Familial Cancer最新文献

This study aimed to characterize, for the first time, the cancer spectrum associated with the most frequent pathogenic CHEK2 variant-NM_007194.4(CHEK2):c.707T > C p.(Leu236Pro)-in Mexican individuals. Although this variant is frequently detected through multi-gene panel testing, limited data on its associated cancer risks complicates genetic counseling and surveillance strategies. We retrospectively analyzed 5,759 patients who underwent multi-gene panel testing between August 2015 and August 2024 due to suspected hereditary cancer syndromes. Among them, 58 CHEK2 p.(Leu236Pro) carriers with confirmed cancer diagnoses were identified. Geographical clustering was observed, with 81% of patients originating from central Mexico, suggesting a possible founder effect. Ten distinct clinical indications for genetic testing were identified, with hereditary breast and ovarian cancer (HBOC) syndrome being the most common (74.1%). The mean age at first diagnosis among carriers was 43.8 ± 12 years, and 61.1% of them reported a family history of cancer in first- or second-degree relatives. A second or third primary cancer occurred in 20.7% of cases. Tumors were identified in 12 anatomical sites. Breast cancer predominated (67.6%, including one male case), followed by ovarian (8.1%), prostate (6.7%), gastric (4.1%), thyroid (2.7%), and endometrial (2.7%) cancers. Lymphoma, lung, sacrococcygeal bone, colorectal, and non-melanoma skin cancers each occurred in a single patient. Significant risk association was identified only for breast, ovarian, and gastric cancers. These results highlight the need for personalized surveillance, especially for breast cancer. Incorporating CHEK2 p.(Leu236Pro) into clinical decision-making tools may enhance risk assessment in the Mexican population, but larger studies are needed to refine risk estimates and to clarify the possible founder effect.

Li-Fraumeni syndrome (LFS) is an early-onset cancer syndrome caused by pathogenic germline TP53 variants. Adolescents and young adults (AYAs) with LFS may have challenges navigating new romantic partnerships given the significant effects of LFS on multiple life domains that also affect partners (e.g., reproductive decision-making). Disclosing LFS-related information to new partners may be especially difficult given the uncertainty, complexity, and chronicity of LFS. This qualitative-descriptive study aimed to explore AYAs' LFS disclosure decisions and experiences in new romantic partnerships. Participants were individuals with LFS aged 15-39 years at enrollment in a National Cancer Institute study. The analytic sample included 33 AYAs who completed at least one telephone interview. Greene's disclosure decision-making model guided thematic analysis. Participants were mostly female (67%) and married/in a long-term relationship (58%), with mean age 29 years and ≥ 1 primary cancer (61%). Key factors in LFS disclosure decision-making included perceived relevancy to partners (e.g., future children's genetic risk), partner traits (e.g., trustworthiness), and relationship quality (e.g., closeness). AYAs described LFS disclosures in new partnerships as a process. Disclosing LFS diagnosis often occurred early to fulfill a sense of moral obligation and emotionally self-protect from future rejection, while subsequent LFS disclosures depended on relationship quality and the topic's emotional valence or complexity. Partners often earned AYAs' trust by demonstrating a willingness to learn about and try to understand LFS. Clinicians and LFS communities could support AYAs by providing opportunities to discuss, normalize, and ameliorate challenges with LFS disclosures in new romantic partnerships (e.g., peer support groups, psychotherapy).

Familial adenomatous polyposis (FAP) is an inherited condition that predisposes individuals to colorectal cancer without preventive treatment. Surgical management typically involves restorative proctocolectomy with an ileal pouch anal anastomosis or colectomy with ileorectal anastomosis. Complete removal of the large intestine and rectum with a permanent stoma may also be required in selected cases. This narrative review highlights decision-making in FAP regarding the timing, extent, and modality of large bowel surgery. Key considerations include the extent of polyps, cancer risk in the remaining rectum, and associated extra-colonic manifestations like desmoid disease. The timing of surgery and the extent of bowel removal are critical factors requiring a personalized approach that considers patient preferences and clinical factors. Regardless of the chosen strategy, continued surveillance is essential to monitor disease progression.

