Recurrent giant neobladder calculus extrusion after bladder exstrophy repair.

Introduction: Patients with bladder exstrophy subjected to reconstructive surgeries are at risk of developing urinary calculus. Case presentation: We report the case of a 29-year-old male patient with bladder exstrophy who presented with a recurrent episode of extrusion of calculus through the neobladder and anterior abdominal wall. Calculus removal and reconstructive repair of the neobladder and abdominal wall were performed in 2010. Nine years following the procedure, the patient returned with new large neobladder calculus extrusion. Conclusion: Recurrence of large calculus should be seen as the new paradigm for the importance of close follow-up in bladder exstrophy patients.

An Extremely Rare and Demanding Diagnosis of Primary Renal Synovial Sarcoma: A Case Report.

Primary renal synovial sarcoma (PRSS) is an extremely rare malignancy. The diagnosis of PRSS is unforeseen due to the absence of clinical and radiological typical aspects. Here, we present a case of a 69-year-old male with complaints of hematuria and left lumbar pain. Abdominal-pelvic computed tomography scan with contrast injection showed a solid mass of 8cm diameter in the left kidney and renal vein tumor thrombus. The patient was further subjected to robotic-assisted left radical nephrectomy and renal vein thrombectomy. We concomitantly performed left adrenalectomy and paraaortic lymphadenectomy. Immunohistochemical and genetic analysis revealed PRSS. This entity is characterized by abnormal chromosomal translocation t(X;18)(p11.2; q11.2) and consequently the characteristic SYT-SSX fusion gene. Due to the disease's rarity and severity, diagnosis and management of PRSS rely upon a demanding and multidisciplinary approach.

Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes.

BACKGROUND: Truncating pathogenic or likely pathogenic variants of CDH1 cause hereditary diffuse gastric cancer (HDGC), a tumour risk syndrome that predisposes carrier individuals to diffuse gastric and lobular breast cancer. Rare CDH1 missense variants are often classified as variants of unknown significance. We conducted a genotype-phenotype analysis in families carrying rare CDH1 variants, comparing cancer spectrum in carriers of pathogenic or likely pathogenic variants (PV/LPV; analysed jointly) or missense variants of unknown significance, assessing the frequency of families with lobular breast cancer among PV/LPV carrier families, and testing the performance of lobular breast cancer-expanded criteria for CDH1 testing. METHODS: This genotype-first study used retrospective diagnostic and clinical data from 854 carriers of 398 rare CDH1 variants and 1021 relatives, irrespective of HDGC clinical criteria, from 29 institutions in ten member-countries of the European Reference Network on Tumour Risk Syndromes (ERN GENTURIS). Data were collected from Oct 1, 2018, to Sept 20, 2022. Variants were classified by molecular type and clinical actionability with the American College of Medical Genetics and Association for Molecular Pathology CDH1 guidelines (version 2). Families were categorised by whether they fulfilled the 2015 and 2020 HDGC clinical criteria. Genotype-phenotype associations were analysed by Student's t test, Kruskal-Wallis, χ2, and multivariable logistic regression models. Performance of HDGC clinical criteria sets were assessed with an equivalence test and Youden index, and the areas under the receiver operating characteristic curves were compared by Z test. FINDINGS: From 1971 phenotypes (contributed by 854 probands and 1021 relatives aged 1-93 years), 460 had gastric and breast cancer histology available. CDH1 truncating PV/LPVs occurred in 176 (21%) of 854 families and missense variants of unknown significance in 169 (20%) families. Multivariable logistic regression comparing phenotypes occurring in families carrying PV/LPVs or missense variants of unknown significance showed that lobular breast cancer had the greatest positive association with the presence of PV/LPVs (odds ratio 12·39 [95% CI 2·66-57·74], p=0·0014), followed by diffuse gastric cancer (8·00 [2·18-29·39], p=0·0017) and gastric cancer (7·81 [2·03-29·96], p=0·0027). 136 (77%) of 176 families carrying PV/LPVs fulfilled the 2015 HDGC criteria. Of the remaining 40 (23%) families, who did not fulfil the 2015 criteria, 11 fulfilled the 2020 HDGC criteria, and 18 had lobular breast cancer only or lobular breast cancer and gastric cancer, but did not meet the 2020 criteria. No specific CDH1 variant was found to predispose individuals specifically to lobular breast cancer, although 12 (7%) of 176 PV/LPV carrier families had lobular breast cancer only. Addition of three new lobular breast cancer-centred criteria improved testing sensitivity while retaining high specificity. The probability of finding CDH1 PV/LPVs in patients fulfilling the lobular breast cancer-expanded criteria, compared with the 2020 criteria, increased significantly (AUC 0·92 vs 0·88; Z score 3·54; p=0·0004). INTERPRETATION: CDH1 PV/LPVs were positively associated with HDGC-related phenotypes (lobular breast cancer, diffuse gastric cancer, and gastric cancer), and no evidence for a positive association with these phenotypes was found for CDH1 missense variants of unknown significance. CDH1 PV/LPVs occurred often in families with lobular breast cancer who did not fulfil the 2020 HDGC criteria, supporting the expansion of lobular breast cancer-centred criteria. FUNDING: European Reference Network on Genetic Tumour Risk Syndromes, European Regional Development Fund, Fundação para a Ciência e a Tecnologia (Portugal), Cancer Research UK, and European Union's Horizon 2020 research and innovation programme.

