Familial Cancer最新文献

In the 33 years since the first diagnostic cancer predisposition gene (CPG) tests in the Manchester Centre for Genomic Medicine, there has been substantial changes in the identification of index cases and cascade testing for at-risk family members. National guidelines in England and Wales are usually determined from the National Institute of healthcare Evidence and these have impacted on the thresholds for testing BRCA1/2 in Hereditary Breast Ovarian Cancer (HBOC) and in determining that all cases of colorectal and endometrial cancer should undergo screening for Lynch syndrome. Gaps for testing other CPGs relevant to HBOC have been filled by the UK Cancer Genetics Group and CanGene-CanVar project (web ref. https://www.cangene-canvaruk.org/ ). We present time trends (1990-2020) of identification of index cases with germline CPG variants and numbers of subsequent cascade tests, for BRCA1, BRCA2, and the Lynch genes (MLH1, MSH2, MSH6 and PMS2). For BRCA1/2 there was a definite increase in the proportion of index cases with ovarian cancer only and pre-symptomatic index tests both doubling from 16 to 32% and 3.2 to > 8% respectively. A mean of 1.73-1.74 additional family tests were generated for each BRCA1/2 index case within 2 years. Overall close to one positive cascade test was generated per index case resulting in > 1000 risk reducing surgery operations. In Lynch syndrome slightly more cascade tests were performed in the first two years potentially reflecting the increased actionability in males with 42.2% of pre-symptomatic tests in males compared to 25.8% in BRCA1/2 (p < 0.0001).

Lynch syndrome is an underdiagnosed genetic condition that increases lifetime colorectal, endometrial, and other cancer risk. Cascade testing in relatives is recommended to increase diagnoses and enable access to cancer prevention services, yet uptake is limited due to documented multi-level barriers. Individual barriers such as feelings of fear, guilt, and anxiety and limited knowledge about Lynch syndrome as well as interpersonal barriers including complex family dynamics and language barriers limit family communication about Lynch syndrome and prevent uptake of genetic screening for relatives. Organizational and environmental barriers including a shortage of genetics professionals, high costs, and fears of discrimination also reduce cascade testing. These multi-level barriers may disproportionately impact underserved populations in the United States, such as individuals with lower incomes, limited English-speaking proficiency, lower educational attainment, and inadequate access to health systems. Multi-level facilitators of cascade testing include interpersonal support from family members, peers, and healthcare providers, educational resources, and motivation to improve family health. Taken together, these barriers and facilitators demonstrate a need for interventions and strategies that address multi-level factors to increase cascade testing in families with Lynch syndrome and other hereditary cancer conditions. We provide an example of a cascade testing intervention that has been developed for use in individuals diagnosed with Lynch syndrome and discuss the variety of current approaches to addressing these multi-level barriers.

Genomic sequencing has emerged as a powerful tool with significant implications for patients and their relatives, however, empirical evidence suggests that effective dissemination of risk information within families remains a challenge. Policy responses to address this issue vary across countries, with Belgium notably lacking specific regulations governing nondisclosure of genetic risk. In this study, we conducted semi-structured interviews with clinicians from Belgian clinical genetics centers to gain insight into their perspectives on policy approaches to the disclosure of genetic risk within families. Using real-world examples of legislation and court rulings from France, Australia, and the UK, we explored clinician viewpoints on the roles and responsibilities of both patients and clinicians in the family communication process. Clinicians expressed confusion regarding what was legally permissible regarding contacting at-risk relatives. While there was a consensus among participants that patients have a responsibility to inform their at-risk relatives, participants were hesitant to support the legal enforcement of this duty. Clinicians mostly recognized some responsibility to at-risk relatives, but the extent of this responsibility was a subject of division. Our findings highlight the need for a comprehensive policy that clarifies the roles and responsibilities of clinicians and patients to inform at-risk relatives. Furthermore, the study underscores the practical challenges clinicians face in supporting patients through the complex process of family communication, suggesting a need for additional resources and the exploration of alternative approaches to communication.

