancer surveillance as an alternative to prophylactic total gastrectomy in hereditary diffuse gastric cancer: a prospective cohort study. Lancet Oncol 2023; 24:383-391. [PMID: 36990610 PMCID: PMC10084814 DOI: 10.1016/s1470-2045(23)00057-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 01/30/2023] [Accepted: 01/31/2023] [Indexed: 03/29/2023]
Abstract
BACKGROUND Loss of function variants in CDH1 are the most frequent cause of hereditary diffuse gastric cancer. Endoscopy is regarded as insufficient for early detection due to the infiltrative phenotype of diffuse-type cancers. Microscopic foci of invasive signet ring cells are pathognomonic of CDH1 and precede development of diffuse gastric cancer. We aimed to assess the safety and effectiveness of endoscopy for cancer interception in individuals with germline CDH1 variants, particularly in those who declined prophylactic total gastrectomy. METHODS In this prospective cohort study, we included asymptomatic patients aged 2 years or older with pathogenic or likely pathogenic germline CDH1 variants who underwent endoscopic screening and surveillance at the National Institutes of Health (Bethesda, MD, USA) as part of a natural history study of hereditary gastric cancers (NCT03030404). Endoscopy was done with non-targeted biopsies and one or more targeted biopsy and assessment of focal lesions. Endoscopy findings, pathological data, personal and family cancer history, and demographics were recorded. Procedural morbidity, gastric cancer detection by endoscopy and gastrectomy, and cancer-specific events were assessed. Screening was defined as the initial endoscopy and all subsequent endoscopies were considered surveillance; follow-up endoscopy was at 6 to 12 months. The primary aim was to determine effectiveness of endoscopic surveillance for detection of gastric signet ring cell carcinoma. FINDINGS Between Jan 25, 2017, and Dec 12, 2021, 270 patients (median age 46·6 years [IQR 36·5-59·8], 173 [64%] female participants, 97 [36%] male participants; 250 [93%] were non-Hispanic White, eight [3%] were multiracial, four [2%] were non-Hispanic Black, three [1%] were Hispanic, two [1%] were Asian, and one [<1%] was American Indian or Alaskan Native) with germline CDH1 variants were screened, in whom 467 endoscopies were done as of data cutoff (April 30, 2022). 213 (79%) of 270 patients had a family history of gastric cancer, and 176 (65%) reported a family history of breast cancer. Median follow-up was 31·1 months (IQR 17·1-42·1). 38 803 total gastric biopsy samples were obtained, of which 1163 (3%) were positive for invasive signet ring cell carcinoma. Signet ring cell carcinoma was detected in 76 (63%) of 120 patients who had two or more surveillance endoscopies, of whom 74 had occult cancer detected; the remaining two individuals developed focal ulcerations each corresponding to pT3N0 stage carcinoma. 98 (36%) of 270 patients proceeded to prophylactic total gastrectomy. Among patients who had a prophylactic total gastrectomy after an endoscopy with biopsy samples negative for cancer (42 [43%] of 98), multifocal stage IA gastric carcinoma was detected in 39 (93%). Two (1%) participants died during follow-up, one due to metastatic lobular breast cancer and the other due to underlying cerebrovascular disease, and no participants were diagnosed with advanced stage (III or IV) cancer during follow-up. INTERPRETATION In our cohort, endoscopic cancer surveillance was an acceptable alternative to surgery in individuals with CDH1 variants who declined total gastrectomy. The low rate of incident tumours (>T1a) suggests that surveillance might be a rational alternative to surgery in individuals with CDH1 variants. FUNDING Intramural Research Program, National Institutes of Health.
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Affiliation(s)
- Bilal Asif
- National Institute of Diabetes and Digestive and Kidney Diseases, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Amber Leila Sarvestani
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Lauren A Gamble
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Sarah G Samaranayake
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Amber L Famiglietti
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Grace-Ann Fasaye
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Martha Quezado
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Markku Miettinen
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Louis Korman
- National Institute of Diabetes and Digestive and Kidney Diseases, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Christopher Koh
- National Institute of Diabetes and Digestive and Kidney Diseases, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Theo Heller
- National Institute of Diabetes and Digestive and Kidney Diseases, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jeremy L Davis
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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Gamble LA, Grant RRC, Samaranayake SG, Fasaye GA, Koh C, Korman L, Asif B, Heller T, Hernandez JM, Blakely AM, Davis JL. Decision-making and regret in patients with germline CDH1 variants undergoing prophylactic total gastrectomy. J Med Genet 2023; 60:241-246. [PMID: 35817563 DOI: 10.1136/jmg-2022-108733] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 07/05/2022] [Indexed: 11/03/2022]
Abstract
INTRODUCTION Prophylactic total gastrectomy (PTG) can eliminate gastric cancer risk and is recommended in carriers of a germline CDH1 pathogenic variant. PTG has established risks and potential life-long morbidity. Decision-making regarding PTG is complex and not well-understood. METHODS Individuals with germline CDH1 pathogenic or likely pathogenic variants who underwent surveillance endoscopy and recommended for PTG were evaluated. Factors associated with decision to pursue PTG (PTGpos) or not (PTGneg) were queried. A decision-regret survey was administered to patients who elected PTG. RESULTS Decision-making was assessed in 120 patients. PTGpos patients (63%, 76/120) were younger than PTGneg (median 45 vs 58 years) and more often had a strong family history of gastric cancer (80.3% vs 34.1%). PTGpos patients reported decision-making based on family history more often and decided soon after diagnosis (8 vs 27 months) compared with PTGneg. Negative endoscopic surveillance results were more common among PTGneg patients. Age >60 years, male sex and longer time to decision were associated with deferring PTG. Strong family history, a family member who died of gastric cancer and carcinoma on endoscopic biopsies were associated with decision to pursue PTG. In the PTGpos group, 30 patients (43%) reported regret which was associated with occurrence of a postoperative complication and no carcinoma detected on final pathology. CONCLUSION The decision to undergo PTG is influenced by family cancer history and surveillance endoscopy results. Regret is associated with surgical complications and pathological absence of cancer. Individual cancer-risk assessment is necessary to improve pre-operative counselling and inform the decision-making process. TRIAL REGISTRATION NUMBER NCT03030404.
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Affiliation(s)
- Lauren A Gamble
- National Cancer Institute, Surgical Oncology Program, National Institutes of Health, Bethesda, Maryland, USA
| | - Robert R C Grant
- National Cancer Institute, Surgical Oncology Program, National Institutes of Health, Bethesda, Maryland, USA
| | - Sarah G Samaranayake
- National Cancer Institute, Surgical Oncology Program, National Institutes of Health, Bethesda, Maryland, USA
| | - Grace-Ann Fasaye
- National Cancer Institute, Genetics Branch, National Institutes of Health, Bethesda, Maryland, USA
| | - Christopher Koh
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Louis Korman
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Bilal Asif
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Theo Heller
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Jonathan M Hernandez
- National Cancer Institute, Surgical Oncology Program, National Institutes of Health, Bethesda, Maryland, USA
| | - Andrew M Blakely
- National Cancer Institute, Surgical Oncology Program, National Institutes of Health, Bethesda, Maryland, USA
| | - Jeremy L Davis
- National Cancer Institute, Surgical Oncology Program, National Institutes of Health, Bethesda, Maryland, USA
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Decourtye-Espiard L, Guilford P. Hereditary Diffuse Gastric Cancer. Gastroenterology 2023; 164:719-735. [PMID: 36740198 DOI: 10.1053/j.gastro.2023.01.038] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 02/07/2023]
Abstract
Hereditary diffuse gastric cancer (HDGC) is a dominantly inherited cancer syndrome characterized by a high incidence of diffuse gastric cancer (DGC) and lobular breast cancer (LBC). HDGC is caused by germline mutations in 2 genes involved in the epithelial adherens junction complex, CDH1 and CTNNA1. We discuss the genetics of HDGC and the variability of its clinical phenotype, in particular the variable penetrance of advanced DGC and LBC, both within and between families. We review the pathology of the disease, the mechanism of tumor initiation, and its natural history. Finally, we describe current best practice for the clinical management of HDGC, including emerging genetic testing criteria for the identification of new families, methods for endoscopic surveillance, the complications associated with prophylactic surgery, postoperative quality of life, and the emerging field of HDGC chemoprevention.
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Affiliation(s)
- Lyvianne Decourtye-Espiard
- Cancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Parry Guilford
- Cancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin, New Zealand.
