Familial Cancer最新文献

Familial adenomatous polyposis (FAP) is a hereditary cancer syndrome characterized by germline mutations in the APC gene that result in the development of hundreds of premalignant adenomas throughout the colon and rectum. Prophylactic surgery remains the primary intervention strategy, as there are currently no pharmacological treatment options for FAP patients. Previous therapeutic approaches have predominantly focused on reducing polyp size rather than preventing their initiation, thereby missing a key opportunity for early intervention. Crucially, to effectively target the earliest stages of tumour development requires a deeper understanding of the molecular mechanisms underlying adenoma formation. In this review, we evaluate the latest models and methods employed to investigate the origin of FAP adenomas. We describe how mutant cells expand from their initial emergence within the intestinal epithelium and how they compete with normal cells within intestinal crypts. In addition, we discuss how multiple mutant crypts cooperate to collectively form polyclonal adenomas, and how these polyclonal lesions gradually transition towards monoclonality as adenomas progress towards colorectal cancer. Finally, we highlight how these insights inform the development of targeted cancer prevention strategies for individuals with FAP.

Familial adenomatous polyposis (FAP) is a hereditary disorder caused by constitutional pathogenic variants in the APC gene, leading to the development of up to hundreds of colorectal adenomas and a near-inevitable risk of colorectal cancer (CRC) if untreated. Traditional management relies on prophylactic colectomy, but advances in endoscopic techniques and chemoprevention offer alternative strategies to delay or even avoid surgery. This review explores the role of endoscopic surveillance, polypectomy strategies, and chemopreventive agents in FAP management, evaluating their efficacy, limitations, and the need for personalized approaches.

The Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (CGA-IGC) is an organization of healthcare providers, researchers, and advocates whose mission is to be a leading global authority in advancing the science and clinical management of hereditary gastrointestinal cancer syndromes. In 2024, the Executive Council developed a Strategic Plan, outlined here, to guide the organization's work over the next 3 years. The Strategic Plan is based on the four pillars of Education, Discovery & Innovation, Community & Collaboration, and Organizational Vitality, with associated goals, action plans, and metrics for each pillar. Ultimately, the Strategic Plan will help CGA-IGC fulfill its vision and mission to advance the science and clinical management of hereditary gastrointestinal cancers.

Background: Tatars and Bashkirs are large and closely related ethnic communities that reside in the territory of the Russian Federation but have managed to preserve their national identity through the course of history.

Methods: This study included 446 Tatars, 53 Bashkirs, and 26 women of mixed Tatar-Bashkir ethnicity. Germline DNA analysis was performed for 349 breast cancer (BC) patients with clinical features of hereditary disease (family history, or young onset (

Results: BRCA1 pathogenic variants (PVs) were detected in 63 women; surprisingly, five Slavic founder alleles accounted for 30 (48%) of the BRCA1 PVs. The genuine Tatar BRCA1 allele, c.5161C > T, was observed in 11 subjects. Among 27 women with BRCA2 PVs, six and five women were carriers of the c.-39-1_-39del and c.468dup variants, respectively. The loss-of-heterozygosity (LOH) test confirmed the pathogenic nature of the c.-39-1_-39del [rs758732038] allele, which is located in the 5'UTR of BRCA2. Analysis of other BC-associated genes revealed single instances of PVs affecting PALB2, TP53, ATM, RAD51, and RAD51D genes.

Conclusion: Tatars and Bashkirs, which are ethnically and religiously separated from Russians, carry an unexpectedly high proportion of Slavic BRCA1/2 founder alleles. The identification of recurrent Tatar/Bashkir BRCA2 pathogenic 5'UTR variant c.-39-1_-39del calls for a systematic analysis of regulatory regions of cancer-predisposing genes in patients with missing heritability.

Since panel genetic testing has become widely available, national guidelines recommend that individuals who previously underwent BRCA1/2-only testing should undergo updated testing to include other hereditary breast and ovarian cancer predisposition genes. Our study assessed the yield of additional hereditary cancer predisposition testing in patients who previously underwent negative BRCA1/2 testing. Additionally, our study included a small pilot to evaluate whole exome sequencing in patients with a strong family history. Patients enrolled in a registry study who previously underwent negative BRCA1/2 testing were included and stratified into three categories based on personal and family cancer history-strongly suggestive, moderately suggestive, and possibly suggestive. Updated testing with a 36-gene pan-cancer panel was performed on most participants. A selected set of participants had whole exome sequencing. Patients with a pathogenic variant identified were offered clinical confirmatory testing. Rates of positive test results were compared among the three groups. Clinically relevant pathogenic variants in non-BRCA1/2 genes from the 36-gene panel test were identified in 8.1% of participants, most commonly in PALB2 (1.9%), ATM (1.2%), and MSH6 (1.2%). Positive findings were more common in patients with strongly suggestive history, but the differences were not statistically significant. Exome testing in individuals with a strongly suggestive personal and family history did not yield novel findings. Our findings aligned with previous studies and support the use of expanded gene panel testing in all patients meeting testing criteria who previously underwent negative BRCA1/2 testing. Our small pilot whole exome sequencing did not identify any novel finding.

