Familial Cancer最新文献

Background: 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.

Materials and methods: 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.

Results: 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).

Conclusion: 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.

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.

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.

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.

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.

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.

Limited data exist on hereditary breast cancer characteristics and treatment driven by germline mutations beyond BRCA. Our primary aim is to describe the tumour and patient characteristics, treatment patterns and outcomes in patients with non-BRCA hereditary breast cancer with a focus on CHEK2, ATM, PALB2 and TP53 variants. This is a retrospective single centre hospital-based cohort study of adult patients with a known (likely) pathogenic germline mutation and breast cancer diagnosis in UZ Leuven before April 2022. Data collection included baseline demographics, breast cancer characteristics, treatment patterns and disease outcome variables. Cohorts of patients with variants in different genes will be compared. We retrieved 185 patients with variants in ATM (N = 40), CHEK2 (N = 114), PALB2 (N = 8) and TP53 (N = 23). Median age was significantly lower in the TP53 group (36 years, p = 0.001). Only estrogen receptor (ER) status (p = 0.005) and breast cancer subtype (p < 0.001) differed significantly across the defined gene cohorts. HER2-positive disease was more frequent in the TP53 subgroup (59.1%, p < 0.001). Neoadjuvant chemotherapy was more commonly administered in the PALB2 and TP53 cohorts (p = 0.011). Univariate and multivariate survival analysis by gene cohort showed no significant difference in survival outcomes. In our series, we confirm that TP53 carriers are younger at breast cancer diagnosis and have more often HER2-positive breast cancer. Triple-negative breast cancer is more frequent in the PALB2 carriers, while ER-positivity is most common in ATM and CHEK2 carriers. Survival outcomes were similar across different gene cohorts in this study.

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.