An Unexpected and Unpredictable Emergence of Muscle-Invasive Bladder Cancer in a Patient Successfully Treated With Nivolumab for Small-Cell Bladder Cancer.

Small-cell bladder cancer (SCBC) is a rare subtype of bladder cancer with aggressive behavior and poor prognosis. Here, we report the case of a 50-year-old man who presented with hematuria for one month. A computed tomography scan showed an exophytic lesion on the right posterolateral wall of the bladder and a single liver metastasis with a 14 mm diameter. Transurethral resection of the bladder tumor was performed, and postoperative examination of the specimen showed muscle-invasive SCBC. Initially, the patient was treated with neoadjuvant chemotherapy. Rapid clinical and imaging deterioration was observed after the premature end of cisplatin and etoposide therapy. Second-line therapy with nivolumab demonstrated systemic and local complete response. However, the patient was further diagnosed with unpredictable and unexpected urothelial muscle-invasive bladder cancer. After 76 months of regular follow-up, imaging workup did not demonstrate SCBC recurrence or urothelial bladder cancer progression. This report highlights this disease's rarity and severity and no typical or even pathognomonic clinical and radiological presentation. Therefore, histopathology and immunohistochemistry findings play a key role in diagnosis. Immunotherapy has opened a new window in cancer treatment and maybe SCBC patients can benefit from it.

The Identification of Large Rearrangements Involving Intron 2 of the CDH1 Gene in BRCA1/2 Negative and Breast Cancer Susceptibility.

E-cadherin, a CDH1 gene product, is a calcium-dependent cell-cell adhesion molecule playing a critical role in the establishment of epithelial architecture, maintenance of cell polarity, and differentiation. Germline pathogenic variants in the CDH1 gene are associated with hereditary diffuse gastric cancer (HDGC), and large rearrangements in the CDH1 gene are now being reported as well. Because CDH1 pathogenic variants could be associated with breast cancer (BC) susceptibility, CDH1 rearrangements could also impact it. The aim of our study is to identify rearrangements in the CDH1 gene in 148 BC cases with no BRCA1 and BRCA2 pathogenic variants. To do so, a zoom-in CGH array, covering the exonic, intronic, and flanking regions of the CDH1 gene, was used to screen our cohort. Intron 2 of the CDH1 gene was specifically targeted because it is largely reported to include several regulatory regions. As results, we detected one large rearrangement causing a premature stop in exon 3 of the CDH1 gene in a proband with a bilateral lobular breast carcinoma and a gastric carcinoma (GC). Two large rearrangements in the intron 2, a deletion and a duplication, were also reported only with BC cases without any familial history of GC. No germline rearrangements in the CDH1 coding region were detected in those families without GC and with a broad range of BC susceptibility. This study confirms the diversity of large rearrangements in the CDH1 gene. The rearrangements identified in intron 2 highlight the putative role of this intron in CDH1 regulation and alternative transcripts. Recurrent duplication copy number variations (CNV) are found in this region, and the deletion encompasses an alternative CDH1 transcript. Screening for large rearrangements in the CDH1 gene could be important for genetic testing of BC.

