Familial Cancer最新文献

Genetic testing in patients with ovarian carcinoma (OC) is crucial, as around 10-15% of these women have a genetic predisposition to OC. Although guidelines have recommended universal germline testing for all patients with OC for a decade, implementation has proved challenging, thus resulting in low germline-testing rates (around 30-50%). Many new initiatives to improve genetic-testing rates have emerged, but most have been carried out at the local level, leading to differences in workflows within and between countries. We present an example of a nationwide implementation project that has successfully led to a uniform, high-quality genetic-testing workflow for women with OC. Nationwide multidisciplinary meetings generated consensus on the preferred workflow for OC genetic testing: the "Tumor-First" workflow. This workflow means starting by testing the tumor DNA for the presence of pathogenic variants in OC-risk genes, thus providing a prescreen to germline testing while yielding information on the effectiveness of treatment with PARP inhibitors. This new workflow efficiently stratifies genetic counseling and germline testing and reduces healthcare costs. Although challenging, the nationwide implementation of this workflow was successful, resulting in tumor-DNA testing rates exceeding 80%. In this article, we present our structured implementation approach, illustrate our implementation strategies-which were tailored to identified factors important to implementation-and share the lessons learned from the Tumor-First implementation project. This knowledge could facilitate the future implementation of workflows aimed at optimizing the recognition of hereditary cancers.

Background: Birt-Hogg-Dubé (BHD) syndrome is a genetic condition caused by pathogenic variants in the FLCN gene resulting in benign skin lesions, spontaneous pneumothorax, and increased risk for a variety of renal tumors. Skin manifestations of BHD include trichodiscoma (TD) and fibrofolliculoma (FF), which may represent the same pathologic entity. These lesions can identify BHD patients, who upon positive genetic testing can be considered for life-long surveillance for renal neoplasms.

Objective: To characterize patients diagnosed with TD and FF including rates and outcomes of genetics referral.

Methods: Retrospective chart reviews of patients with confirmed or possible diagnosis of TD or FF at the University of Michigan from September 2002 through October 2020 to assess pathologic findings, personal and family history of BHD manifestations, referral for genetic evaluation, and genetic testing results.

Results: 64 patients had a pathologic diagnosis of TD or FF, 16 of whom (25%) were referred to cancer genetics. Fourteen patients completed genetic evaluation, 9 of whom were diagnosed with BHD (64%), with 6 unique pathogenic variants in FLCN.

Conclusion: Providers should consider referral for genetic evaluation for patients with biopsy-proven TD or FF, as early diagnosis of BHD provides the opportunity for early detection and treatment of other BHD-associated conditions.

Peutz-Jeghers syndrome is a rare, autosomal dominant polyposis syndrome. Presenting with a remarkable phenotype including development of characteristic gastrointestinal polyps, mucocutaneous pigmentations, and an increased risk of cancer, the syndrome has been subject to many studies concerning the natural course of disease. In most patients, pathogenic germline variants are detected in the STK11 gene including cases of mosaicism and structural variants. Yet, studies assessing the effect of surveillance, understanding of cancer development, as well as clinical studies evaluating chemoprevention are lacking. In addition, the impact of Peutz-Jeghers syndrome on mental health, education, and family planning are insufficiently addressed. In this progress report, we describe current knowledge, clinical phenotype, surveillance strategies, and future areas of research.

Telomerase Reverse Transcriptase (TERT) encodes the telomerase reverse transcriptase enzyme and is the most frequently mutated gene in patients with telomeropathies. Heterozygous variants impair telomerase activity by haploinsufficiency and pathogenic variants are associated with bone marrow failure syndrome and predisposition to acute myeloid leukaemia. Owing to their rarity, telomeropathies are often unrecognised and misdiagnosed. Herein, we report a novel TERT gene variant, c.2605G > A p.(Asp869Asn) in a family with hereditary aplastic anaemia. This report emphasises the importance of routine deep genetic screening for rare TERT variants in patients with a family history of cytopenia or aplastic anaemia, which could identify clinically inapparent telomere disorders.