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Muranaka F, Kise E, Tokumaru S, Kitazawa M, Miyagawa Y, Suga T, Uehara T, Iwaya M, Kobayashi S, Sato M, Gomi D, Yamada H, Sugimura H, Kosho T, Soejima Y, Koizumi T. Hereditary diffuse gastric cancer in a Japanese family with CDH1 mutation three case reports. Discov Oncol 2023; 14:14. [PMID: 36719602 PMCID: PMC9889585 DOI: 10.1007/s12672-023-00623-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 01/25/2023] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND Germline pathogenic variants in the E-cadherin gene CDH1 cause hereditary diffuse gastric cancer (HDGC), which is an autosomal dominant cancer syndrome, accounting for 1-3% of all gastric cancers. HDGC harboring a CDH 1 variant is extremely rare in Japan. METHOD In this study we report the clinical courses of three cases with HDGC from a single Japanese family. RESULTS The proband exhibited advanced and metastatic gastric cancer, and was found to have a previously reported heterozygous frameshift variant in CDH1 (NM_004360.3:c.1009_1010del:p.Ser337Phefs*12). Five at-risk relatives underwent presymptomatic molecular testing after careful genetic counseling, and three were molecularly diagnosed as positive for the variant. Esophagogastroduodenoscopy was performed in these relatives revealing abnormal small pale mucosal patches, small ulcerative lesion and no abnormal findings. Moreover, random and targeted biopsies were compatible with pathological diagnosis of HDGC in the three cases, all of which underwent total prophylactic gastrectomy. CONCLUSION It is critical for the assessment and management of HDGC patients to be actively offered a multidisciplinary and familial-oriented approach. Notably, genetic screening in suspected individuals and familial members is a determining piece for a higher detection rate and the identification of clinical relevant mutations in both low and high-incidence gastric cancer countries.
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Affiliation(s)
- Futoshi Muranaka
- Department of Surgery, Division of Gastroenterological, Transplantation and Pediatric Surgery, Hepato-Biliary-Pancreatic, Shinshu University School of Medicine, Matsumoto, Japan
| | - Emiko Kise
- Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Japan
| | - Shigeo Tokumaru
- Department of Surgery, Division of Gastroenterological, Transplantation and Pediatric Surgery, Hepato-Biliary-Pancreatic, Shinshu University School of Medicine, Matsumoto, Japan
| | - Masato Kitazawa
- Department of Surgery, Division of Gastroenterological, Transplantation and Pediatric Surgery, Hepato-Biliary-Pancreatic, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yusuke Miyagawa
- Department of Surgery, Division of Gastroenterological, Transplantation and Pediatric Surgery, Hepato-Biliary-Pancreatic, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tomoaki Suga
- Endoscopic Examination Center, Shinshu University Hospital, Matsumoto, Japan
| | - Takeshi Uehara
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Mai Iwaya
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Shota Kobayashi
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Midori Sato
- Department of Pathology, Kurashiki Central Hospital, Kurashiki City, Japan
| | - Daisuke Gomi
- Department of Hematology and Medical Oncology, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan
| | - Hidetaka Yamada
- The First Department of Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Haruhiko Sugimura
- The First Department of Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Tomoki Kosho
- Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Japan
- Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan
- Research Center for Supports to Advanced Science, Shinshu University, Matsumoto, Japan
- Division of Clinical Sequencing, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yuji Soejima
- Department of Surgery, Division of Gastroenterological, Transplantation and Pediatric Surgery, Hepato-Biliary-Pancreatic, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tomonobu Koizumi
- Department of Hematology and Medical Oncology, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan.
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13
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Giunta EF, Arrichiello G, Pappalardo A, Federico P, Petrillo A. Transversal Perspectives of Integrative Oncology Care in Gastric and Lobular Breast Cancer. Cancer Treat Res 2023; 188:89-104. [PMID: 38175343 DOI: 10.1007/978-3-031-33602-7_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
The occurrence of gastric cancer has been associated with an increased risk of lobular breast tumors in a subset of patients harboring selected germline mutations. Among all, the germline alteration of the gene coding for E-Cadherin (CDH1) was associated with an increased risk of gastric cancer diffuse-histotype and lobular breast cancer. However, the risk assessment of breast neoplasms and the role of multiple prophylactic procedures in these patients has never been systematically addressed. In addition, the performance of the common screening procedures for lobular breast cancer like mammography is suboptimal. Therefore, recalling the need for a better articulation of the patient-centered strategies of surveillance for individuals with germline CDH1 and other similar alterations, to offer comprehensive approaches for prevention, early diagnosis, and treatment. Accordingly, this chapter aims to discuss the value and the role of integrated oncological care in the era of oncology sub-specializations. Additionally, it sheds light on how the harmonization across the health providers can enhance patient care in this setting.
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Affiliation(s)
- Emilio Francesco Giunta
- Department of Precision Medicine, School of Medicine, University of Study of Campania, 80131, Naples, Italy
| | - Gianluca Arrichiello
- Department of Precision Medicine, School of Medicine, University of Study of Campania, 80131, Naples, Italy
| | | | - Piera Federico
- Medical Oncology Unit, Ospedale del Mare, Via E. Russo, 80147, Naples, Italy
| | - Angelica Petrillo
- Medical Oncology Unit, Ospedale del Mare, Via E. Russo, 80147, Naples, Italy.
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14
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Lee CYC, Olivier A, Honing J, Lydon AM, Richardson S, O'Donovan M, Tischkowitz M, Fitzgerald RC, di Pietro M. Endoscopic surveillance with systematic random biopsy for the early diagnosis of hereditary diffuse gastric cancer: a prospective 16-year longitudinal cohort study. Lancet Oncol 2023; 24:107-116. [PMID: 36509094 DOI: 10.1016/s1470-2045(22)00700-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 11/03/2022] [Accepted: 11/09/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Hereditary diffuse gastric cancer, generally caused by germline pathogenic variants in CDH1, presents with early-onset signet ring cell carcinoma. Prophylactic total gastrectomy is the definitive treatment. Endoscopic surveillance can inform the timing of prophylactic total gastrectomy through detection of microscopic signet ring cell carcinoma foci. However, evidence is scarce about the optimal endoscopic sampling technique and characterisation of signet ring cell carcinoma foci in hereditary diffuse gastric cancer. We aimed to formally assess the diagnostic yield of different sampling strategies and to identify criteria for the characterisation of endoscopic lesions. METHODS For this prospective longitudinal cohort study, we included individuals aged 18 years or older at the Cambridge University Hospitals National Health Service (NHS) Foundation Trust who fulfilled testing criteria for hereditary diffuse gastric cancer between June 1, 2005, and July 31, 2021. The primary outcome was detection of intramucosal signet ring cell carcinoma foci. We assessed the detection rate and anatomical location of signet ring cell carcinoma in random biopsy samples taken according to a systematic protocol compared with biopsies targeted to endoscopic findings. Endoscopic lesions were examined with white-light and narrow band imaging with magnification to assess the likelihood of cancerous foci. FINDINGS 145 individuals were included, of whom 68 (47%) were male and 92 (63%) carried the CDH1 pathogenic variant. 58 (40%) patients were diagnosed with invasive signet ring cell carcinoma over a median follow-up time of 51 months (IQR 18-80). The first diagnosis of signet ring cell carcinoma was most commonly made from random biopsies (29 [50%] of 58 patients), rather than targeted biopsies (15 [26%] patients). The anatomical distribution of signet ring cell carcinoma foci detected by random biopsies more accurately reflected those identified in prophylactic total gastrectomy specimens than did targeted biopsies. Omitting random biopsies in our cohort would have led to an under-diagnosis rate of 42%. Using a novel panel of endoscopic criteria, gastric lesions containing signet ring cell carcinoma were predicted with a sensitivity of 67·3% and a specificity of 90·2%. INTERPRETATION Random biopsies enhance the early detection of signet ring cell carcinoma and are complementary to targeted biopsies in surveillance of hereditary diffuse gastric cancer. This sampling method should be the standard of care when performing all surveillance endoscopies for individuals with hereditary diffuse gastric cancer. FUNDING UK Medical Research Council.
