Familial Cancer最新文献

{"title":"SMARCB1-related schwannomatosis and other SMARCB1-associated phenotypes: clinical spectrum and molecular pathogenesis.","authors":"Hildegard Kehrer-Sawatzki, David N Cooper","doi":"10.1007/s10689-025-00486-4","DOIUrl":"10.1007/s10689-025-00486-4","url":null,"abstract":"<p><p>SMARCB1 is a core unit of the BAF chromatin remodelling complex and its functional impairment interferes with the self-renewal and pluripotency of stem cells, lineage commitment, cellular identity and differentiation. SMARCB1 is also an important tumour suppressor gene and somatic SMARCB1 pathogenic variants (PVs) have been detected in ~ 5% of all human cancers. Additionally, germline SMARCB1 PVs have been identified in patients with conditions as clinically diverse as Rhabdoid Tumour Predisposition Syndrome type 1 (RTPS1), schwannomatosis and neurodevelopmental disorders such as Coffin-Siris syndrome (CSS). RTPS1 is characterized by the occurrence of highly malignant atypical teratoid rhabdoid tumours (AT/RT) affecting mostly infants, whereas SMARCB1-related schwannomatosis is generally diagnosed after the age of 30 and is characterized by benign schwannomas. Patients with germline SMARCB1 PVs and neurodevelopmental disorders do not usually develop SMARCB1-deficient tumours but instead exhibit severe intellectual disability and congenital malformations. It is intriguing how germline SMARCB1 PVs can be responsible for these very different pathologies. However, a network of different factors has emerged that play important roles in this context. Thus, the tumour phenotype associated with germline SMARCB1 PVs is determined by the nature and location of the SMARCB1 mutation and the timing of SMARCB1 inactivation in specific progenitor cells. Biallelic complete loss of SMARCB1 function during a narrow time window of early embryonic development in neural crest cells is essential for AT/RT development. By contrast, hypomorphic SMARCB1 PVs during later developmental stages affecting more differentiated Schwann cell precursors give rise to schwannomas. However, the loss of the wild-type SMARCB1 allele is insufficient for schwannoma growth which appears to be dependent upon concomitant somatic NF2 PVs in patients with SMARCB1-related schwannomatosis according to the four-hit/three-step model of tumorigenesis. In patients with neurodevelopmental disorders such as CSS, germline PVs would appear to cluster within the C-terminal SMARCB1 domain, interfering with the nucleosomal interactions of SMARCB1 but not with its tumour suppressor activity.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"24 3","pages":"64"},"PeriodicalIF":2.0,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12343709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144821060","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":"Parental perspectives on the use of tumor molecular profiling and germline genetic testing during their children's cancer treatment.","authors":"Marcelo M Sleiman, Muriel R Statman, Mary Rose Yockel, Yelena P Wu, Jada G Hamilton, Wendy K Kohlmann, Jennie Vagher, Soren Feola, Luke D Maese, Jing Chen, Burton Appel, Casey J Mehrhoff, Beth N Peshkin, Nina S Kadan-Lottick, Gary M Kupfer, Kenneth P Tercyak","doi":"10.1007/s10689-025-00488-2","DOIUrl":"10.1007/s10689-025-00488-2","url":null,"abstract":"<p><p>Tumor molecular profiling (TMP) with germline genetic testing (GGT) is becoming standard practice in pediatric cancer care. Yet, little is known about parents' understanding of these practices, or testing's psychosocial risks and benefits. This study characterized parental knowledge, attitudes, and beliefs about TMP and GGT. A cross-sectional, mixed-methods study was conducted among N = 75 parents of children with cancer. Parents completed a survey on cancer-related knowledge, attitudes toward GGT, psychological stress, communication, and decision-making. A subset (N = 31, 41%) then completed interviews about TMP and GGT that were content-coded and interpreted in light of survey findings. Correlative analyses indicated that parents' greater understanding of cancer and genetics was associated with favorable attitudes toward GGT (r = 0.34), preferences for more information about GGT results (r = 0.56) and reduced decisional regret about GGT (r = -0.61). Families who communicated less openly held more favorable views on GGT (r = -0.38) and preferred more information about GGT (r = -0.39), but had children who were more anxious (r = -0.36). Parents who were more anxious (r = 0.40) and who favored GGT (r = 0.41) also had children who were more anxious (all p's < 0.05). Thematically, most parents recalled their children's test results (94%), but recollection of testing type was suboptimal (58% for TMP, 61% for GGT). Nearly 70% believed it would be helpful to speak to other families for psychosocial support; additional potential resources included healthcare providers (31%) and websites (23%). When children with cancer undergo TMP and/or GGT, their parents would benefit psychoeducational resources to improve outcomes.