Familial Cancer最新文献

{"title":"Clinical and surveillance outcomes of the TP53 c.1000G > C (p.Gly334Arg) variant.","authors":"Yehudit Peerless, Rinat Bernstein-Molho, Iris Kventsel, Zehavit Frenkel, Lilach Levi, Inbal Kedar, Aviad Zick, Tamar Peretz, Yael Goldberg, Naama Halpern","doi":"10.1007/s10689-026-00591-y","DOIUrl":"10.1007/s10689-026-00591-y","url":null,"abstract":"<p><strong>Background: </strong>Germline TP53 pathogenic variants are classically associated with Li-Fraumeni syndrome, although penetrance and tumor spectrum vary substantially across specific alleles. The Ashkenazi Jewish TP53 c.1000G > C (p.Gly334Arg) variant has been reported as a lower-penetrance, later-onset cancer predisposition allele, but its clinical classification and penetrance remain subjects of ongoing discussion. Consequently, the optimal surveillance approach for carriers remains uncertain, and real-world surveillance outcome data are limited.</p><p><strong>Methods: </strong>We performed a retrospective descriptive study of heterozygous TP53 p.Gly334Arg carriers followed at two Israeli hereditary cancer clinics between 2021 and 2025. Clinical records were reviewed for demographic data, personal and family cancer history, and surveillance outcomes. Whole-body magnetic resonance imaging (WB-MRI) findings were analyzed for carriers who underwent serial surveillance.</p><p><strong>Results: </strong>Eighteen carriers from five families were identified, all of Ashkenazi Jewish ancestry. Seven of 18 carriers (39%) had a personal history of malignancy. Breast cancer was the most common malignancy, occurring in four women, all diagnosed after age 50; available pathology showed hormone receptor-positive disease. No pediatric malignancies were observed, and none of the carriers met classic or Chompret clinical criteria for Li-Fraumeni syndrome. Ten carriers underwent serial WB-MRI surveillance, totaling 36 examinations (mean 3.6 per patient). No malignancies were detected. However, surveillance generated nine abnormal findings (0.25 per scan), all false positives, including one that led to invasive procedures.</p><p><strong>Conclusions: </strong>In this clinic-based cohort, TP53 p.Gly334Arg was observed in association with a later-onset, potentially lower-penetrance cancer phenotype and low short-term surveillance yield. These findings support phenotypic heterogeneity among TP53 variants and raise questions regarding the optimal intensity of surveillance in this population; however, current data are insufficient to support modification of existing TP53 surveillance protocols. Larger multicenter studies with longer follow-up are needed to define penetrance and guide genotype-informed management.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"25 3","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13391678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148548450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of updated NCCN guidelines on clinical management and risk communication for CHEK2 p.I157T carriers in breast cancer.","authors":"Emma A Kell, Michael P Mullane, Jennifer L Geurts, Brenda Ramczyk, Tessa M Bachinski","doi":"10.1007/s10689-026-00590-z","DOIUrl":"10.1007/s10689-026-00590-z","url":null,"abstract":"<p><p>In 2023, the National Comprehensive Cancer Network^® (NCCN^®) updated its guidelines for managing breast cancer risk in patients with a CHEK2 p.I157T variant, recommending de-escalation of enhanced screening based on this variant alone. This shift reflects evidence that some missense variants carry a lower cancer risk than CHEK2 loss-of-function variants. A reduced cancer risk is particularly well established for the CHEK2 p.I157T variant, prompting the updated guidelines. This study examines healthcare providers' understanding of these updated guidelines and explores how providers communicate these changes to patients affected by hereditary cancer risks. We conducted a survey targeting healthcare providers involved in hereditary cancer management, capturing their perceptions of the clinical implications of CHEK2 p.I157T and the approaches used to communicate de-escalated management recommendations. Additionally, a retrospective records review was performed to approximate the percentage of patients impacted by these de-escalation recommendations. This research aims to evaluate factors shaping provider recommendations and communication following guideline changes in hereditary cancer care. Results may inform best practice considerations for patient-provider communication in hereditary cancer care, particularly when new evidence leads to modified screening or management recommendations.