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Affiliation(s)
- Colin Y C Lee
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Adriaan Olivier
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Judith Honing
- Early Cancer Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Anne-Marie Lydon
- Early Cancer Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Susan Richardson
- Early Cancer Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Maria O'Donovan
- Department of Histopathology, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - Marc Tischkowitz
- Department of Medical Genetics, National Institute for Health Research, Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
| | - Rebecca C Fitzgerald
- Early Cancer Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Massimiliano di Pietro
- Early Cancer Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
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15
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Surgery for Hereditary Diffuse Gastric Cancer: Long-Term Outcomes. Cancers (Basel) 2022; 14:cancers14030728. [PMID: 35158993 PMCID: PMC8833660 DOI: 10.3390/cancers14030728] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 01/26/2022] [Indexed: 01/04/2023] Open
Abstract
Simple Summary This study reports the long-term results of total gastrectomy for patients with a family history of gastric cancer and CDH1 gene mutations that predispose to hereditary diffuse gastric cancer (HDGC). Total gastrectomy was performed in 8 symptomatic patients and 22 asymptomatic patients of whom only 3 had HDGC diagnosed preoperatively. 7 of 8 symptomatic had metastatic lymph nodes with cancer. 21 of 22 asymptomatic patients had gastric cancer localized to the stomach and each was cured. 15 of those patients had 9-year follow-up. Each had significant weight loss (23% body weight) with a normal body mass index, 40% had bile reflux controlled with medication, and each returned to work and said they would do it again. Long-term quality of life following gastrectomy was acceptable. Abstract Introduction: Gastric cancer is inherited as an autosomal dominant condition in hereditary diffuse gastric cancer (HDGC). The gene associated with HDGC is an E-cadherin gene CDH1. At the time of initiation of this study, it was estimated that 70% of patients who inherited the CDH1 gene mutation would develop gastric cancer. We hypothesized that the rate of signet ring cell cancer in asymptomatic patients with CDH1 mutations may be higher than anticipated and that the surgery could be conducted with acceptable short-term and long-term complications suggesting that the quality of life with the surgery is acceptable. Methods: We prospectively studied the role of total gastrectomy in symptomatic and asymptomatic patients with CDH1 mutations. A total of 43 patients with mutations of the CDH1 gene were studied prospectively, including 8 with symptoms and 35 without symptoms. Total gastrectomy was recommended to each. Quality of life was assessed in patients who underwent prophylactic gastrectomy. Proportions are compared with Fisher’s exact test. Results: In total, 13 (30%) asymptomatic patients declined surgery. Total gastrectomy was performed in 8 symptomatic patients and 22 asymptomatic patients of whom only 3 asymptomatic patients (14%) had endoscopically proven signet ring cell cancer preoperatively, while 21 of 22 (95%) had it on final pathology (p = 0.05). Each asymptomatic patient was T1, N0, while seven out of eight symptomatic patients had T3-T4 tumors and six had positive lymph nodes. None had operative complications or operative death. The median follow-up was 7 years. Five (63%) symptomatic patients died, while only one (95%) prophylactic patient died of a non-gastric cancer- or surgery-related issue (p = 0.05). A total of 15 prophylactic patients had long-term follow-up. Each had significant weight loss (mean 23%) but all had a normal body mass index. In total, 40% had bile reflux gastritis controlled with sucralfate. Each returned to work and, if given the choice, said that they would undergo the surgery again. Conclusions: Total gastrectomy is indicated for patients who have an inherented CDH1 mutation. Endoscopic screening is not reliable for diagnosing signet ring cell stomach cancer. If patients wait for symptoms, they will have a more advanced disease and significantly reduced survival. Operative complications of prophylactic gastrectomy are minimal, and long-term quality of life is acceptable.
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16
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Liu Y, Calzone K, Fasaye GA, Quillin J. CDH1 variants leading to gastric cancer risk management decision-making experiences in emerging adults: 'I am not ready yet'. J Genet Couns 2021; 30:1091-1104. [PMID: 33655597 PMCID: PMC8358785 DOI: 10.1002/jgc4.1393] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 01/19/2021] [Accepted: 01/23/2021] [Indexed: 11/10/2022]
Abstract
Pathogenic/likely pathogenic variants (PLPV) in CDH1 are associated with a significantly increased lifetime risk for diffuse gastric cancer, with an average age of onset of 47 years. CDH1 PLPV carriers are recommended to have prophylactic total gastrectomy (PTG) or routine endoscopy surveillance. Emerging adults (EAs) may have unique circumstances that affect their medical management decision-making about PTG versus endoscopy. The study aim was to use qualitative interpretative phenomenological analysis method to understand the lived experience and medical management decision-making process for EAs carrying a CDH1 PLPV. Eligible participants were unaffected CDH1 PLPV carriers, ages 18 to 29, who had not undergone PTG and had discussed CDH1 medical management with a health provider. Semi-structured telephone interviews were transcribed verbatim and analyzed for major themes. Results show EAs wanted to avoid developing diffuse gastric cancer, but most do not feel they are ready for PTG. They had worries about PTG related to their identity exploration, financial stability, and careers. Most did not want to pass the PLPV to their children; however, the cost of preimplantation genetic testing with in vitro fertilization was a concern. Family medical history and self-understanding of endoscopy and PTG highly influenced medical management decision-making. Understanding of diffuse gastric cancer detection rate using endoscopy was inconsistent among participants. Body image was not a concern for most, but they worry about dietary restrictions after PTG. Lastly, connection to peers having the same experience was important. These findings increase our understanding of the medical management decision-making challenges for EA CDH1 carriers. EAs may take an extended time to decide what option is right for them. Thus, genetic counseling for CDH1 PLPV EA carriers requires long-term support and education.
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Affiliation(s)
- Yi Liu
- Genetic Counseling Program, Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
- National Cancer Institute, Center for Cancer Research, Genetics Branch, 37 Convent Drive, Building 37, Bethesda, MD 20892
| | - Kathleen Calzone
- National Cancer Institute, Center for Cancer Research, Genetics Branch, 37 Convent Drive, Building 37, Bethesda, MD 20892
| | - Grace-Ann Fasaye
- National Cancer Institute, Center for Cancer Research, Genetics Branch, 37 Convent Drive, Building 37, Bethesda, MD 20892
| | - John Quillin
- Genetic Counseling Program, Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
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17
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Hoskins C, Tutty E, Purvis R, Shanahan M, Boussioutas A, Forrest L. Young people's experiences of a CDH1 pathogenic variant: Decision-making about gastric cancer risk management. J Genet Couns 2021; 31:242-251. [PMID: 34265132 DOI: 10.1002/jgc4.1478] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/25/2021] [Accepted: 06/27/2021] [Indexed: 11/11/2022]
Abstract
The most effective option for gastric cancer risk management in individuals with a CDH1 germline pathogenic or likely pathogenic variant (PV) in Australia is prophylactic total gastrectomy (PTG). There is, however, increasing confidence in endoscopic surveillance as a risk management strategy thus affording individuals with a CDH1 PV with challenging decisions regarding their gastric cancer risk management. For young people, this decision-making comes at a complex development stage of emerging and young adulthood. This study aims to explore the factors that influence young people's decision-making about their gastric cancer risk management due to a CDH1 PV. Potential participants were identified and approached through the Parkville Familial Cancer Centre in Melbourne, Australia. Thematic analysis was used to interpret and analyze the data. Qualitative interviews were conducted with 13 people with a CDH1 PV aged 18 to 39 years, inclusive. The interviews found that participants' familial and shared experiences of cancer and risk management, perceived tolerance of uncertainty, and desire for control over their cancer risk were fundamental in their decision-making about their gastric cancer risk management. The participants' young adult life stage was also deemed particularly important in decisions about the timing of PTG. The findings of this study are vital to inform decisional counseling discussions with this unique population.
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Affiliation(s)
- Cass Hoskins
- Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.,Parkville Familial Cancer Centre and Genomic Medicine, The Royal Melbourne Hospital, Melbourne, VIC, Australia
| | - Erin Tutty
- Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Rebecca Purvis
- Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.,Parkville Familial Cancer Centre and Genomic Medicine, The Royal Melbourne Hospital, Melbourne, VIC, Australia
| | - Mary Shanahan
- Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.,Parkville Familial Cancer Centre and Genomic Medicine, The Royal Melbourne Hospital, Melbourne, VIC, Australia
| | - Alex Boussioutas
- Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.,Parkville Familial Cancer Centre and Genomic Medicine, The Royal Melbourne Hospital, Melbourne, VIC, Australia.,Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia.,Department of Gastroenterology, The Royal Melbourne Hospital, Melbourne, VIC, Australia.,Department of Surgical Oncology, The University of Melbourne, Parkville, VIC, Australia
| | - Laura Forrest
- Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.,Parkville Familial Cancer Centre and Genomic Medicine, The Royal Melbourne Hospital, Melbourne, VIC, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia
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18
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Mocan L. Surgical Management of Gastric Cancer: A Systematic Review. J Clin Med 2021; 10:jcm10122557. [PMID: 34207898 PMCID: PMC8227314 DOI: 10.3390/jcm10122557] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 05/30/2021] [Accepted: 06/07/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is the fifth most common cancer worldwide, and it is responsible for 7.7% of all cancer deaths. Despite advances in the field of oncology, where radiotherapy, neo and adjuvant chemotherapy may improve the outcome, the only treatment with curative intent is represented by surgery as part of a multimodal therapy. Two concepts may be adopted in appropriate cases, neoadjuvant treatment before gastrectomy (G) or primary surgical resection followed by chemotherapy. Such an approach, combined with early detection and better screening, has led to a decrease in the overall incidence of gastric cancer. Unfortunately, malignant tumors of the stomach are often diagnosed in locally advanced or metastatic stages when the median overall survival remains poor. Surgical care in these cases must be provided by a multidisciplinary team in a high-volume center. Important surgical aspects such as optimum resection margins, surgical technique, and number of harvested lymph nodes are important factors for patient outcomes. The standardization of surgical treatment of gastric cancer in accordance with the patient’s profile is of decisive importance for a better outcome. This review aims to summarize the current standards in the surgical treatment of gastric cancer.