Efficient use of genetic biobank data in support of clinical care would enhance the adoption of personalized medicine. Identification of carriers of medically actionable variants that predispose to cancer enables intensified screening and follow-up to decrease disease risk. Pathogenic variants of the MLH1 gene cause Lynch syndrome with a significant risk of developing cancer. Here, we introduce a novel approach for the large-scale screening of biobank SNP-array-based genotyping data to analyze copy-number variants (CNVs). With the method developed, we analyzed the Helsinki Biobank cohort of 121 073 samples and identified 29 MLH1 exon 16 deletion (MLH1∆Ex16) carriers, of which five (17%) had not been previously identified in healthcare. Our results demonstrate a high positive predictive value for the identification of MLH1∆Ex16 carriers from genotyping data. The cost-efficient method for detection of CNV carriers from large biobank genotyping cohorts described here facilitates intensified screening and follow-up aiming to cancer prevention.

Germline pathogenic variants (GPVs) in RB1 are associated with the pediatric-onset intra-ocular malignancy retinoblastoma and typically present in infancy as multi-focal or bilateral disease. Survivors of retinoblastoma are at high risk for developing subsequent malignant neoplasms (SMNs); indeed, these are the leading cause of death for individuals cured of their retinoblastoma. With the exception of sarcomas, typically occurring at the site of antecedent radiation therapy for the original retinoblastoma diagnosis, and melanoma, little is known of other SMNs in retinoblastoma survivors. Here, we describe a unique case of pancreatic adenocarcinoma (PDAC) in a patient with a RB1 GPV who was diagnosed with retinoblastoma as an infant. At age 57, he was diagnosed with PDAC. Sequence analysis of the PDAC revealed the acquisition of a somatic second-hit in RB1 in the PDAC. Multispectral immunofluorescence analyses of the PDAC tumor illustrated selective loss of the RB protein in the tumor that was accompanied by the continued expression of p16^ink4a, encoded by the CDKN2A gene. In PDAC, CDKN2A loss is a common early event that contributes to carcinogenesis. This case may suggest that PDAC is a rare late component of RB1-associated tumor predisposition and illustrates that biallelic loss of RB1 is an alternative mechanism by which the RB1-pathway can be disrupted in PDAC independent of CDKN2A inactivation.

Colorectal cancer can be prevented in most patients with FAP by performing (procto)colectomy and lifelong endoscopic surveillance. Subsequently, the challenge is to prevent duodenal and gastric cancer. Duodenal cancer is one of the most common FAP-related causes of death and, in the last decade, the incidence of gastric cancer has increased. Performing frequent endoscopic surveillance with removal of neoplasia is important to prevent cancer especially since cancers in the upper GI tract generally have a poor prognosis. Moreover, the goal is to prevent upper GI surgery as these procedures are associated with substantial morbidity. In this review, we provide the prevalence of upper GI polyposis and cancer, describe endoscopic and histologic features, and discuss strategies for surveillance and treatment.

Germline (likely-)pathogenic variants (PV) in CDH1 predispose carriers to hereditary diffuse gastric cancer and lobular breast cancer. Previous studies from the United States suggest CDH1 variant carriers have an increased risk for adenomas or sessile serrated lesions (SSL), yet data linking CDH1 PVs and colorectal neoplasia are scarce. We aimed to investigate colonoscopy findings in CDH1 PVs. Adults carrying a PV/LPV in CDH1 with ≥ 1 colonoscopy between 01/01/2004-12/31/2023 were included. Patients were sourced from the David G. Jagelman Inherited Colorectal Cancer Registries at Cleveland Clinic and the German Consortium for Familial Intestinal Cancer. 103 CDH1 PV carriers were included. Most were female (66%) and white (93.1%). The median age at first colonoscopy was 47 years. The adenoma detection rate (ADR) was 29.4% (95% CI:19.9-41.1%) in the German cohort and 48.6% (95% CI: 33.0-64.4%) in the Cleveland cohort (p = 0.055) and significantly correlated with age (< 45 years, 13.6% (95% CI: 6.40-26.7%); 45-49 years, 52.4% (95% CI: 32.4-71.7%); ≥50 years, 52.6% (95% CI: 37.3-67.5%); p < 0.001). The ADR in Cleveland was higher than the U.S. average ADR but the difference was not statistically significant (48.6% vs. 35.6%, p = 0.08), and the ADR in the German cohort (29.4%) was similar to the national German average risk screening cohort (31.3% in men, p = 0.84; 20.1% in women, p = 0.08). In our screening cohort with CDH1 PV carriers, we demonstrated an ADR of 13.5% in individuals under 45 years, similar to the ADR in patients aged 25-40 years with a family history of CRC. Overall, SSL detection rate was 9.7%. Colorectal cancer was diagnosed in 3 patients (3.2%), 2/3 with an early age of onset before the age of 50 years. This first international study provides preliminary evidence of a higher ADR in U.S. CDH1 PV carriers compared to the general population, with a high number of adenomas detected before the age of 50. This may indicate an increased CRC risk that should be explored in larger studies.