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"24 3","pages":"63"},"PeriodicalIF":2.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144816177","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":"Rate of germline pathogenic sequence variants in cancer susceptibility genes in an Israeli pediatric and adolescent cancer cohort: a single institute experience.","authors":"Dana Nahom, Zehavit Frenkel, Amos Toren, Eitan Friedman, Iris Kventsel","doi":"10.1007/s10689-025-00489-1","DOIUrl":"10.1007/s10689-025-00489-1","url":null,"abstract":"","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"24 3","pages":"62"},"PeriodicalIF":2.0,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144798626","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":"Copy number and structural variant analyses of VHL gene using droplet digital PCR and targeted adaptive sampling long-read sequencing.","authors":"Shota Kato, Hiroko Terui-Kohbata, Atsushi Kudo, Masafumi Seki, Junko Takita, Tomohiro Morio, Yoshiko Nakano, Motohiro Kato, Masayuki Yoshida, Masatoshi Takagi","doi":"10.1007/s10689-025-00487-3","DOIUrl":"10.1007/s10689-025-00487-3","url":null,"abstract":"","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"24 3","pages":"61"},"PeriodicalIF":2.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783923","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":"Experiences with risk-reducing mastectomy in Norwegian BRCA1/2 carriers without prior breast cancer.","authors":"Hanne Kjensli Hyldebrandt, Astrid Tenden Stormorken, Valeria Vitelli, Amy Østertun Geirdal, Eli Marie Grindedal","doi":"10.1007/s10689-025-00484-6","DOIUrl":"10.1007/s10689-025-00484-6","url":null,"abstract":"<p><strong>Background: </strong>BRCA1 and BRCA2 carriers without prior breast cancer have the option to undergo risk-reducing mastectomy (RRM). The aim of this study was to investigate factors associated with their decision, experiences with the process, and satisfaction with the procedure.</p><p><strong>Materials and methods: </strong>We distributed a cross-sectional survey to 425 women aged 25-70 with a pathogenic BRCA1/2 variant. The survey collected data on sociodemographic factors, family cancer history, reasons for choosing RRM or not, experiences with the decision-making process, support from healthcare, and surgery satisfaction. Multivariate logistic regression analysis identified factors associated with the decision to undergo RRM and satisfaction with having undergone surgery.</p><p><strong>Results: </strong>Of the 272 respondents, 190 (69.9%) had undergone RRM. Having children and being a BRCA1 carrier were both associated with higher probability of choosing RRM, with an OR of 3.5 (p = 0.005 and p < 0.001 respectively). Among those who had undergone RRM, 78.9% (150/190) were satisfied with their decision and would choose the same procedure again. Feeling satisfied with support from the health care system gave an OR of 5.5 for being satisfied with having undergone RRM (p < 0.01). Those who found the decision difficult had lower odds of being satisfied (OR 0.2, p = 0.02).</p><p><strong>Conclusion: </strong>Being a BRCA1 carrier and having children were strongly associated with choosing RRM. Most participants felt relieved after RRM, were satisfied with their decision, and would choose the surgery again. Support from healthcare providers during decision-making was linked to higher satisfaction with having undergone surgery while those who struggled with the decision reported lower satisfaction.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"24 3","pages":"60"},"PeriodicalIF":2.0,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12307508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144729118","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":"MLH1 c.27G>A (p.Arg9=) is a synonymous likely/pathogenic variant underlying variably mosaic constitutional MLH1 methylation in Lynch syndrome.","authors":"Rocio Alvarez, Paula Climent-Cantó, GiWon Shin, Francesca Paola Aguirre, Lisa Zhou, Dennis J Hazelett, Brent K Larson, Covadonga Vara, Gabriel Capellá, Víctor Lorca Castellanos, Pilar Garre Rubio, Françoise Desseigne, Hanlee Ji, Jackie Cook, Miranda Durkie, Marta Pineda, Julie Leclerc, Megan P Hitchins","doi":"10.1007/s10689-025-00482-8","DOIUrl":"10.1007/s10689-025-00482-8","url":null,"abstract":"<p><p>The MLH1 synonymous variant c.27G>A (p.Arg9 =) has been reported in four index cases with suspected Lynch syndrome, but is variably classified as \"likely pathogenic\" or \"variant of uncertain significance\" due to insubstantial clinical and functional evidence. We report three new MLH1 c.27G>A index cases with family histories fulfilling Amsterdam criteria for Lynch syndrome and reassessed collective evidence for pathogenicity. Two are European families from the UK (two siblings) and Spain (three members spanning three generations), and the third is a proband from Mongolia, the first non-European