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"25 3","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148548453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Breast cancer phenotypes in carriers of pathogenic POT1 variants.","authors":"Tal Hadar, Aasem Abu Shtaya, Rinat Bernstein-Molho, Marina Eskin-Schwartz, Inbal Kedar, Tamar Peretz-Yablonsky, Shiri Shkedi-Rafid, Rinat Yerushalmi, Aviad Zick, Gili Reznick-Levi, Tanir Allweis, Yael Goldberg","doi":"10.1007/s10689-026-00589-6","DOIUrl":"10.1007/s10689-026-00589-6","url":null,"abstract":"<p><p>Germline pathogenic variants (PVs) in POT1, one of the shelterin complex genes, correlate with tumor predisposition, primarily with melanoma, hematologic malignancies, sarcoma, papillary thyroid carcinoma and glioma. Breast cancer (BC) risk has not been shown to be elevated. We analyzed BC occurrence and features in a cohort of 29 female PV heterozygotes, of whom 13/29 (45%) were diagnosed with BC. Data regarding genetic, clinical, pathologic, treatment, and outcome characteristics were extracted. Patients in our cohort harbored three different POT1 PVs; The c.233T > C Ashkenazi founder PV occurred in 11/13 (84.6%). Median age at first BC diagnosis was 54 years (range 44-72); no patient was diagnosed before the age of 40. Pathological subtypes varied; invasive ductal carcinoma was the most common. All primary tumors were estrogen receptor positive; one was HER2-enriched; no triple-negative cancers were observed. Stage at diagnosis varied: 6 of 10 tumors with known staging were stage 0 or I, and one patient presented with metastatic disease. Treatment approaches were diverse as clinically appropriate. After a median follow-up of 110 months, three second BC events occurred, with no BC-related mortality. Personal and family history of other malignancies were frequent. This is the first dedicated report describing BC phenotypes in POT1 PV heterozygotes. Our findings suggest that enhanced BC surveillance may be warranted in this population. Larger cohorts are needed to further characterize the clinicopathological features of BC in POT1 carriers, to define lifetime BC risk and determine whether BC-specific screening recommendations should be established for this group.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"25 3","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13354631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lynch syndrome caused by a pathogenic SINE-VNTR-Alu (SVA) insertion in MSH2 gene identified by long-read DNA sequencing.","authors":"Jihoon E Joo, Khalid Mahmood, Mark Clendenning, Peter Georgeson, Romy Walker, Julia Como, Fiona Phillips, Bernard J Pope, Steven Batinovic, Natalie Diepenhorst, Julie McDonald, Toni Rice, Christophe Rosty, Mark A Jenkins, Finlay A Macrae, Ingrid M Winship, Hilda High, Daniel D Buchanan","doi":"10.1007/s10689-026-00588-7","DOIUrl":"10.1007/s10689-026-00588-7","url":null,"abstract":"<p><p>Lynch syndrome, the most common hereditary cancer syndrome, is caused by germline pathogenic variants in DNA mismatch repair (MMR) genes. Identifying complex or structural MMR gene pathogenic variants can be challenging with short-read sequencing resulting in patients with unexplained MMR-deficient tumours. In this study, we report multiple members of a family who developed MSH2-deficient tumours where clinical multi-gene panel testing of the DNA MMR genes using short-read sequencing did not find a germline pathogenic variant. Oxford Nanopore Technologies adaptive sampling (ONT-AS) long-read sequencing, targeting 104 hereditary cancer genes, identified a shared ~ 3.2 kb SINE-VNTR-Alu (SVA) family F retrotransposon insertion within exon 12 of MSH2 in both the proband and her father. Segregation of this MSH2 SVA insertion by targeted PCR confirmed three additional family members as carriers, including a paternal uncle with three colorectal cancers and an MSH2-deficient sebaceous adenoma. Three of the five heterozygous carriers were cancer affected with at least one MSH2-deficient tumour each. This study demonstrates that long-read sequencing can identify structural variants that are missed by current short-read sequencing multi-gene panel testing, improving the diagnosis of Lynch syndrome. These findings support incorporating long-read sequencing into routine diagnostic workflows for patients with suspected Lynch syndrome following a negative germline test.