Inherited cardiovascular diseases cover the inherited cardiovascular disease familial hypercholesterolemia and inherited cardiac diseases, like inherited cardiomyopathies and inherited arrhythmia syndromes. Cascade genetic counseling and testing in inherited cardiovascular diseases have had three decades of academic attention. Inherited cardiovascular diseases affect around 1-2% of the population worldwide and cascade genetic counseling and testing are considered valuable since preventive measures and/or treatments are available. Cascade genetic counseling via a family-mediated approach leads to an uptake of genetic counseling and testing among at-risk relatives of around 40% one year after identification of the causal variant in the proband, with uptake remaining far from complete on the long-term. These findings align with uptake rates among relatives at-risk for other late onset medically actionable hereditary diseases, like hereditary cancer syndromes. Previous interventions to increase uptake have focused on optimizing the process of informing relatives through the proband and on contacting relatives directly. However, despite successful information dissemination to at-risk relatives, these approaches had little or no effect on uptake. The limited research into the barriers that impede at-risk relatives from seeking counseling has revealed knowledge, attitudinal, social and practical barriers but it remains unknown how these factors contribute to the decision-making process for seeking counseling in at-risk relatives. A significant effect on uptake of genetic testing has only been reached in the setting of familial hypercholesterolemia, where active information provision was accompanied by a reduction of health-system-related barriers. We propose that more research is needed on barriers -including health-system-related barriers- and how they hinder counseling and testing in at-risk relatives, so that uptake can be optimized by (adjusted) interventions.

Healthy carriers of BRCA1/2 pathogenic variants (PVs) may benefit from risk-reducing measures of proven efficacy. The main approach to identify these individuals is cascade testing, and strategies to support this complex process are under investigation. In Italy, cascade testing has received little attention; therefore, we analyzed the uptake and characteristics of BRCA1/2 cascade testing in families diagnosed with HBOC between 2017 and 2019 at two Italian genetics centers. All blood relatives aged 18 years or older at September 2022 and who could be involved in the first step of cascade testing (i.e., all the living relatives closest to the proband) were included. In addition to first-degree relatives, individuals who were second-, third- or fourth-degree relatives were included if the closest relative(s) was/were deceased. Overall, 213 families were included (103, Genoa; 110, Bologna). Most probands were women affected by breast and/or ovarian cancer (86.4%, Genoa; 84.5%, Bologna), and the branch segregating the PV was known/suspected in 62% of families (62.1%, Genoa; 60.9%, Bologna). Overall, the uptake of cascade testing was 22.8% (25.8%, Genoa; 19.9%, Bologna; OR = 0.59: 95%CI 0.43-0.82). It was strongly associated with female gender (OR = 3.31, 95%CI 2.38-4.59), age ≤ 70 years (< 30 years OR = 3.48, 95%CI 1.85-6.56; 30-70 years OR = 3.08, 95%CI 2.01-4.71), first-degree relationship with the proband (OR = 16.61, 95%CI 10.50-26.28) and segregation of the PV in both the maternal (OR = 2.54, 95%CI 1.72-3.75) and the paternal branch (OR = 4.62, 95%CI 3.09-6.91). These real-world data may be important to inform the design and implementation of strategies aimed at improving the uptake of HBOC cascade testing in Italy.

The Precision Medicine Initiative was launched upon the potential of genomic information to tailor medical care. Cascade genetic testing represents a powerful application of precision medicine and involves the process of familial diffusion or the "cascade" of genomic risk information. When an individual (proband) is found to carry a cancer-associated germline pathogenic mutation, the information should be cascaded or shared with at-risk relatives. First degree relatives have a 50% likelihood of carrying the same cancer-associated mutation. This process of cascade testing offers at-risk relatives the opportunity for genetic testing and, for those who also carry the cancer-associated mutation, genetically targeted primary disease prevention through intensive cancer surveillance, chemoprevention and risk-reducing surgery, reducing morbidity and preventing mortality. Cascade testing has been designated by the Centers for Disease Control and Prevention as a Tier 1 genomic application for hereditary breast and ovarian cancer. In this manuscript we describe a cascade genetic testing and in particular focus on its potential to provide necessary care to medically underserved and vulnerable populations.

Some patients with metastatic prostate cancer carry a pathogenic germline variant (PV) in a gene, that is mainly associated with an increased risk of breast cancer in women. If they test positive for such a PV, prostate cancer patients are encouraged to disclose the genetic test result to relatives who are at risk in case the carrier status changes the relatives' medical care. Our study aimed to investigate how men who learned they carry a PV in BRCA1, BRCA2, PALB2, CHEK2 or ATM disclosed their carrier status to at-risk relatives and to assess the possible psychological burden for the carrier and their perception of the burden for relatives. In total, 23 men with metastatic prostate cancer carrying a PV completed the IRI questionnaire about family communication; 14 also participated in a semi-structured interview. Patients felt highly confident in discussing the genetic test result with relatives. The diagnosis of prostate cancer was experienced as a burden, whereas being informed about genetic testing results did in most cases not add to this burden. Two patients encountered negative experiences with family communication, as they considered the genetic test result to be more urgent than their relatives. This mixed-methods study shows that metastatic prostate cancer patients with a PV in genes mainly associated with increased risk of breast cancer feel well-equipped to communicate about this predisposition in their families. Carriers felt motivated to disclose their genetic test result to relatives. Most of them indicated that the disclosure was not experienced as a psychological burden.