reported with this variant. Blood-based constitutional MLH1 methylation testing in six heterozygotes from the three families revealed varying levels of mosaic methylation, even within the same family, ranging from extremely low (≤ 1%) to ~ 16%. Two heterozygotes with blood methylation ≤ 1% had elevated methylation (5-8%) in normal colon distant from their colon cancers. Mosaic constitutional MLH1 methylation was linked in cis to the variant c.27A allele in all six heterozygotes and segregated together across generations. Three archived early-onset colon cancers available from three heterozygotes (UK siblings, Mongolian proband) each displayed MLH1 loss, MLH1 hypermethylation, and loss-of-heterozygosity of the wild-type c.27G allele, consistent with methylated c.27A alleles within a fraction of colon cells predisposing to tumorigenesis. Nanopore sequencing in the two European families found no significant shared ancestry and no other candidate variants. Multifactorial data collated from these and prior observational studies now provide sufficient evidence for the classification of MLH1 c.27G>A as likely/pathogenic via a functional mechanism of variably mosaic \"secondary\" constitutional MLH1 epimutation.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"24 3","pages":"59"},"PeriodicalIF":2.0,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717845","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":"Gastric-type endocervical adenocarcinoma in situ as the presenting feature in a mosaic STK11 pathogenic variant carrier with a Peutz-Jeghers syndrome child.","authors":"Anqi Jiang, Yingfei Ye, Haowen Tan, Xiang Tao, Fenghua Ma, Hui Wang, Congjian Xu, Yu Kang","doi":"10.1007/s10689-025-00485-5","DOIUrl":"10.1007/s10689-025-00485-5","url":null,"abstract":"<p><p>We present the first documented case of gastric-type endocervical adenocarcinoma in situ in a mosaic STK11 pathogenic variant carrier, who delivered a child with classic Peutz-Jeghers syndrome (PJS). A 53-year-old woman presented with persistent watery vaginal discharge for 2 years. Histopathology confirmed gastric-type endocervical adenocarcinoma in situ. Familial genetic investigation was initiated after her son's diagnosis of PJS with an apparent de novo STK11 germline variant [NM_000455.4:c.842del (p.Pro281Argfs*6)]. Comprehensive STK11 screening via Sanger sequencing of peripheral blood from both parents showed no pathogenic variants. Following multidisciplinary tumor board review, ultra-deep next-generation sequencing was performed on multiple tissue specimens. Molecular analysis revealed low-level mosaicism for the familial STK11 variant in cervical tissue with no detectable mutations in blood, saliva, urine, or ovarian stroma. This case demonstrates three key clinical insights: (1) parental mosaicism may underlie apparent de novo PJS cases, (2) tissue-specific STK11 mosaicism can manifest as localized neoplastic transformation without classic PJS manifestations, and (3) ultra-deep sequencing may be considered in genetic counseling paradigms for parents of children with \"de novo\" cancer predisposition syndromes. These findings highlight the importance of considering mosaic phenomena in tumor prevention for hereditary cancer syndrome families.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"24 3","pages":"58"},"PeriodicalIF":2.0,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12287200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144689764","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":"Completeness of colorectal cancer registration in the Danish hereditary non-polyposis colorectal cancer (HNPCC) register.","authors":"Lars Joachim Lindberg, Inge Bernstein, Henrik Møller, Lone Sunde, Christina Therkildsen","doi":"10.1007/s10689-025-00483-7","DOIUrl":"10.1007/s10689-025-00483-7","url":null,"abstract":"<p><p>The Danish Hereditary Non-Polyposis Colorectal Cancer Register (HNPCC-R) has formed the basis for many epidemiologic studies supporting risk stratification and both national and international guidelines on surveillance. However, the HNPCC-R is based on voluntary reporting and the completeness of registration is unknown. Hence, we aimed to assess the validity and completeness of the colorectal cancer (CRC) registrations in the HNPCC-R. We combined the registrations in the HNPCC-R with the registrations in the national Danish Cancer Registry (DCR), which is validated and based on mandatory reporting, and matched the cases from each register using a 13-step algorithm based on unique, national Central Population Registration number, date of diagnosis, location, and morphology thus identifying 9160 verified CRCs in 49,799 individuals. The overall agreement between the registers was 85%, and the completeness of the HNPCC-R was 95%. The DCR had the highest number of registrations before 1975, and the HNPCC-R had the highest number of registrations after 1985-especially more synchronous and metachronous cases. In conclusion, data from the HNPCC-R on CRC are valid and should be preferred for studies on CRC in families with a heritable increased risk of colorectal cancer-especially in Lynch syndrome, which is known for multiple CRCs, though a combination of both registers would secure the most optimal dataset.