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"25 3","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13350196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148411019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CGA-IGC 2025 Abstracts.","authors":"Çağla Avcıoğlu","doi":"10.1007/s10689-026-00561-4","DOIUrl":"https://doi.org/10.1007/s10689-026-00561-4","url":null,"abstract":"","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"25 Suppl 2","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endoscopic detection of signet ring cell carcinoma in CDH1 carriers: a 15-year single-centre experience.","authors":"Omar Salehi, Douglas Tjandra, Jadon Karp, Alex Boussioutas","doi":"10.1007/s10689-026-00586-9","DOIUrl":"10.1007/s10689-026-00586-9","url":null,"abstract":"<p><p>CDH1 pathogenic variant carriers are at high lifetime risk of hereditary diffuse gastric cancer (HDGC). Endoscopic surveillance is recommended for individuals who delay risk-reducing total gastrectomy, although detection of signet ring cell carcinoma (SRCC) remains challenging. No Australian cohort has reported real-world endoscopic performance with surgical correlation in this population. We performed a 15-year retrospective cohort study of adult CDH1 carriers undergoing esophagogastroduodenoscopy (EGD) at a tertiary familial cancer centre (2008-2023). Patients presenting with symptomatic invasive gastric cancer at initial endoscopy were excluded. Most EGDs were conducted as preoperative assessments prior to risk-reducing total gastrectomy, with a minority undertaken as longitudinal surveillance. Endoscopic findings, biopsy performance, surgical pathology, and postoperative outcomes were analysed. Eighty-two CDH1 carriers from 31 families underwent 136 EGDs (median 1 per patient). SRCC was detected endoscopically in 38 patients (46.3%), predominantly via random biopsies. Overall sensitivity for SRCC detection was 67.9%, with random biopsies outperforming targeted sampling. Most lesions were identified at the initial EGD. Sixty-nine patients (84.1%) proceeded to total gastrectomy; SRCC was confirmed in 56 (81.2%), with variable tumour burden (1-73 foci). Invasive disease beyond pT1a was uncommon (2.9%). Postoperative complications occurred in 43.5%, most frequently anastomotic strictures requiring dilatation; there were no procedure-related deaths. Although occult SRCC was common, invasive malignancy beyond pT1a was infrequent, suggesting that many intramucosal lesions may have a more indolent course than previously assumed. Detection of SRCC at endoscopy remains challenging; however, these findings support a more individualized, risk-adapted approach to CDH1 management. Longer-term prospective data are required to better define SRCC progression risk and guide decisions regarding surveillance and risk-reducing surgery.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"25 3","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13337865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148389984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peutz-Jeghers Syndrome and lung cancer: does the risk meet the threshold for lung cancer screening?","authors":"Faizah Shareef, Mounica Konjeti, Samir Gupta, Jennifer M Weiss","doi":"10.1007/s10689-026-00587-8","DOIUrl":"10.1007/s10689-026-00587-8","url":null,"abstract":"<p><p>Peutz-Jeghers Syndrome (PJS) is caused by germline pathogenic variants in the STK11 gene and is associated with elevated lifetime risks for several cancers, including lung cancer. Currently, no formal recommendations exist for lung cancer screening in PJS. This structured narrative review compares lung cancer risk in PJS with lung cancer risk in individuals currently eligible for screening based on age and smoking history. PubMed and Web of Science were searched from 1/1/1980 to 9/11/2023 using the terms \"Peutz-Jeghers Syndrome\" AND \"Cancer.\" Studies reporting lung cancer risk in PJS were included. Reported lung cancer risks were compared to 5-year, 10-year, and lifetime lung cancer risks in the general population based on age and pack-years of smoking. Seventeen studies were included. Across the studies, the incidence of lung cancer ranged from 0.8 to 13.3%. Studies that included lung cancer risk relative to the general population reported a relative risk range of 2.9-22.9. Cumulative risk was reported in 5 studies and surpassed 5% by age 60 (range 7 to 17%). Guidelines for low-dose CT (LDCT) lung cancer screening for individuals aged 50-80 with a smoking history of at least 20 pack-years are associated with a similar or higher threshold for lung cancer risk. The lifetime lung cancer risk for individuals with PJS is similar to current guideline-based risk thresholds for screening based on age and smoking status. Given their elevated lifetime risk, individuals with PJS may be candidates for LDCT for lung cancer screening and should be formally studied to elucidate the risks, benefits, and optimal implementation in this patient population.