Magnetic resonance imaging target fusion biopsy vs. transrectal ultrasound-guided biopsy - A comparative study of ISUP score upgrading risk in the final radical prostatectomy specimen.

OBJECTIVES: The aim of this study was to com-pare the risk of International Society of Urological Pathology (ISUP) score upgrading between magnetic resonance imaging targeted fusion biopsy (MRI-TB) and tran-srectal ultrasound-guided biopsy (TRUS-B) in the final radical prostatectomy (RP) specimen pathological report. MATERIALS AND METHODS: This retrospective single center study included 51 patients with prostate cancer (PCa) diagnosed with MRI-TB and 83 patients diagnosed with TRUS-B between October/2019 and July/2021. We compared the rates of ISUP score upgrading between both groups after robotic-assisted radi-cal prostatectomy (RARP) and the specific transition of each ISUP score based on biopsy modality. The rate of ISUP score concordance and downgrading were also assessed. To define the intra and interobserver concordance for each ISUP score in biopsy and RP specimen for each biopsy modality, the Cohen's Kappa coefficient was calculated. ISUP scores and biopsy modal-ity were selected for multivariate analysis and a logistic regres-sion model was built to provide independent risk factors of ISUP score upgrading. RESULTS: The difference of the rate of upgrading between MRI-TB group and TRUS-B group was statistically significant (p = 0.007) with 42.2% of patients of TRUS-B group experiencing an upgrade in their ISUP score while only 19.6% in MRI-TB group. Concordance and downgrading rates did not statistically differ between the two groups. Strength of concordance using Cohen's Kappa coefficient was fair in both groups but higher in MRI-TB group (TRUS-B group k = 0.230; p < 0.001; concordance: 47%vs. MRI/TB group k = 0.438; p < 0.001; concordance: 62.7%). Biopsy modality and ISUP 1 on biopsy were independent predic-tors of ISUP upgrading after RP. CONCLUSIONS: MRI-TB is highly accurate with lower risk of PCa upgrading after RP than TRUS-B. Patients with ISUP 1 on biopsy have greater susceptibility to upgrading their ISUP score.

The CDH1 c.1901C>T Variant: A Founder Variant in the Portuguese Population with Severe Impact in mRNA Splicing.

Hereditary diffuse gastric cancer (HDGC) caused by CDH1 variants predisposes to early-onset diffuse gastric (DGC) and lobular breast cancer (LBC). In Northern Portugal, the unusually high number of HDGC cases in unrelated families carrying the c.1901C>T variant (formerly known as p.A634V) suggested this as a CDH1-founder variant. We aimed to demonstrate that c.1901C>T is a bona fide truncating variant inducing cryptic splicing, to calculate the timing of a potential founder effect, and to characterize tumour spectrum and age of onset in carrying families. The impact in splicing was proven by using carriers' RNA for PCR-cloning sequencing and allelic expression imbalance analysis with SNaPshot. Carriers and noncarriers were haplotyped for 12 polymorphic markers, and the decay of haplotype sharing (DHS) method was used to estimate the time to the most common ancestor of c.1901C>T. Clinical information from 58 carriers was collected and analysed. We validated the cryptic splice site within CDH1-exon 12, which was preferred over the canonical one in 100% of sequenced clones. Cryptic splicing induced an out-of-frame 37bp deletion in exon 12, premature truncation (p.Ala634ProfsTer7), and consequently RNA mediated decay. The haplotypes carrying the c.1901C>T variant were found to share a common ancestral estimated at 490 years (95% Confidence Interval 445-10,900). Among 58 carriers (27 males (M)-31 females (F); 13-83 years), DGC occurred in 11 (18.9%; 4M-7F; average age 33 ± 12) and LBC in 6 females (19.4%; average age 50 ± 8). Herein, we demonstrated that the c.1901C>T variant is a loss-of-function splice-site variant that underlies the first CDH1-founder effect in Portugal. Knowledge on this founder effect will drive genetic testing of this specific variant in HDGC families in this geographical region and allow intrafamilial penetrance analysis and better estimation of variant-associated tumour risks, disease age of onset, and spectrum.

Redefinition of familial intestinal gastric cancer: clinical and genetic perspectives.