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"24 3","pages":"57"},"PeriodicalIF":2.0,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12206165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144527124","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":"A coordinated multidisciplinary model of care is needed for child and family centered care in pediatric genetic cancer risk services: a scoping review.","authors":"Andrew M Grant, Natalie Taylor, Jane Maguire, Sharon de Graves, Christina Signorelli, Noemi A Fuentes-Bolanos, Katherine M Tucker, Marilyn Cruickshank","doi":"10.1007/s10689-025-00474-8","DOIUrl":"10.1007/s10689-025-00474-8","url":null,"abstract":"<p><p>Cancer remains a leading cause of death in children/adolescents. Approximately 8-18% of children/adolescents with cancer have an underlying pediatric Genetic Cancer Risk (p-GCR). P-GCR clinics offer surveillance aimed at improving survival outcomes. Yet children/adolescents require more than surveillance protocols to support holistic health. A multidisciplinary model of care (MoC), including Advanced Practice Nurses (APN) is needed. Yet a MoC and formal description of the APN is lacking in p-GCR clinics. To explore existing evidence of holistic, multidisciplinary approaches to care for children/adolescents and families with a p-GCR; to identify how Advanced Practice Nurses (APN) contribute to care delivery in p-GCR services. A scoping review was conducted in three databases: MEDLINE (Ovid), Embase (Ovid) and CINAHL Complete. JBI methodology for conducting and reporting scoping reviews was used to search MEDLINE, Embase and CINAHL Complete. Gray and white literature was considered from 1991 to 2023. Thirty two studies met inclusion criteria. Thirteen aspects of a MoC in p-GCR were identified including: clinic scope, clinic locality, clinicians involved, care coordination, clinic activity, geography, centralisation of care, psychosocial aspects, shared decision making, education, referrals, transition to adult services and research. There were 10 APN roles described that supported the service/organisation and the delivery of holistic care to children/adolescents with a p-GCR. Using a systematic approach, this review identified how services provide care to children/adolescents with a p-GCR and the APN role in these services. A multidisciplinary MoC with dedicated care coordination can enable child and family centred care with a holistic healthcare approach.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"24 3","pages":"55"},"PeriodicalIF":2.0,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332685","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":"Updates and controversies for desmoids in familial adenomatous polyposis.","authors":"Rami James N Aoun, Matthew F Kalady","doi":"10.1007/s10689-025-00481-9","DOIUrl":"10.1007/s10689-025-00481-9","url":null,"abstract":"<p><p>Desmoids are rare non-cancerous fibrous growths with variable behavior ranging from slow indolent growth or even regression, to locally aggressive and progressive tumors that can cause significant morbidity or mortality. Approximately 10-15% of patients with familial adenomatous polyposis (FAP) develop desmoid disease, most commonly located in the abdomen, on the abdominal wall, or in limbs. The majority of desmoids in FAP occur after abdominal surgery. Management is quite challenging and employing a multidisciplinary team at a specialized center is important for success. New treatment modalities have emerged, including tyrosine kinase inhibitors, γ-secretase inhibitors, and ablation techniques, complementing the existing repertoire of therapies such as NSAIDs, anti-hormonal therapy, chemotherapy, radiotherapy, and surgical interventions. Surgery remains the treatment of choice for easily resectable abdominal wall desmoids and intra-abdominal desmoids that cause intractable symptoms, or progressive disease despite alternate therapies, or complications from the invasion of nearby organs. When considering prophylactic colectomies in FAP patients, it's essential to account for the desmoidogenic potential of surgical interventions, especially in high-risk individuals with a positive family history of desmoids, presence of extracolonic manifestations and carriers of certain genotypes. Given the rarity of the disease and the variability in both anatomical presentation and clinical course, desmoids should be managed by a multidisciplinary team capable of coordinating patient specific care and optimizing treatment options.</p>","PeriodicalId":12336,"journal":{"name":"Familial Cancer","volume":"24 3","pages":"56"},"PeriodicalIF":2.0,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332686","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}