PMS2, a Lynch Syndrome gene, presents challenges in genetic testing due to the existence of multiple pseudogenes. This study aims to describe a series of cases harboring a variant in the PMS2CL pseudogene that has been incorrectly assigned to PMS2 with different nomenclatures. We reviewed data from 647 Brazilian patients who underwent multigene genetic testing at a single center to identify those harboring the PMS2 V1:c.2186_2187delTC or V2:c.2182_2184delACTinsG variants, allegedly located at PMS2 exon 13. Gene-specific PCR and transcript sequencing was performed. Among the 647 individuals, 1.8% (12) carried the investigated variants, with variant allele frequencies ranging from 15 to 34%. By visually inspecting the alignments, we confirmed that both V1 and V2 represented the same variant and through gene-specific PCR and PMS2 transcript analysis, we demonstrated that V1/V2 is actually located in the PMS2CL pseudogene. Genomic databases (ExAC and gnomAD) report an incidence of 2.5 - 5.3% of this variant in the African population. Currently, V1 is classified as "uncertain significance" and V2 as "conflicting" in ClinVar, with several laboratories classifying them as "pathogenic". We identified a frequent African PMS2CL variant in the Brazilian population that is misclassified as a PMS2 variant. It is likely that V1/V2 have been erroneously assigned to PMS2 in several manuscripts and by clinical laboratories, underscoring a disparity-induced matter. Considering the limitations of short-read NGS differentiating between certain regions of PMS2 and PMS2CL, using complementary methodologies is imperative to provide an accurate diagnosis.

Epithelial ovarian cancer (EOC) is the most lethal type of gynaecological cancer, due to lack of effective screening possibilities and because the disease tends to metastasize before onset of symptoms. Women with an increased inherited risk for EOC are advised to undergo a risk-reducing salpingo-oophorectomy (RRSO), which decreases their EOC risk by 96% when performed within guideline ages. However, it also induces premature menopause, which has harmful consequences. There is compelling evidence that the majority of EOCs originate in the fallopian tube. Therefore, a risk-reducing salpingectomy with delayed oophorectomy (RRS with DO) has gained interest as an alternative strategy. Previous studies have shown that this alternative strategy has a positive effect on menopause-related quality of life and sexual health when compared to the standard RRSO. It is hypothesized that the alternative strategy is non-inferior to the standard RRSO with respect to oncological safety (EOC incidence). Three prospective studies are currently including patients to compare the safety and/or quality of life of the two distinct strategies. In this article we discuss the background, opportunities, and challenges of the current and alternative strategy.

TP53 pathogenic variants cause Li-Fraumeni syndrome (LFS), with some variants causing an attenuated phenotype. Herein, we describe the clinical phenotype and genetic characteristics of carriers of NM_000546.6 (TP53): c.541C > T, (p.Arg181Cys) treated at Hadassah Medical Center. We retrospectively examined our genetic databases to identify all carriers of TP53 p.Arg181Cys. We reached out to carriers and their relatives and collected clinical and demographic data, lifestyle factors, carcinogenic exposures as well as additional blood samples for genetic testing and whole exome sequencing. Between 2005 and 2022 a total of 2875 cancer patients underwent genetic testing using genetic panels, whole exome sequencing or targeted TP53 assays. A total of 30 cancer patients, all of Arab-Muslim descent, were found to be carriers of TP53 p.Arg181Cys, the majority from Jerusalem and Hebron, two of which were homozygous for the variant. Carriers were from 24 distinct families of them, 15 families (62.5%) met updated Chompret criteria for LFS. Median age of diagnosis was 35 years-old (range 1-69) with cancers characteristic of LFS (16 Breast cancer; 6 primary CNS tumors; 3 sarcomas) including 4 children with choroid plexus carcinoma, medulloblastoma, or glioblastoma. A total of 21 healthy carriers of TP53 p.Arg181Cys were identified at a median age of 39 years-old (range 2-54)-19 relatives and 2 additional pediatric non-cancer patients, in which the finding was incidental. We report a shared haplotype of 350kb among carriers, limited co-morbidities and low BMI in both cancer patients and healthy carriers. There were no demographic factors or carcinogenic exposures unique to carriers who developed malignancy. Upon exome analysis no other known pathogenic variants in cancer predisposing genes were identified. TP53 p.Arg181Cys is a founder pathogenic variant predominant to the Arab-Muslim population in Jerusalem and Hebron, causing attenuated-LFS. We suggest strict surveillance in established carriers and encourage referral to genetic testing for all cancer patients of Arab-Muslim descent in this region with LFS-associated malignancies as well as family members of established carriers.