BACKGROUND: Familial intestinal gastric cancer (FIGC) remains genetically unexplained and without testing/clinical criteria. Herein, we characterised the age of onset and disease spectrum of 50 FIGC families and searched for genetic causes potentially underlying a monogenic or an oligogenic/polygenic inheritance pattern. METHODS: Normal and tumour DNA from 50 FIGC probands were sequenced using Illumina custom panels on MiSeq, and their respective germline and somatic landscapes were compared with corresponding landscapes from sporadic intestinal gastric cancer (SIGC) and hereditary diffuse gastric cancer cohorts. RESULTS: The most prevalent phenotype in FIGC families was gastric cancer, detected in 138 of 208 patients (50 intestinal gastric cancer probands and 88 unknown gastric cancer histology relatives), followed by colorectal and breast cancers. After excluding benign and intronic variants lacking impact in splicing, 12 rare high-quality variants were found exclusively in 11 FIGC probands. Only two probands carried potentially deleterious variants, but lacked somatic second-hits, weakly supporting the monogenic hypothesis for FIGC. However, FIGC probands developed gastric cancer at least 10 years earlier and carried more TP53 germline common variants than SIGC (p=4.5E-03); FIGC and SIGC could be distinguished by specific germline and somatic variant profiles; there was an excess of FIGC tumours presenting microsatellite instability (38%); and FIGC tumours displayed significantly more somatic common variants than SIGC tumours (p=4.2E-06). CONCLUSION: This study proposed the first data-driven testing criteria for FIGC families, and supported FIGC as a genetically determined, likely polygenic, gastric cancer-predisposing disease, with earlier onset and distinct from patients with SIGC at the germline and somatic levels.

Tecnologias educativas direcionadas à cardiopatas / Educational technologies for cardiopathy / Tecnologías educativas dirigidas a las cardiopatas

Objetivo: identificar as tecnologias utilizadas por enfermeiros no processo educativo de pessoas com cardiopatia no ambiente hospitalar. Método: trata-se de uma revisão integrativa realizada nas bases de dados virtuais Pubmed, Scielo e Lilacs. Foram selecionados dez publicações e ao final, foi realizado uma análise dos estudos selecionados a fim de identificar sua relevância e aplicabilidade. Resultados: verifica-se a grande diversidade de tecnologias elaboradas e implementadas, variando entre programas educativos com a utilização de vídeos, questionários e instrumentos, programas de rastreamento, de acompanhamento após alta hospitalar, encontros grupais e momentos educativos direcionados aos pacientes no ambiente da pesquisa. Conclusão: foi identificado uma grande variedade de tecnologias utilizadas por enfermeiros no processo educativo de pessoas com cardiopatia no ambiente hospitalar, o que contribui para diminuição do tempo de internação hospitalar, menores índices de reinternações e reincidências por Doenças Cardiovasculares, atuando ainda na reabilitação cardiovascular do paciente

Objective: to identify the technologies used by nurses in the educational process of people with heart disease in the hospital environment. Method: it is an integrative review carried out in the virtual databases Pubmed, Scielo and Lilacs. Ten publications were selected and at the end, an analysis of the selected studies was carried out to identify their relevance and applicability. Results: there is a great diversity of technologies developed and implemented, varying between educational programs with the use of videos, questionnaires and instruments, tracking programs, follow-up after hospital discharge, group meetings and educational moments directed to patients in the research environment. Conclusion: a great variety of technologies used by nurses in the educational process of people with cardiopathy in the hospital environment was identified, which contributes to a reduction in hospitalization time, lower readmissions and recidivism rates for Cardiovascular Diseases, and also to cardiovascular rehabilitation patient

Objetivo: identificar las tecnologías utilizadas por enfermeros en el proceso educativo de personas con cardiopatía en el ambiente hospitalario. Método: se trata de una revisión integrativa realizada en las bases de datos virtuales Pubmed, Scielo y Lilacs. Se seleccionaron diez publicaciones y al final se realizó un análisis de los estudios seleccionados para identificar su relevancia y aplicabilidad. Resultados: se verifica la gran diversidad de tecnologías elaboradas e implementadas, variando entre programas educativos con la utilización de videos, cuestionarios e instrumentos, programas de rastreo, de seguimiento tras alta hospitalaria, encuentros grupales y momentos educativos dirigidos a los pacientes en el ambiente de la investigación. Conclusión: se identificó una gran variedad de tecnologías utilizadas por enfermeros en el proceso educativo de personas con cardiopatía en el ambiente hospitalario, lo que contribuye a disminuir el tiempo de internación hospitalaria, menores índices de reinternaciones y reincidencias por Enfermedades Cardiovasculares, actuando aún en la rehabilitación cardiovascular del paciente paciente

CDH1 somatic alterations in Mexican patients with diffuse and mixed sporadic gastric cancer.