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Affiliation(s)
- Lucian Mocan
- Department of Surgery, Iuliu Hatieganu University of Medicine and Pharmacy, RO-400012 Cluj-Napoca, Romania; or ; Tel.: +40-745-362-345
- Regional Institute of Gastroenterology and Hepatology, 19-21 Croitorilor Street, RO-400162 Cluj-Napoca, Romania
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19
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Ithurralde-Argerich J, Rosner L, Rizzolo M, Faerberg A, Puma R, Ferro D, Duque C, Kujaruk M, Cuenca-Abente F. Laparoscopic Prophylactic Total Gastrectomy for Hereditary Diffuse Gastric Cancer in CDH1 Mutation Carriers. J Laparoendosc Adv Surg Tech A 2021; 31:729-737. [PMID: 34097461 DOI: 10.1089/lap.2021.0239] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Background: Patients with hereditary diffuse gastric cancer (HDGC) and germline mutations in the E-cadherin gene, CDH1, have a very high cumulative lifetime risk of developing diffuse gastric cancer. In these patients, it is formally recommended to perform a prophylactic total gastrectomy (PTG). Materials and Methods: We analyzed the course of patients with HDGC who have undergone PTG in our institution. Pedigree analysis, preoperative screening results, operative course, postoperative data, and complete stomach pathologic examination were performed in all patients. Results: Seven patients with confirmed CDH1 mutation underwent PTG, five were women, and average age was 27 years (range 17-42). Signet ring cell carcinoma was found in 1 patient in the preoperative surveillance endoscopic biopsies. Laparoscopic PTG was performed in all patients. There were two complications, an intestinal obstruction that required reintervention and an asymptomatic esophagojejunal anastomosis leak that resolved with conservative treatment. In all gastrectomy specimens, intramucosal signet ring cell carcinoma foci limited to the lamina propria were found (range 1-31), 83.5% were in the body-fundus region. The mean follow-up was 28.5 months (range 8-72). The mean weight loss was 9% (range 2-18). Postoperative symptoms associated with Dumping syndrome were the most frequent. All the patients reported of being very satisfied with the procedure and of having a better quality of life than expected before the procedure. Conclusion: Laparoscopic PTG is an excellent resource to prevent the development of advanced diffuse gastric cancer (DGC) in patients with HDGC with CDH1 mutation. The procedure was well tolerated with a high satisfaction rate and very good functional results. It should be considered in these patients due to the high risk of developing advanced DGC and the lack of effective and reliable surveillance studies.
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Affiliation(s)
- Javier Ithurralde-Argerich
- Department of Surgery and Hospital de Gastroenterología "Dr. Carlos Bonorino Udaondo," Ciudad Autónoma de Buenos Aires, Argentina
| | - Laura Rosner
- Department of Surgery and Hospital de Gastroenterología "Dr. Carlos Bonorino Udaondo," Ciudad Autónoma de Buenos Aires, Argentina
| | - Mariana Rizzolo
- Department of Pathology, Hospital de Gastroenterología "Dr. Carlos Bonorino Udaondo," Ciudad Autónoma de Buenos Aires, Argentina
| | - Alejandro Faerberg
- Department of Surgery and Hospital de Gastroenterología "Dr. Carlos Bonorino Udaondo," Ciudad Autónoma de Buenos Aires, Argentina
| | - Rolando Puma
- Department of Surgery and Hospital de Gastroenterología "Dr. Carlos Bonorino Udaondo," Ciudad Autónoma de Buenos Aires, Argentina
| | - Diego Ferro
- Department of Surgery and Hospital de Gastroenterología "Dr. Carlos Bonorino Udaondo," Ciudad Autónoma de Buenos Aires, Argentina
| | - Camilo Duque
- Department of Surgery and Hospital de Gastroenterología "Dr. Carlos Bonorino Udaondo," Ciudad Autónoma de Buenos Aires, Argentina
| | - Mirta Kujaruk
- Department of Pathology, Hospital de Gastroenterología "Dr. Carlos Bonorino Udaondo," Ciudad Autónoma de Buenos Aires, Argentina
| | - Federico Cuenca-Abente
- Department of Surgery and Hospital de Gastroenterología "Dr. Carlos Bonorino Udaondo," Ciudad Autónoma de Buenos Aires, Argentina
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20
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CDH1 Gene Mutation Hereditary Diffuse Gastric Cancer Outcomes: Analysis of a Large Cohort, Systematic Review of Endoscopic Surveillance, and Secondary Cancer Risk Postulation. Cancers (Basel) 2021; 13:cancers13112622. [PMID: 34073553 PMCID: PMC8199234 DOI: 10.3390/cancers13112622] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/13/2021] [Accepted: 05/22/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Some patients carry a mutated copy of the CDH1 gene that can lead to a very rare form of hereditary gastric cancer called signet-ring cell adenocarcinoma (SRCC). SRCCs rarely form visible tumors prior to spreading. Hence, patients are recommended to have prophylactic gastrectomies at a young age. Many patients wish to avoid surgery and thus have regular checks with upper endoscopy with biopsies to rule out cancer. Further, these patients may also be at risk of other cancers beyond the already known breast cancer risks, but this is not known. In this study, we show that despite systematic biopsy protocols, many early cancers might be missed on endoscopy. Therefore, patients should not rely on endoscopy to delay surgery. These patients may also be at increased risk of colorectal SRCC, which has very poor survival outcomes. To confirm this, we need a central database that captures outcomes for this patient population. Abstract Hereditary diffuse gastric cancer (HDGC) is a rare signet-ring cell adenocarcinoma (SRCC) linked to CDH1 (E-cadherin) inactivating germline mutations, and increasingly other gene mutations. Female CDH1 mutation carriers have additional risk of lobular breast cancer. Risk management includes prophylactic total gastrectomy (PTG). The utility of endoscopic surveillance is unclear, as early disease lacks macroscopic lesions. The current systematic biopsy protocols have unknown efficacy, and other secondary cancer risks are postulated. We conducted a retrospective study of consecutive asymptomatic HDGC patients undergoing PTG, detailing endoscopic, pathologic, and outcome results. A systematic review compared endoscopic biopsy foci detection via random sampling versus Cambridge Protocol against PTG findings. A population-level secondary-cancer-risk postulation among sporadic gastric SRCC patients was completed using the Surveillance, Epidemiology, and End Results database. Of 97 patients, 67 underwent PTG, with 25% having foci detection on random endoscopic biopsy despite 75% having foci on final pathology. There was no improvement in the endoscopic detection rate by Cambridge Protocol. The postulated hazard ratio among sporadic gastric SRCC patients for a secondary colorectal SRCC was three-fold higher, relative to conventional adenocarcinoma patients. Overall, HDGC patients should not rely on endoscopic surveillance to delay PTG, and may have secondary SRCC risks. A definitive determination of actual risk requires collaborative patient outcome data banking.
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21
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Gamble LA, Heller T, Davis JL. Hereditary Diffuse Gastric Cancer Syndrome and the Role of CDH1: A Review. JAMA Surg 2021; 156:387-392. [PMID: 33404644 DOI: 10.1001/jamasurg.2020.6155] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Importance Inherited variants in the tumor suppressor gene CDH1 are associated with an increased risk of gastric and breast cancers. This review aims to address the most current topics in management of the hereditary diffuse gastric cancer syndrome attributed to CDH1. Observations Consensus management guidelines have broadened genetic testing criteria for CDH1. Prophylactic total gastrectomy is recommended for any pathogenic or likely pathogenic CDH1 variant carrier starting at the age of 20 years. Annual surveillance endoscopy is recommended to those who defer prophylactic total gastrectomy. Women with a CDH1 variant should initiate magnetic resonance imaging breast surveillance starting at age 30 years. Further research is needed to understand the pathogenesis of early-stage gastric cancers (T1a), which are pathognomonic of hereditary diffuse gastric cancer syndrome, that lead to advanced gastric cancer to develop both treatment and prevention strategies for this patient population. Conclusions and Relevance The heritable CDH1 gene mutation is of importance to today's surgeons because it is associated with a substantial increased risk of developing both gastric and breast cancers. Management of this cancer syndrome currently uses prophylactic surgery and enhanced cancer surveillance strategies.