Non-small cell lung cancer is the most common cause of cancer death globally. When apparent incidental pathogenic germline variants (PGVs) are uncovered with routine next generation sequencing (NGS) of NSCLCs, germline testing (GT) is recommended to confirm that PGV. Because it is far more common that an uncovered tumor TP53 variant is related to a somatic event than an incidental PGV, however, GT for Li Fraumeni syndrome (LFS) is not recommended based solely on uncovering a NSCLC TP53 variant. Because nearly all tumor EGFR variants are also somatic in origin, GT is not recommended based solely on uncovering a tumor EGFR variant.However, there is evidence that patients with coexisting NSCLC variants in both EGFR and TP53 have significant likelihoods of having LFS. For patients with LFS, there are recommended measures for prevention and early detection of LFS-associated cancers and cascade GT of relatives for LFS. Although co-existing genetic variants in NSCLC are not currently used as a biomarker for GT to identify patients with PGVs, given the evidence reviewed here, select patients with NSCLCs that harbor this dual biomarker (i.e., co-existing TP53/EGFR variants) might reasonably be considered for GT for LFS.

Germline genomic sequencing is increasingly integrated into pediatric cancer care, with pathogenic cancer-predisposing variants identified among 5-18% of affected children and variants of uncertain significance (VUS) in up to 70%. Given the potential medical implications for children and their families, parents' psychosocial responses to learning results are important to understand. Parents of children with cancer who learned their children's germline pathogenic or VUS results following paired tumor and germline genomic sequencing described their cognitive and affective responses to results in an open-ended write-in question after disclosure (M = 10 months post-disclosure; range = 1-28). Responses were coded and categorized using content analysis, then compared across results using chi-square and Fisher's exact test. Parents of children with pathogenic (n = 9), VUS (n = 52), and pathogenic plus VUS results (n = 9) described negative emotions, positive reactions, mixed emotions (i.e., positive and negative emotions), and neutral reactions. Negative emotions were described significantly more frequently with pathogenic results than VUS only (χ² = 5.19; p = .02), with peace of mind and empowerment only described for those with VUS. Parents also described approach(es) to coping (e.g., faith, plan of action) and reactions specific to the uncertainty of VUS (e.g., disappointment at no explanation for cancer etiology). A subset with VUS described decreasing worry/distress with increased understanding of results, whereas others displayed misconceptions regarding VUS. Screening for emotional adjustment is warranted for parents of children with cancer receiving pathogenic germline results, and screening for understanding is warranted with VUS. Findings highlight the importance of pre-and posttest genetic counseling.

Fanconi anemia (FA) is an inherited bone marrow failure syndrome (IBMFS) characterized by pathogenic variants in the FA/BRCA DNA repair pathway genes. Individuals with FA have an elevated risk of developing myelodysplastic syndrome, acute myeloid leukemia, and solid tumors. Hematopoietic cell transplantation (HCT) is the most effective treatment for FA related bone marrow failure but can increase the risk of cancer development. Information on benign tumors and NMSC is lacking in patients with FA. Our objective was to characterize patients with FA enrolled in the National Cancer Institute IBMFS Study who have experienced non-melanoma skin cancers (NMSC) and/or benign tumors (BT). A total of 200 patients diagnosed with FA were enrolled in the Institutional Review Board approved study "Etiologic Investigation of Cancer Susceptibility in IBMFS: A Natural History Study" (NCT00027274). Through medical records review, we identified 30 patients with at least one NMSC, either squamous or basal cell carcinoma, or benign tumor. The remaining 170 patients comprised the control group. Out of 200 patients, 12 had NMSC, 25 had benign tumors, with an age range of 11-64 and 0-56 years, respectively. The median age at HCT was 30.5 years for NMSC patients, 9 years for benign tumor patients, and 9.1 years for controls. The most common genotype observed was FANCA, followed by FANCC and FANCI. Benign tumors spanned diverse anatomical locations. Early onset NMSC in patients with FA compared to the general population emphasizes the need for consistent monitoring in patients with FA, while the diverse anatomical locations of benign tumors underscore the importance of comprehensive surveillance for timely interventions in managing symptomatology and heightened cancer risk.