This study compares three hereditary colorectal cancer (CRC) registries-the Iranian Hereditary Colorectal Cancer Registry (IHCCR), the Singapore Polyposis Registry (SPR), and the University of Cape Town Familial CRC Registry-to illuminate diverse approaches to identification, management, and research across different healthcare systems. Each registry, while emphasizing patient diversity, employed unique strategies reflecting available resources and epidemiological contexts. The IHCCR, leveraging WES, revealed considerable genetic heterogeneity, including novel mutations. The SPR, a nationalized service, focused on structured surveillance and management of FAP and other polyposis syndromes, highlighting the challenges of cultural conservatism and limited public awareness. The UCT registry, initially concentrating on Lynch syndrome, expanded to encompass other hereditary CRC syndromes, revealing a high prevalence of these conditions within the South African population. All three registries encountered challenges related to access to genetic testing and early diagnosis. The registries' combined experiences underscore the critical need for integrated, culturally sensitive strategies combining genetic testing, enhanced surveillance, and family-based management to improve outcomes for individuals and families affected by hereditary CRC. Future efforts should focus on addressing disparities in access to care and expanding research to improve understanding and management of this complex disease.

Pathogenic variants in the APC gene are classically associated with autosomal dominant familial adenomatous polyposis (FAP), characterized by tens-to-thousands of colonic adenomatous polyps and a high-penetrance predisposition to colorectal cancer. More recently, specific PVs in the YY1 binding motif of APC promoter 1B have been associated with autosomal dominant gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), characterized by tens-to-thousands of fundic gland polyps and a predisposition to gastric cancer but which are only rarely associated with features consistent with FAP. Although management guidelines currently treat FAP and GAPPS as mutually exclusive conditions, the extent of phenotypic overlap is not well-characterized. Here, we present a multi-clinic and -laboratory collaboration reporting a previously undescribed APC promoter 1B insertion/deletion likely pathogenic variant in a family with mixed GAPPS and FAP phenotype. The family proband is a female of unspecified white ancestry. She was diagnosed with GAPPS at age 30 and, after developing gastric cancer at age 39, underwent curative gastrectomy. She is now 61 with a cumulative history of between 50 and 100 colon adenomas and recently completed subtotal colectomy. Her multi-gene panel testing in 2022 demonstrated a likely pathogenic insertion/deletion (indel) within the APC promoter 1B YY1 binding motif (APC c.-192_-191delATinsTAGCAAGGG). Review of a four-generation pedigree revealed the ages of gastric cancer presentation in the family ranged from 39-60's, with advanced gastric polyposis and prophylactic gastrectomy as early as ages 11 and 13 in the proband's daughter and nephew, respectively. Six of 10 (60%) family members known or presumed to carry the APC likely pathogenic variant underwent colectomy or hemicolectomy due to colon polyposis. The youngest known carrier in the family is a 12-year-old female, and the oldest living carrier is the proband's brother, age 66. A novel APC indel causes concomitant GAPPS and FAP presentations in this previously unreported large kindred. Mixed gastric and colon phenotypes have been rarely described in GAPPS families and the ages of presentation of gastric polyposis are strikingly young in the current family with prophylactic gastrectomies completed as early as age 11 and 13. These ages are significantly younger than the 15 years of age at which national guidelines currently recommend initiation of EGD for screening in GAPPS. Although the mechanism for this combined GAPPS-FAP phenotype is unclear, patients in this family and those with similar APC promoter 1B variants should be offered both gastric and colon cancer risk management.

This study aimed to develop and validate a Multidimensional Impact of Cancer Risk Assessment questionnaire-Japanese version (MICRA-J) as an assessment of the psychosocial impact of genetic testing. The MICRA was translated into Japanese using standardized translation procedures. The reliability and validity of the MICRA-J were evaluated in individuals who underwent BRCA1/2 testing for hereditary breast and ovarian cancer diagnosis. The 72 respondents included patients with BRCA1/2 pathogenic variants (n = 20), BRCA1/2 negative (n = 35), variants of uncertain significance (VUS, n = 6), participants with cascade testing positive (n = 7), and participants with cascade testing negative (n = 4). Total MICRA-J scores were positively correlated with Hospital Anxiety and Depression Scale (HADS) scores and negatively correlated with the 36-item short-form version 2 acute (SF-36v2 acute) scores (P < 0.05). The MICRA-J showed good internal consistency coefficients (α > 0.70). Furthermore, high test-retest correlations were obtained when the 64 participants responded to the MICRA-J twice within a short period (Pearson's correlation coefficient = 0.85). The MICRA-J Total score was higher in the groups with BRCA1/2 pathogenic variant carriers than in the BRCA1/2 negative group, whereas the HADS and SF36v2 acute did not differ significantly. These results suggest that the reliability and validity of the MICRA-J have been established. The MICRA-J, similar to the MICRA in other languages, is considered a useful tool to specifically measure the psychosocial impact of genetic testing.

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.