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Affiliation(s)
- Lauren A Gamble
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Theo Heller
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Jeremy L Davis
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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22
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Pilonis ND, Tischkowitz M, Fitzgerald RC, di Pietro M. Hereditary Diffuse Gastric Cancer: Approaches to Screening, Surveillance, and Treatment. Annu Rev Med 2020; 72:263-280. [PMID: 33217247 DOI: 10.1146/annurev-med-051019-103216] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with a significant lifetime risk of diffuse gastric cancer (DGC), a malignancy characterized by late clinical presentation and poor prognosis, as well as lobular breast cancer. HDGC is linked to germline pathogenic variants in the E-cadherin gene (CDH1) that are inherited in an autosomal dominant pattern; however, in many families with DGC clustering, no genetic cause has been identified. This review discusses key elements that allow risk assessment of potential inherited DGC susceptibility. We provide a practical overview of the recommendations for surveillance and treatment of individuals at risk and patients with early disease. The review also outlines future research avenues to improve our understanding of the genetic background and natural history of the disease, the endoscopic detection of early lesions, and the outcome of prophylactic surgery in young individuals.
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Affiliation(s)
- Nastazja Dagny Pilonis
- MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, United Kingdom; .,The Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw 02-781, Poland
| | - Marc Tischkowitz
- Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 0QQ, United Kingdom
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23
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Blair VR, McLeod M, Carneiro F, Coit DG, D'Addario JL, van Dieren JM, Harris KL, Hoogerbrugge N, Oliveira C, van der Post RS, Arnold J, Benusiglio PR, Bisseling TM, Boussioutas A, Cats A, Charlton A, Schreiber KEC, Davis JL, Pietro MD, Fitzgerald RC, Ford JM, Gamet K, Gullo I, Hardwick RH, Huntsman DG, Kaurah P, Kupfer SS, Latchford A, Mansfield PF, Nakajima T, Parry S, Rossaak J, Sugimura H, Svrcek M, Tischkowitz M, Ushijima T, Yamada H, Yang HK, Claydon A, Figueiredo J, Paringatai K, Seruca R, Bougen-Zhukov N, Brew T, Busija S, Carneiro P, DeGregorio L, Fisher H, Gardner E, Godwin TD, Holm KN, Humar B, Lintott CJ, Monroe EC, Muller MD, Norero E, Nouri Y, Paredes J, Sanches JM, Schulpen E, Ribeiro AS, Sporle A, Whitworth J, Zhang L, Reeve AE, Guilford P. Hereditary diffuse gastric cancer: updated clinical practice guidelines. Lancet Oncol 2020; 21:e386-e397. [PMID: 32758476 DOI: 10.1016/s1470-2045(20)30219-9] [Citation(s) in RCA: 250] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 03/26/2020] [Accepted: 03/31/2020] [Indexed: 02/07/2023]
Abstract
Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined.
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Affiliation(s)
- Vanessa R Blair
- Department of Surgery, University of Auckland, Auckland, New Zealand; St Marks Breast Centre, Auckland, New Zealand
| | - Maybelle McLeod
- Kimihauora Health and Research Clinic, Mt Maunganui, New Zealand
| | - Fátima Carneiro
- Instituto de Investigação e Inovação em Saúde & Institute of Molecular Pathology and Immunology of the University of Porto, Department of Pathology, University of Porto, Porto, Portugal
| | - Daniel G Coit
- Memorial Sloan Kettering Cancer Center and Weill Cornell Medical School, New York, NY, USA
| | | | - Jolanda M van Dieren
- Department of Gastrointestinal Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | | | - Nicoline Hoogerbrugge
- Department of Human Genetics, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Carla Oliveira
- Instituto de Investigação e Inovação em Saúde & Institute of Molecular Pathology and Immunology of the University of Porto, Department of Pathology, University of Porto, Porto, Portugal
| | | | - Julie Arnold
- New Zealand Familial Gastrointestinal Cancer Service, Auckland Hospital, Auckland, New Zealand
| | - Patrick R Benusiglio
- Consultation d'Oncogénétique, Unité Fonctionnelle d'Oncogénétique, Département de Génétique, DMU BioGeM, Groupe Hospitalier Pitié-Salpêtrière, Sorbonne Université, Paris, France
| | - Tanya M Bisseling
- Department of Gastroenterology, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Alex Boussioutas
- Department of Medicine, Royal Melbourne Hospital and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
| | - Annemieke Cats
- Department of Gastrointestinal Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Amanda Charlton
- Department of Histopathology, Auckland Hospital, Auckland, New Zealand
| | | | - Jeremy L Davis
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | | | | | - James M Ford
- Division of Oncology, Departments of Medicine and Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Kimberley Gamet
- Genetic Health Service New Zealand Northern Hub, Auckland Hospital, Auckland, New Zealand
| | - Irene Gullo
- Instituto de Investigação e Inovação em Saúde & Institute of Molecular Pathology and Immunology of the University of Porto, Department of Pathology, University of Porto, Porto, Portugal
| | - Richard H Hardwick
- Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK
| | - David G Huntsman
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Pardeep Kaurah
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; Hereditary Cancer Program, British Columbia Cancer, Vancouver, BC, Canada
| | - Sonia S Kupfer
- Section of Gastroenterology, Nutrition and Hepatology, University of Chicago, Chicago, IL, USA
| | - Andrew Latchford
- St Mark's Hospital, London, UK; Department of Cancer and Surgery, Imperial College, London, UK
| | | | - Takeshi Nakajima
- Department of Clinical Genetic Oncology, Cancer Institute Hospital, Tokyo, Japan
| | - Susan Parry
- New Zealand Familial Gastrointestinal Cancer Service, Auckland Hospital, Auckland, New Zealand
| | - Jeremy Rossaak
- Department of Surgery, Tauranga Hospital, Tauranga, New Zealand
| | - Haruhiko Sugimura
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Magali Svrcek
- Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Department of Pathology, Hôpital Saint-Antoine, Paris, France
| | - Marc Tischkowitz
- Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
| | - Toshikazu Ushijima
- Division of Epigenomics, National Cancer Centre Research Institute, Tokyo, Japan
| | - Hidetaka Yamada
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | | | - Adrian Claydon
- Department of Gastroenterology, Tauranga Hospital, Tauranga, New Zealand
| | - Joana Figueiredo
- Instituto de Investigação e Inovação em Saúde & Institute of Molecular Pathology and Immunology of the University of Porto, Department of Pathology, University of Porto, Porto, Portugal
| | - Karyn Paringatai
- Te Tumu School of Māori, Pacific and Indigenous Studies, University of Otago, Dunedin, New Zealand
| | - Raquel Seruca
- Instituto de Investigação e Inovação em Saúde & Institute of Molecular Pathology and Immunology of the University of Porto, Department of Pathology, University of Porto, Porto, Portugal
| | - Nicola Bougen-Zhukov
- Cancer Genetics Laboratory, Te Aho Matatū, Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Tom Brew
- Cancer Genetics Laboratory, Te Aho Matatū, Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | | | - Patricia Carneiro
- Instituto de Investigação e Inovação em Saúde & Institute of Molecular Pathology and Immunology of the University of Porto, Department of Pathology, University of Porto, Porto, Portugal
| | | | | | - Erin Gardner
- Kimihauora Health and Research Clinic, Mt Maunganui, New Zealand
| | - Tanis D Godwin
- Cancer Genetics Laboratory, Te Aho Matatū, Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Katharine N Holm
- Department of Biochemistry and Molecular Medicine, University of California Davis School Of Medicine, Davis, CA, USA
| | - Bostjan Humar
- Laboratory of the Swiss Hepato-Pancreato-Biliary and Transplantation Centre, Department of Surgery, University Hospital Zürich, Zurich, Switzerland
| | - Caroline J Lintott
- Genetic Health Service New Zealand South Island Hub, Christchurch Hospital, Christchurch, New Zealand
| | | | | | - Enrique Norero
- Esophagogastric Surgery Unit, Digestive Surgery Department, Hospital Dr Sotero del Rio, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Yasmin Nouri
- Cancer Genetics Laboratory, Te Aho Matatū, Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Joana Paredes
- Instituto de Investigação e Inovação em Saúde & Institute of Molecular Pathology and Immunology of the University of Porto, Department of Pathology, University of Porto, Porto, Portugal
| | - João M Sanches
- Institute for Systems and Robotics, Instituto Superior Técnico, Lisbon, Portugal
| | - Emily Schulpen
- Cancer Genetics Laboratory, Te Aho Matatū, Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Ana S Ribeiro
- Instituto de Investigação e Inovação em Saúde & Institute of Molecular Pathology and Immunology of the University of Porto, Department of Pathology, University of Porto, Porto, Portugal
| | - Andrew Sporle
- Healthier Lives National Science Challenge, University of Otago, Dunedin, New Zealand
| | - James Whitworth
- Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
| | - Liying Zhang
- Department of Pathology and Laboratory Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Anthony E Reeve
- Cancer Genetics Laboratory, Te Aho Matatū, Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Parry Guilford
- Cancer Genetics Laboratory, Te Aho Matatū, Department of Biochemistry, University of Otago, Dunedin, New Zealand.