BACKGROUND: Diffuse gastric cancer (DGC) is associated with the reduction or absence of the expression of the cell adhesion protein E-cadherin (encoded by the CDH1 gene). Molecular characteristics are less well described for mixed gastric cancer (MGC). The main somatic alterations that have been described in the CDH1 gene are mutations, loss of heterozygosity (LOH) and promoter methylation. The aim was to analyze CDH1 somatic alterations in Mexican patients with diffuse and mixed gastric cancer. METHODS: We searched for mutations in the CDH1 gene in tumor DNA from DGC (n = 13) and MGC (n = 7) patients by next generation sequencing (NGS). Validation of findings was performed using Sanger sequencing. LOH was analyzed using dinucleotide repeat markers surrounding the CDH1 gene, and methylation was investigated by DNA bisulfite conversion and sequencing. E-cadherin protein deficiency was analyzed by immunohistochemistry. RESULTS: Seventeen point variants were identified by NGS, 13 of them were validated by Sanger sequencing. Only 1/13 had not been previously reported (c.-137C > A), and 12/13 were already reported as polymorphisms. Two DGC cases presented LOH at the locus 16q22.1 (13.3%). CDH1 promoter methylation was positive in (7/11) 63.6% and (4/6) 66.6% of the cases with DGC and MGC, respectively. E-cadherin protein deficiency was observed in 58.3% of DGC cases while 100% in MGC cases. CONCLUSIONS: While no pathogenic somatic mutations were found that could explain the diffuse histology of gastric cancer in DGC and MGC, methylation was the most common somatic inactivation event of the CDH1 gene, and LOH was rare. The previously unreported c.-137C > A variant modify the CDH1 gene expression since it alters the binding sites for transcription factors.

New insights into the inflamed tumor immune microenvironment of gastric cancer with lymphoid stroma: from morphology and digital analysis to gene expression.

BACKGROUND: Gastric cancer with lymphoid stroma (GCLS) is characterized by prominent stromal infiltration of T-lymphocytes. The aim of this study was to investigate GCLS biology through analysis of clinicopathological features, EBV infection, microsatellite instability (MSI), immune gene-expression profiling and PD-L1 status in neoplastic cells and tumor immune microenvironment. METHODS: Twenty-four GCLSs were analyzed by RNA in situ hybridization for EBV (EBER), PCR/fragment analysis for MSI, immunohistochemistry (PD-L1, cytokeratin, CD3, CD8), co-immunofluorescence (CK/PD-L1, CD68/PD-L1), NanoString gene-expression assay for immune-related genes and PD-L1 copy number alterations. CD3+ and CD8+ T-cell densities were calculated by digital analysis. Fifty-four non-GCLSs were used as control group. RESULTS: GCLSs displayed distinctive clinicopathological features, such as lower pTNM stage (p = 0.02) and better overall survival (p = 0.01). EBV+ or MSI-high phenotype was found in 66.7 and 16.7% cases, respectively. GCLSs harbored a cytotoxic T-cell-inflamed profile, particularly at the invasive front of tumors (p < 0.01) and in EBV+ cases (p = 0.01). EBV+ GCLSs, when compared to EBV- GCLSs, showed higher mRNA expression of genes related to Th1/cytotoxic and immunosuppressive biomarkers. PD-L1 protein expression, observed in neoplastic and immune stromal cells (33.3 and 91.7%, respectively), and PD-L1 amplification (18.8%) were restricted to EBV+/MSI-high tumors and correlated with high values of PD-L1 mRNA expression. CONCLUSIONS: This study shows that GCLS has a distinctive clinico-pathological and molecular profile. Furthermore, through an in-depth study of tumor immune microenvironment-by digital analysis and mRNA expression profiling-it highlights the role of EBV infection in promoting an inflamed tumor microenvironment, with putative therapeutic implications.

Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing.

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.

The Use of Apnea During Ureteroscopy.

OBJECTIVE: To describe and discuss the feasibility and the use of apnea during retrograde intrarenal surgery (RIRS). MATERIALS AND METHODS: A discussion of the current literature about the different anesthesia techniques and the use of apnea to improve RIRS by avoiding renal movements over diaphragmatic excursion was performed. RESULTS: To date, there are no mentions in the literature about the use of apnea as a mechanism to facilitate this procedure that requires extremely precise laser use. A description of the feasibility of apnea during RIRS is described as a technical consideration and discussed. CONCLUSION: The use of apnea during RIRS has facilitated the procedure, avoiding renal movements, particularly in special cases where extremely precise maneuvers during laser use are required.

KRAS mutations in microsatellite instable gastric tumours: impact of targeted treatment and intratumoural heterogeneity.

In gastric cancer (GC), epidermal growth factor receptor (EGFR) overexpression associates with poor prognosis. Addition of a chimeric monoclonal antibody against EGFR (cetuximab) to first-line treatment of metastatic colorectal tumours improved outcomes of patients (stratified for KRAS wild-type cancers), whereas GC patients did not benefit from this approach. In GC, however, stratification based on KRAS mutations was not performed, and the 30 % KRAS mutation frequency in microsatellite instable cancers (MSI), which represents ∼4 % of total GC, was disregarded. Further, intratumoural heterogeneity regarding KRAS mutant subpopulations might also contribute to anti-EGFR therapy failure. We assessed the mutational status of the entire KRAS coding sequence in 19 MSI-GC cases by multiplex PCR/sequencing and used peak height ratio determined from electropherograms from KRAS heterozygous mutants and histopathological evaluation to infer tumour heterogeneity in GC. Using 2 multiplex reactions per sample, we found that 26 % (5/19) of MSI-GC cases harboured KRAS mutations (2 G12D, 2 G13D, 1 G12V). No mutations were found outside the codon 12 and 13 hotspots. Our analysis supported the co-existence of KRAS-positive and KRAS-negative tumour populations in 4/5 MSI-GC cases. In conclusion, the method developed stands as a cost-effective and practical way for mutation screening of the entire KRAS coding sequence. KRAS mutations are frequent in our series of MSI cases and are often found in a subpopulation of the tumour and not in the whole tumour. Further studies are needed to access the implications of this heterogeneity in KRAS mutant and wild-type tumour clones in anti-EGFR therapy response.

Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond.

IMPORTANCE: E-cadherin (CDH1) is a cancer predisposition gene mutated in families meeting clinically defined hereditary diffuse gastric cancer (HDGC). Reliable estimates of cancer risk and spectrum in germline mutation carriers are essential for management. For families without CDH1 mutations, genetic-based risk stratification has not been possible, resulting in limited clinical options. OBJECTIVES: To derive accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and determine if germline mutations in other genes are associated with HDGC. DESIGN, SETTING, AND PARTICIPANTS: Testing for CDH1 germline mutations was performed on 183 index cases meeting clinical criteria for HDGC. Penetrance was derived from 75 mutation-positive families from within this and other cohorts, comprising 3858 probands (353 with gastric cancer and 89 with breast cancer). Germline DNA from 144 HDGC probands lacking CDH1 mutations was screened using multiplexed targeted sequencing for 55 cancer-associated genes. MAIN OUTCOMES AND MEASURES: Accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and the relative contribution of other cancer predisposition genes in familial gastric cancers. RESULTS: Thirty-one distinct pathogenic CDH1 mutations (14 novel) were identified in 34 of 183 index cases (19%). By the age of 80 years, the cumulative incidence of gastric cancer was 70% (95% CI, 59%-80%) for males and 56% (95% CI, 44%-69%) for females, and the risk of breast cancer for females was 42% (95% CI, 23%-68%). In CDH1 mutation-negative index cases, candidate mutations were identified in 16 of 144 probands (11%), including mutations within genes of high and moderate penetrance: CTNNA1, BRCA2, STK11, SDHB, PRSS1, ATM, MSR1, and PALB2. CONCLUSIONS AND RELEVANCE: This is the largest reported series of CDH1 mutation carriers, providing more precise estimates of age-associated risks of gastric and breast cancer that will improve counseling of unaffected carriers. In HDGC families lacking CDH1 mutations, testing of CTNNA1 and other tumor suppressor genes should be considered. Clinically defined HDGC families can harbor mutations in genes (ie, BRCA2) with different clinical ramifications from CDH1. Therefore, we propose that HDGC syndrome may be best defined by mutations in CDH1 and closely related genes, rather than through clinical criteria that capture families with heterogeneous susceptibility profiles.

Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers.

Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patient's perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.

Familial gastric cancer: genetic susceptibility, pathology, and implications for management.

Familial gastric cancer comprises at least three major syndromes: hereditary diffuse gastric cancer, gastric adenocarcinoma and proximal polyposis of the stomach, and familial intestinal gastric cancer. The risk of development of gastric cancer is high in families affected b-y these syndromes, but only hereditary diffuse gastric cancer is genetically explained (caused by germline alterations of CDH1, which encodes E-cadherin). Gastric cancer is also associated with a range of several cancer-associated syndromes with known genetic causes, such as Lynch, Li-Fraumeni, Peutz-Jeghers, hereditary breast-ovarian cancer syndromes, familial adenomatous polyposis, and juvenile polyposis. We present contemporary knowledge on the genetics, pathogenesis, and clinical features of familial gastric cancer, and discuss research and technological developments, which together are expected to open avenues for new genetic testing approaches and novel therapeutic strategies.

Hereditary diffuse gastric cancer - pathophysiology and clinical management.

Hereditary Diffuse Gastric Cancer is an autosomal dominant inherited gastric cancer syndrome caused by germline alterations in CDH1 (E-cadherin) and CTNNA1 (alpha-E-catenin) genes. Germline CDH1 alterations encompass small frameshifts, splice-site, nonsense, and missense mutations, as well as large rearrangements. Most CDH1 truncating mutations are pathogenic, and several missense CDH1 mutations have a deleterious effect on E-cadherin function. CDH1 testing should be performed in probands. Screening of at-risk individuals is indicated from the age of consent following counselling with a multidisciplinary team. In mutation-positive individuals prophylactic gastrectomy is recommended. Endoscopic surveillance is an option for those refusing/postponing gastrectomy, those with mutations of undetermined significance, and in CDH1-negative families. Ongoing research focus on the search of genetic causes other than CDH1 or CTNNA1 germline defects; assessment of the pathogenicity and penetrance of CDH1 missense mutations and identification of somatic mechanisms behind the progression from early (indolent) lesions to invasive (lethal) carcinomas.

Germline mutations in MAP3K6 are associated with familial gastric cancer.

Gastric cancer is among the leading causes of cancer-related deaths worldwide. While heritable forms of gastric cancer are relatively rare, identifying the genes responsible for such cases can inform diagnosis and treatment for both hereditary and sporadic cases of gastric cancer. Mutations in the E-cadherin gene, CDH1, account for 40% of the most common form of familial gastric cancer (FGC), hereditary diffuse gastric cancer (HDGC). The genes responsible for the remaining forms of FGC are currently unknown. Here we examined a large family from Maritime Canada with FGC without CDH1 mutations, and identified a germline coding variant (p.P946L) in mitogen-activated protein kinase kinase kinase 6 (MAP3K6). Based on conservation, predicted pathogenicity and a known role of the gene in cancer predisposition, MAP3K6 was considered a strong candidate and was investigated further. Screening of an additional 115 unrelated individuals with non-CDH1 FGC identified the p.P946L MAP3K6 variant, as well as four additional coding variants in MAP3K6 (p.F849Sfs*142, p.P958T, p.D200Y and p.V207G). A somatic second-hit variant (p.H506Y) was present in DNA obtained from one of the tumor specimens, and evidence of DNA hypermethylation within the MAP3K6 gene was observed in DNA from the tumor of another affected individual. These findings, together with previous evidence from mouse models that MAP3K6 acts as a tumor suppressor, and studies showing the presence of somatic mutations in MAP3K6 in non-hereditary gastric cancers and gastric cancer cell lines, point towards MAP3K6 variants as a predisposing factor for FGC.