Hormonal contraception (HC) is a well-recognized protection against endometrial cancer (EC) in the general population. It has not been established if this is also applicable to women with Lynch syndrome (LS), a condition associated with a up to 50% lifetime risk of developing EC. The objective of this study was to evaluate if the use of HC influences the incidence of endometrial hyperplasia and EC in women with LS by comparing the histology of annual endometrial biopsies obtained in patients with LS who are using HC versus non-users. This is a retrospective cohort study conducted with endometrial biopsies obtained in women 30 to 50 years of age with LS. The Pearson Chi-square test was performed to compare the prevalence of cancer and hyperplasia in the HC users and in the non-HC users groups. A total of 164 endometrial biopsies obtained among 75 women were suitable for analysis. Among the 86 biopsies obtained in the non-HC group, 81.4% (70/86) were normal. Two cases of endometrial carcinoma (2.3%) and 6 endometrial hyperplasia without atypia were found (7.0%). Among the 78 biopsies performed in patients using HC, 78.2% (61/78) were normal. Three endometrial hyperplasia without atypia (3.8%) and three cases of EC were diagnosed (3.8%). This study suggests that, in women of 30 to 50 years of age with LS, the use of hormonal contraception does not seem to decrease the occurrence of endometrial hyperplasia/carcinoma on annual endometrial histology.

MUTYH-Associated Polyposis (MAP) is caused by biallelic pathogenic germline variants in the MUTYH gene. However, individuals harboring monoallelic MUTYH pathogenic variants in the presence of a positive family history have been reported to have a twofold increased risk of colorectal cancer (CRC) and extra colonic cancers. Our aim was to characterize the spectrum of monoallelic and biallelic germline MUTYH pathogenic variants in Latin American patients and to describe their clinical and genetic characteristics. Patients were identified from eight high-risk genetic cancer centers of five Latin American countries. Statistical analysis was performed using the two-sided P test using the Vassarstats statistical tools. Statistical significance was set at a p value ≤ 0.05. Of the 105 unrelated patients with cancer or colorectal polyposis, 84.8% and 15.2% carried pathogenic monoallelic and biallelic MUTYH variants, respectively. The most common pathogenic variants were p.Gly396Asp and p.Tyr179Cys (55% and 23%, respectively). The mean age at first diagnosis was 48.29 years (range 31–71) and 49.90 years (range 27–87) in biallelic and monoallelic MUTYH patients, respectively. CRC was the only cancer diagnosed in patients with biallelic MUTYH pathogenic variants (75%), while breast cancer (46.1%) was more common than CRC (24.7%) in individuals with monoallelic MUTYH pathogenic variants. We reported a high frequency of European founder variants in our diverse population. Some phenotypic differences from current studies were identified, such as a higher breast cancer burden in monoallelic carriers and a complete absence of extra-colon tumors in biallelic patients.

Constitutional Mismatch Repair Deficiency (CMMRD) is a rare childhood cancer predisposition syndrome, caused by biallelic pathogenic germline variants in the mismatch repair genes. Diagnosis and management of this syndrome is challenging, especially in low-resource settings. This study describes a patient diagnosed with colorectal cancer and grade 3 astrocytoma at the age of 11 and 12 respectively. Immunohistochemistry analysis showed a loss of MSH2 and MSH6 protein expression in CRC tissues of the patient. We identified by Targeted Exome Sequencing a homozygous pathogenic germline variant in exon 9 of the MSH6 gene (c.3991 C > T; p.Ala1268Glyfs*6). Genetic investigation of the family showed that the father was heterozygous for the identified pathogenic variant while the brother was wild type for this variant. Our study highlights the importance of a correct and timely diagnosis of CMMRD which can have implications for treatment. It also underlines the imperative need to enhance awareness, diagnostic standards, and surveillance that are crucial for patients and their families.