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McGarragle KM, Hart TL, Swallow C, Brar S, Govindarajan A, Cohen Z, Aronson M. Barriers and facilitators to CDH1 carriers contemplating or undergoing prophylactic total gastrectomy. Fam Cancer 2020; 20:157-169. [PMID: 32754788 DOI: 10.1007/s10689-020-00197-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Accepted: 07/25/2020] [Indexed: 12/11/2022]
Abstract
Hereditary diffuse gastric cancer (HDGC) is an inherited cancer syndrome associated with high lifetime risk of diffuse-type gastric cancer. Current guidelines recommend individuals with HDGC undergo prophylactic total gastrectomy (PTG) to eliminate this risk. However, PTG is associated with significant lifestyle changes, post-surgical recovery, and symptom burden. This study examined factors related to decision-making about PTG in three groups of individuals who: (1) underwent PTG immediately after receiving genetic testing results; (2) delayed PTG by ≥ 1 year or; (3) declined PTG. Participants were recruited from a familial gastric cancer registry at a tertiary care hospital. Patients with CDH1 pathogenic or likely pathogenic variants who contemplated and/or underwent PTG were eligible. 24 individuals contemplated PTG: 9 had immediate surgery (within a year), 8 delayed surgery, and 7 declined surgery. Data on PTG barriers and facilitators were obtained on all participants using quantitative surveys (n = 7), qualitative interviews (n = 8) or both methods (n = 9). PTG barriers included age, positive beliefs about screening, close relatives with negative PTG experiences, fertility-related concerns, and life stress. Facilitators included social support, trust in healthcare providers, understanding risk, negative beliefs about screening, family-related factors, positive or abnormal screening results, and positive attitude toward PTG. This study highlights factors related to the PTG decision-making process among individuals with HDGC from three distinct groups. Future research should explore educational interventions aimed at addressing surgery-related concerns and the limitations of screening, and might also consider incorporating close relatives as informational supports.
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Affiliation(s)
- Kaitlin M McGarragle
- Zane Cohen Centre for Digestive Diseases, Sinai Health System, Box 24-60, Murray Street, Toronto, ON, M5T 3L9, Canada
| | - Tae L Hart
- Zane Cohen Centre for Digestive Diseases, Sinai Health System, Box 24-60, Murray Street, Toronto, ON, M5T 3L9, Canada.
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
| | - Carol Swallow
- Zane Cohen Centre for Digestive Diseases, Sinai Health System, Box 24-60, Murray Street, Toronto, ON, M5T 3L9, Canada
- Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Canada
- Department of Surgery, University of Toronto, Toronto, ON, Canada
| | - Savtaj Brar
- Zane Cohen Centre for Digestive Diseases, Sinai Health System, Box 24-60, Murray Street, Toronto, ON, M5T 3L9, Canada
- Department of Surgery, University of Toronto, Toronto, ON, Canada
- Department of Surgery, Mount Sinai Hospital, Toronto, ON, Canada
| | - Anand Govindarajan
- Zane Cohen Centre for Digestive Diseases, Sinai Health System, Box 24-60, Murray Street, Toronto, ON, M5T 3L9, Canada
- Department of Surgery, University of Toronto, Toronto, ON, Canada
- Department of Surgery, Mount Sinai Hospital, Toronto, ON, Canada
| | - Zane Cohen
- Zane Cohen Centre for Digestive Diseases, Sinai Health System, Box 24-60, Murray Street, Toronto, ON, M5T 3L9, Canada
- Department of Surgery, University of Toronto, Toronto, ON, Canada
- Department of Surgery, Mount Sinai Hospital, Toronto, ON, Canada
| | - Melyssa Aronson
- Zane Cohen Centre for Digestive Diseases, Sinai Health System, Box 24-60, Murray Street, Toronto, ON, M5T 3L9, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
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25
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Laszkowska M, Silver ER, Schrope B, Kastrinos F, Wang TC, Hur C. Optimal Timing of Total Gastrectomy to Prevent Diffuse Gastric Cancer in Individuals With Pathogenic Variants in CDH1. Clin Gastroenterol Hepatol 2020; 18:822-829.e4. [PMID: 31220641 DOI: 10.1016/j.cgh.2019.06.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 05/07/2019] [Accepted: 06/07/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Carriers of pathogenic variants in CDH1 have a high risk of hereditary diffuse gastric cancer (HDGC). Guidelines recommend prophylactic total gastrectomy (PTG) at age 20-30 years, although there is controversy over the optimal age. We developed a simulation model to analyze the effects of PTG at different ages on quality-adjusted life-years (QALYs), cancer mortality, and life expectancy. METHODS We used a Markov model of HDGC progression associated with pathogenic variants in CDH1 to simulate outcomes of hypothetical cohorts with different ages at time of PTG (ages 20-79 years). Model inputs including health state transition probabilities, mortality and complication rates, quality of life utility values, and endoscopic surveillance sensitivity were derived from publications. The primary outcome, used to determine the optimal strategy, was age at which PTG yielded the highest QALYs. Secondary outcomes were cancer mortality and unadjusted life-years. RESULTS Our model found that for men, the optimal age for PTG is 39 years, resulting in 32.01 incremental QALYs, 58.81 life-years (biologic age, 72.81 years), and lifetime cancer mortality of 8.5%. Incorporating endoscopic surveillance prior to PTG decreased cancer mortality to 6.7%, but had lower QALYs (31.59). PTG at age 30 reduced cancer mortality to 3.2%, with 31.45 incremental QALYs. For women, the optimal age for PTG was calculated to be 30 years, with 33.09 incremental QALYs, 66.17 life-years (biologic age, 80.17 years), and lifetime cancer mortality of 1.6%. Addition of endoscopic surveillance did not decrease the risk of HDGC mortality in women. CONCLUSIONS Using a Markov model of HDGC progression associated with pathogenic variants in CDH1 to simulate outcomes, we found the optimal ages for PTG to be 39 years for men and 30 years for women, when QALYs are the primary endpoint. These ages for PTG are older than those of current recommendations.
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Affiliation(s)
- Monika Laszkowska
- Department of Medicine, Division of Digestive and Liver Diseases, New York Presbyterian Columbia University Medical Center, New York, New York
| | - Elisabeth R Silver
- Department of Medicine, Division of General Medicine, New York Presbyterian Columbia University Medical Center, New York, New York
| | - Beth Schrope
- Columbia University Irving Cancer Center, New York, New York; Department of Surgery, New York Presbyterian Columbia University Medical Center, New York, New York
| | - Fay Kastrinos
- Department of Medicine, Division of Digestive and Liver Diseases, New York Presbyterian Columbia University Medical Center, New York, New York; Columbia University Irving Cancer Center, New York, New York
| | - Timothy C Wang
- Department of Medicine, Division of Digestive and Liver Diseases, New York Presbyterian Columbia University Medical Center, New York, New York; Columbia University Irving Cancer Center, New York, New York
| | - Chin Hur
- Department of Medicine, Division of Digestive and Liver Diseases, New York Presbyterian Columbia University Medical Center, New York, New York; Department of Medicine, Division of General Medicine, New York Presbyterian Columbia University Medical Center, New York, New York; Columbia University Irving Cancer Center, New York, New York.
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26
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Katona BW, Clark DF, Domchek SM. CDH1 on Multigene Panel Testing: Look Before You Leap. J Natl Cancer Inst 2020; 112:330-334. [PMID: 31841163 PMCID: PMC7156936 DOI: 10.1093/jnci/djz229] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 10/18/2019] [Accepted: 12/10/2019] [Indexed: 02/06/2023] Open
Abstract
Multigene panel testing (MGPT) has become a critical component of cancer risk assessment in clinical practice. As technology and access improve and costs decrease, more individuals than ever are undergoing MGPT for genetic evaluation. One gene that deserves special consideration when included on MGPT is CDH1, which codes for the cell-cell adhesion protein E-cadherin. Pathogenic and likely pathogenic germline variants in CDH1 have been associated with hereditary diffuse gastric cancer syndrome, and in highly penetrant families, testing for these variants is critical for proper risk management. However, recent data demonstrated that gastric cancer penetrance in unselected CDH1 carriers may be lower than expected. Further complicating matters are the lack of effective screening strategies for gastric cancer and recommendation for risk-reducing total gastrectomy in CDH1 carriers. Therefore, the discovery of an unexpected pathogenic or likely pathogenic CDH1 variant on multigene panel testing, when testing for CDH1 would not normally be considered based on personal or family history alone, creates dilemmas for both patients and providers. In this commentary, we highlight the potential for unexpected CDH1 variants on MGPT, outline the uncertainties associated with these variants, and emphasize the importance of pretest counseling regarding the potential for an unexpected CDH1 variant. Although CDH1 testing is often important for clinical decision-making, individuals and providers need to be aware of the potential for an unexpected CDH1 variant when CDH1 is included on MGPT for cancer risk assessment.