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"25 3","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13331894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148375115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transitioning from the Prospective Lynch Syndrome Database (PLSD) to the International Lynch Syndrome Database (ILSD).","authors":"Mev Dominguez-Valentin","doi":"10.1007/s10689-026-00583-y","DOIUrl":"10.1007/s10689-026-00583-y","url":null,"abstract":"","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"25 3","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13323406/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148360088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding access to hereditary cancer genetic testing: a quality improvement initiative of mainstreaming in a diverse urban gynecology clinic.","authors":"Alex Raghunandan, Lauren Davis-Rivera, Muhammad Danyal Ahsan, Isabelle R Chandler, Steve Lopez, Amanda Laterza Ozarowski, Michelle Primiano, Christina Pardo, Ravi N Sharaf, Melissa K Frey","doi":"10.1007/s10689-026-00575-y","DOIUrl":"10.1007/s10689-026-00575-y","url":null,"abstract":"<p><p>Most individuals with hereditary cancer syndromes remain undiagnosed and cannot benefit from cancer mitigation strategies. Mainstreaming, or the process of integrating genetic testing into routine care, can expand access, but implementation in primary care settings has proven challenging. In a quality improvement initiative, stakeholder feedback guided the development of care algorithms, patient/provider resources, and streamlined lab workflows for mainstreaming in an urban, diverse, Medicaid-predominant benign gynecology clinic. The mainstreaming initiative was launched in December 2024; over the subsequent four months, 274 consecutive patients presented for gynecologic care and 32 (11.7%) completed same-day genetic testing. This model demonstrates a feasible and scalable approach to integrating genetic testing into benign gynecology clinics serving diverse patient populations.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"25 3","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of international care networks on the clinical management of constitutional mismatch repair deficiency (CMMRD): a review of recent developments.","authors":"Hans F A Vasen, Katharina Wimmer, Mariëtte van Kouwen, Léa Guerrini-Rousseau, Daniela Gattini, Lucie Stengs, Uri Tabori, Chrystelle Colas, Anirban Das","doi":"10.1007/s10689-026-00584-x","DOIUrl":"10.1007/s10689-026-00584-x","url":null,"abstract":"<p><p>Constitutional mismatch repair deficiency (CMMRD) is a rare and likely the most penetrant cancer predisposition syndrome caused by biallelic germline variants in a mismatch repair gene. Patients typically develop a spectrum of malignancies, including brain tumors, gastrointestinal cancers, and hematological neoplasms within the first two decades of life. Since its initial description in 1999, two international consortia, the International Replication Repair Deficiency Consortium (IRRDC) and Care for CMMRD (C4CMMRD), have been established to better understand the syndrome, leading to the creation of diagnostic guidelines and surveillance protocols. This review summarizes recent data on the CMMRD tumor spectrum and discusses the consortia's updated diagnostic criteria and management guidelines, including novel blood-based assays for detecting constitutional microsatellite instability. Furthermore, we present the initial results and subsequent adjustments to international surveillance protocols. Finally, we discuss the demonstrated efficacy of immune checkpoint inhibitor (ICI) treatment, a key therapeutic advancement for CMMRD patients.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"25 3","pages":""},"PeriodicalIF":2.1,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13303765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148316429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}