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Affiliation(s)
- Bryson W Katona
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Dana Farengo Clark
- Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Susan M Domchek
- Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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27
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Abstract
Germline CDH1 mutation carriers are at risk for early-onset diffuse gastric cancer (DGC) and female carriers have an additional risk of lobular breast cancer. The reported literature GC risk of 70% has led to the recommendation for germline mutation carriers to undergo prophylactic total gastrectomy (PTG). The objective of this research was to examine post-surgical clinical outcomes and to identify which of the domains/symptoms from the European Organisation for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30) were determinants of overall quality of life (QOL) in individuals undergoing PTG. Participants were recruited through multiple sources. Postsurgical clinical outcomes were obtained from hospital records. Participants completed validated questionnaires measuring generic and condition specific QOL (PROMIS, EORTC and SF 36v.II) at a single point in time. The mean QOL in this cohort was 70.6 (SD = 25.6), which is better than reference values from the general populations in USA and Canada Role and social function plus the symptoms anxiety, pain, taste, dyspnea and diarrhea were significant predictor variables for QOL (p < 0.05). Although this study reveals good overall QOL for individuals after PTG, attention should be given to managing symptoms as part of long term care to further enhance QOL. The function/symptom scores were associated with worse overall health and global health status and thus may mark a real need for more attentive post-surgical care.
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28
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Shenoy S. CDH1 (E-Cadherin) Mutation and Gastric Cancer: Genetics, Molecular Mechanisms and Guidelines for Management. Cancer Manag Res 2019; 11:10477-10486. [PMID: 31853199 PMCID: PMC6916690 DOI: 10.2147/cmar.s208818] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Accepted: 12/03/2019] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Germline mutation in CDH1 (E-cadherin) tumor suppressor gene is associated with hereditary diffuse gastric cancer (HDGC) and lobular breast cancers (LBC). E-Cadherin protein is necessary for physiological signaling pathways, such as cell proliferation, maintenance of cell adhesion, cell polarity and epithelial-mesenchymal transition. Dysregulation leads to tumor proliferation, invasion, migration and metastases. We review current perspectives in CDH1 genetics with molecular mechanisms and also discuss management strategies for this aggressive form of gastric cancer. METHODS Relevant articles from PubMed/Medline and Embase (1994-2019) were searched and collected using the phrases "Hereditary diffuse gastric cancer, Familial gastric cancer, CDH1 mutation, E-Cadherin, Lobular breast cancer, Prophylactic total gastrectomy". RESULTS Current guidelines suggest maintaining a high degree of suspicion of hereditary etiology and recommend testing for CDH1 mutations in patients with familial clustering of HDGC and LBC, especially onset at an early age (before 40 years). In families lacking CDH1 mutations but with high suspicion for hereditary predisposition, testing of CTNNA1 and other closely related HDGC susceptibility genes could be considered. Prophylactic total gastrectomy is recommended for individuals with identified pathogenic germline variants. Endoscopic surveillance with biopsies is recommended for those choosing to delay prophylactic gastrectomy. CONCLUSION Mutation or transcriptional silencing of the CDH1 gene is associated with familial diffuse gastric cancer. Further studies on the expression and the alteration in the proteins in the E-cadherin pathways may serve as biomarkers for early detection; stratify risk and selection of appropriate therapy in these families. Until then prophylactic total gastrectomy is recommended for individuals with CDH1 mutations and family history of diffuse gastric cancer. Endoscopic surveillance and biopsies by experienced gastroenterologists is recommended for those choosing not to have prophylactic gastrectomy and in individuals with CDH1 variants.
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Affiliation(s)
- Santosh Shenoy
- Clinical Associate Professor of Surgery, Department of Surgery, Kansas City VA Medical Center, University of Missouri Kansas City, Kansas City, MO 64128, USA and Cancer Biology and Therapeutics, HMS High-Impact Cancer Research (HI-CR) Program, Harvard Medical School 2018–2019, Boston, MA02115, USA
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29
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Hamilton JG, Long JM, Brandt AC, Brower J, Symecko H, Salo-Mullen EE, Christian SN, Harstad T, Couch FJ, Garber JE, Offit K, Robson ME, Domchek SM. Patients' Medical and Psychosocial Experiences After Detection of a CDH1 Variant With Multigene Panel Testing. JCO Precis Oncol 2019; 3:PO.18.00300. [PMID: 31511843 PMCID: PMC6738946 DOI: 10.1200/po.18.00300] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/19/2018] [Indexed: 12/23/2022] Open
Abstract
PURPOSE Germline CDH1 pathogenic variants (PV) are associated with hereditary diffuse gastric cancer and lobular breast cancer. Although prevalence of CDH1 PV is low in the general population, detection of these variants is increasing with the growing use of multigene panel testing. Little is known about the experiences of individuals tested for CDH1 variants in the multigene panel testing era. METHODS Participants recruited from the Prospective Registry of Multiplex Testing completed a cross-sectional self-report survey regarding CDH1 genetic testing experiences, medical management, and psychosocial adaptation. RESULTS Discordance existed in interpretations of CDH1 results; 13.3% of cases had disagreements in variant classifications among commercial laboratories, and 21.4% had disagreements between participant self-report and ClinVar classification. Survey data were available from 57 individuals reporting either PV (n = 16) or variants of uncertain significance (VUS; n = 41). Those with PV were more likely than those with VUS to report receiving a recommendation for prophylactic gastrectomy, although only 40.0% of those with PV received this recommendation. Participants with VUS were less satisfied with their health care providers' knowledge and reported less CDH1 knowledge, distress, and worry about discrimination. Participants with PV perceived greater breast cancer risks, but similar gastric cancer risks, as those with VUS. CONCLUSION Few individuals with CDH1 PV report receiving recommendations for prophylactic gastrectomy, and no differences in perceived gastric cancer risk were observed based on participants' CDH1 results, suggesting serious unmet informational needs.
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Affiliation(s)
- Jada G. Hamilton
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | | | | | | | | | | | | | | | | | | | - Kenneth Offit
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
| | - Mark E. Robson
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medical College, New York, NY
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30
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Rocha JP, Gullo I, Wen X, Devezas V, Baptista M, Oliveira C, Carneiro F. Pathological features of total gastrectomy specimens from asymptomatic hereditary diffuse gastric cancer patients and implications for clinical management. Histopathology 2018; 73:878-886. [PMID: 30014492 DOI: 10.1111/his.13715] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 07/15/2018] [Indexed: 12/13/2022]
Abstract
Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant syndrome characterised by multigenerational diffuse gastric cancer, and is mainly caused by germline alterations in the CDH1 gene. Currently, endoscopy has limited diagnostic accuracy, and total gastrectomy (TG) is the treatment of choice for asymptomatic CDH1 carriers. In this study, we aimed to obtain a better understanding of HDGC syndrome by exploring the histopathological findings of TG specimens from asymptomatic HDGC patients. A comprehensive literature review was carried out, searching for TGs performed in asymptomatic HDGC patients. Fourteen unpublished cases, analysed in our institution, were also included. The series encompassed 174 CDH1 carriers. Preoperative endoscopic biopsies were positive in 28.3%. A macroscopic lesion was apparent in 11.7% of TGs. Histopathological analysis revealed intraepithelial lesions and/or intramucosal signet ring cell carcinoma in 87.9% of TGs. When we explored the type of protocol used for handling the specimens, we found that microscopic cancer foci were detected in 95.3% of TGs when a total-embedding protocol (assessment of the totality of gastric mucosa) was applied, and only in 62.5% when no specific protocol was used (P < 0.001). Helicobacter pylori infection was found in 23.4% cases. In conclusion, a thorough histopathological examination of gastric mucosa remains the gold standard for detection of cancer foci in HDGC gastrectomy specimens, requiring experienced pathologists for an accurate diagnosis. A better understanding of the natural history of HDGC will enable better clinical management of HDGC patients, particularly regarding the optimal timing for the performance of TG.
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Affiliation(s)
- João P Rocha
- Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
| | - Irene Gullo
- Department of Pathology, Centro Hospitalar de São João (CHSJ), Porto, Portugal.,Department of Pathology, FMUP, Porto, Portugal.,Institute of Molecular Pathology and Immunology at the University of Porto (Ipatimup), Porto, Portugal.,Institute for Research Innovation in Health (i3S), University of Porto, Porto, Portugal
| | - Xiaogang Wen
- Institute of Molecular Pathology and Immunology at the University of Porto (Ipatimup), Porto, Portugal.,Institute for Research Innovation in Health (i3S), University of Porto, Porto, Portugal.,Department of Pathology, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal
| | - Vítor Devezas
- Department of General Surgery, CHSJ, Porto, Portugal.,Department of General Surgery, FMUP, Porto, Portugal.,General Surgery, High Risk Consultation of Digestive Tumours, CHSJ, Porto, Portugal
| | - Manuela Baptista
- Department of General Surgery, CHSJ, Porto, Portugal.,Department of General Surgery, FMUP, Porto, Portugal.,General Surgery, High Risk Consultation of Digestive Tumours, CHSJ, Porto, Portugal
| | - Carla Oliveira
- Department of Pathology, FMUP, Porto, Portugal.,Institute of Molecular Pathology and Immunology at the University of Porto (Ipatimup), Porto, Portugal.,Institute for Research Innovation in Health (i3S), University of Porto, Porto, Portugal
| | - Fátima Carneiro
- Department of Pathology, Centro Hospitalar de São João (CHSJ), Porto, Portugal.,Department of Pathology, FMUP, Porto, Portugal.,Institute of Molecular Pathology and Immunology at the University of Porto (Ipatimup), Porto, Portugal.,Institute for Research Innovation in Health (i3S), University of Porto, Porto, Portugal
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Chiu CC, Lee KT, Lee HH, Wang JJ, Sun DP, Huang CC, Shi HY. Comparison of Models for Predicting Quality of Life After Surgical Resection of Hepatocellular Carcinoma: a Prospective Study. J Gastrointest Surg 2018; 22:1724-1731. [PMID: 29916106 DOI: 10.1007/s11605-018-3833-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 05/31/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND The essential issue of internal validity has not been adequately addressed in prediction models such as artificial neural network (ANN), support vector machine (SVM), Gaussian process regression (GPR), and multiple linear regression (MLR) models. METHODS This prospective study compared the accuracy of these four models in predicting quality of life (QOL) after hepatic resection received by 332 patients with hepatocellular carcinoma (HCC) during 2012-2015. An estimation subset was used to train the models, and a validation subset was used to evaluate their performance. Sensitivity score approach was also used to assess the relative significance of input parameters in the system models. RESULTS The ANN model had significantly higher performance indicators compared to the SVM, GPR, and MLR models (P < 0.05). Additionally, the ANN prediction of QOL at 6 months after hepatic resection significantly correlated with age, gender, marital status, Charlson comorbidity index (CCI) score, chemotherapy, radiotherapy, hospital volume, surgeon volume, and preoperational functional status (P < 0.05). Preoperational functional status was the most influential (sensitive) variable affecting sixth-month QOL followed by surgeon volume, hospital volume, age, and CCI score. CONCLUSIONS The comparisons showed that, in preoperative and postoperative healthcare consultations with HCC surgery candidates, QOL at 6 months post-surgery should be estimated with an ANN model rather than with SVM, GPR, or MLR models. The best QOL predictors identified in this study can also be used to educate candidates for HCC surgery in the expected course of recovery and other surgical outcomes.
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Affiliation(s)
- Chong-Chi Chiu
- Department of General Surgery, Chi Mei Medical Center, Liouying, Taiwan
- Department of General Surgery, Chi Mei Medical Center, Tainan, Taiwan
- Department of Electrical Engineering, Southern Taiwan University of Science and Technology, Tainan, Taiwan
| | - King-Teh Lee
- Division of Hepatobiliary Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical University, 100, Zihyou 1st Road, Kaohsiung, 807, Taiwan
| | - Hao-Hsien Lee
- Department of General Surgery, Chi Mei Medical Center, Liouying, Taiwan
| | - Jhi-Joung Wang
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
| | - Ding-Ping Sun
- Department of General Surgery, Chi Mei Medical Center, Tainan, Taiwan
| | - Chien-Cheng Huang
- Department of Emergency Medicine, Chi Mei Medical Center, Tainan, Taiwan
- Bachelor Program of Senior Service, Southern Taiwan University of Science and Technology, Tainan, Taiwan
| | - Hon-Yi Shi
- Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical University, 100, Zihyou 1st Road, Kaohsiung, 807, Taiwan.
- Department of Business Management, National Sun Yat-sen University, Kaohsiung, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
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32
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Krempely K, Karam R. A novel de novo CDH1 germline variant aids in the classification of carboxy-terminal E-cadherin alterations predicted to escape nonsense-mediated mRNA decay. Cold Spring Harb Mol Case Stud 2018; 4:mcs.a003012. [PMID: 29798843 PMCID: PMC6071572 DOI: 10.1101/mcs.a003012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 05/16/2018] [Indexed: 12/30/2022] Open
Abstract
Most truncating cadherin 1 (CDH1) pathogenic alterations confer an elevated lifetime risk of diffuse gastric cancer (DGC) and lobular breast cancer (LBC). However, transcripts containing carboxy-terminal premature stop codons have been demonstrated to escape the nonsense-mediated mRNA decay pathway, and gastric and breast cancer risks associated with these truncations should be carefully evaluated. A female patient underwent multigene panel testing because of a personal history of invasive LBC diagnosed at age 54, which identified the germline CDH1 nonsense alteration, c.2506G>T (p.Glu836*), in the last exon of the gene. Subsequent parental testing for the alteration was negative and additional short tandem repeat analysis confirmed the familial relationships and the de novo occurrence in the proband. Based on the de novo occurrence, clinical history, and rarity in general population databases, this alteration was classified as a likely pathogenic variant. This is the most carboxy-terminal pathogenic alteration reported to date. Additionally, this alteration contributed to the classification of six other upstream CDH1 carboxy-terminal truncating variants as pathogenic or likely pathogenic. Identifying the most distal pathogenic alteration provides evidence to classify other carboxy-terminal truncating variants as either pathogenic or benign, a fundamental step to offering presymptomatic screening and prophylactic procedures to the appropriate patients.
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Affiliation(s)
| | - Rachid Karam
- Ambry Genetics, Aliso Viejo, California 92656, USA
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Altman AM, Hui JYC, Tuttle TM. Quality-of-life implications of risk-reducing cancer surgery. Br J Surg 2018; 105:e121-e130. [DOI: 10.1002/bjs.10725] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 09/04/2017] [Indexed: 01/15/2023]
Abstract
Abstract
Background
Modern advances in genetic sequencing techniques have allowed for increased availability of genetic testing for hereditary cancer syndromes. Consequently, more people are being identified as mutation carriers and becoming aware of their increased risk of malignancy. Testing is commonplace for many inheritable cancer syndromes, and with that comes the knowledge of being a gene carrier for some patients. With increased risk of malignancy, many guidelines recommend that gene carriers partake in risk reduction strategies, including risk-reducing surgery for some syndromes. This review explores the quality-of-life consequences of genetic testing and risk-reducing surgery.
Methods
A narrative review of PubMed/MEDLINE was performed, focusing on the health-related quality-of-life implications of surgery for hereditary breast and ovarian cancer, familial adenomatous polyposis and hereditary diffuse gastric cancer.
Results
Risk-reducing surgery almost uniformly decreases cancer anxiety and affects patients' quality of life.
Conclusion
Although the overwhelming quality-of-life implications of surgery are neutral to positive, risk-reducing surgery is irreversible and can be associated with short- and long-term side-effects.
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Affiliation(s)
- A M Altman
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - J Y C Hui
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - T M Tuttle
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
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Roberts G, Hardwick R, Fitzgerald RC. Decision making, quality of life and prophylactic gastrectomy in carriers of pathogenic CDH1 mutations. Transl Gastroenterol Hepatol 2017; 2:21. [PMID: 28447056 PMCID: PMC5388634 DOI: 10.21037/tgh.2017.03.12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 03/10/2017] [Indexed: 12/15/2022] Open
Affiliation(s)
- Geoffrey Roberts
- Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
- Cambridge Oesophago-Gastric Centre, Addenbrooke’s Hospital, Cambridge, UK
| | - Richard Hardwick
- Cambridge Oesophago-Gastric Centre, Addenbrooke’s Hospital, Cambridge, UK
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