Living a Cancer Surveillance Life: A Meta-Ethnographic Synthesis of Everyday Experiences and Ambivalences for Women Living With Hereditary Risk of Breast and/or Ovarian Cancer.

Objective: Women with or at risk of hereditary breast- and ovarian cancer (HBOC) often live a surveillance-focused life from young adulthood. As they navigate a life of heightened medical vigilance, or a "cancer surveillance life," we explore how women with HBOC, as well as their partners and families, experience this particular kind of living through a thorough literature review of existing qualitative research.

Methods: We performed Boolean searches in PubMed, EMBASE, EBSCOhost, PSYCHinfo, Scopus, and Web of Science from April-May 2022, identifying 506 relevant articles.

Rare germline chromosome 1 duplication identified in young male with colon cancer: a case report investigating causality.

Background: The occurrence of colorectal cancer (CRC) is increasing among young adults, but the etiology is still largely unknown. In addition to germline monogenetic variants also polygenic risk scores (PRS) have been proven to correctly estimate the risk of CRC.

Case Description: We present a 24-year-old male with disseminated colon cancer who carried a germline duplication on chromosome 1 spanning 200 kb and covering and parts of and .

Reclassification of Two MLH1 Variants of Uncertain Significance Utilizing Clinical and Functional Data.

Background: Pathogenic variants in the mismatch repair genes are associated with an elevated lifetime risk of colorectal cancer (CRC). We previously identified two variants of uncertain significance (VUS) in the MLH1 gene, c.696_698del, p.

Variants in IGLL1 cause a broad phenotype from agammaglobulinemia to transient hypogammaglobulinemia.

Background: Agammaglobulinemia due to variants in IGLL1 has traditionally been considered an exceedingly rare form of severe B-cell deficiency, with only 8 documented cases in the literature. Surprisingly, the first agammaglobulinemic patient identified by newborn screening (NBS) through quantification of kappa-deleting recombination excision circles harbored variants in IGLL1.

Objective: We comprehensively reviewed clinical and immunologic findings of patients with B-cell deficiency attributed to variants in IGLL1.

Actionability and familial uptake following opportunistic genomic screening in a pediatric cancer cohort.

The care for patients with serious conditions is increasingly guided by genomic medicine, and genomic medicine may equally transform care for healthy individual if genomic population screening is implemented. This study examines the medical impact of opportunistic genomic screening (OGS) in a cohort of patients undergoing comprehensive genomic germline DNA testing for childhood cancer, including the impact on their relatives. Medical actionability and uptake after cascade testing in the period following disclosure of OGS results was quantified.

National Experiences from 30 Years of Provider-Mediated Cascade Testing in Lynch Syndrome Families-The Danish Model.

Cascade genetic testing and surveillance reduce morbidity and mortality in Lynch syndrome. However, barriers to conveying information about genetic disorders within families result in low uptake of genetic testing. Provider-mediated interventions may increase uptake but raise legal and ethical concerns.

The evolutionary impact of childhood cancer on the human gene pool.

Germline pathogenic variants associated with increased childhood mortality must be subject to natural selection. Here, we analyze publicly available germline genetic metadata from 4,574 children with cancer [11 studies; 1,083 whole exome sequences (WES), 1,950 whole genome sequences (WGS), and 1,541 gene panel] and 141,456 adults [125,748 WES and 15,708 WGS]. We find that pediatric cancer predisposition syndrome (pCPS) genes [n = 85] are highly constrained, harboring only a quarter of the loss-of-function variants that would be expected.

is a major susceptibility gene in Danish patients with multiple primary melanoma.

encodes the TINF2 protein, which is a subunit in the shelterin complex critical for telomere regulation. Three recent studies have associated six truncating germline variants in that have previously been associated with a cancer predisposition syndrome (CPS) caused by elongation of the telomeres. This has added to the genes, together with other telomere maintenance genes such as , , , and .

Clinical practice guidelines for the diagnosis and surveillance of BAP1 tumour predisposition syndrome.

BRCA1-associated protein-1 (BAP1) is a recognised tumour suppressor gene. Germline BAP1 pathogenic/likely pathogenic variants are associated with predisposition to multiple tumours, including uveal melanoma, malignant pleural and peritoneal mesothelioma, renal cell carcinoma and specific non-malignant neoplasms of the skin, as part of the autosomal dominant BAP1-tumour predisposition syndrome. The overall lifetime risk for BAP1 carriers to develop at least one BAP1-associated tumour is up to 85%, although due to ascertainment bias, current estimates of risk are likely to be overestimated.

The effect of a single SMARCA4 exon deletion on RNA splicing: Implications for variant classification.

Background: Exon deletions are generally considered pathogenic, particularly when they are located out of frame. Here, we describe a pediatric, female patient presenting with hypercalcemia and a small cell carcinoma of the ovary, hypercalcemic type, and carrying a germline de novo SMARCA4 exon 14 deletion.

Methods: The SMARCA4 deletion was identified by whole genome sequencing, and the effect on the RNA level was examined by gel- and capillary electrophoresis and nanopore sequencing.

Germline (epi)genetics reveals high predisposition in females: a 5-year, nationwide, prospective Wilms tumour cohort.

Background: Studies suggest that Wilms tumours (WT) are caused by underlying genetic (5%-10%) and epigenetic (2%-29%) mechanisms, yet studies covering both aspects are sparse.

Methods: We performed prospective whole-genome sequencing of germline DNA in Danish children diagnosed with WT from 2016 to 2021, and linked genotypes to deep phenotypes.

Results: Of 24 patients (58% female), 3 (13%, all female) harboured pathogenic germline variants in WT risk genes ( and ).

New pathogenic germline variants identified in mesothelioma.

Background: Mesothelioma (MM) is associated with asbestos exposure, tumor heterogeneity and aggressive clinical behavior. Identification of germline pathogenic variants (PVs) in mesothelioma is relevant for identifying potential actionable targets and genetic counseling.

Methods: 44 patients underwent whole exome sequencing (WES) or whole genome sequencing (WGS).

Combinatorial batching of DNA for ultralow-cost detection of pathogenic variants.

Background: Next-generation sequencing (NGS) based population screening holds great promise for disease prevention and earlier diagnosis, but the costs associated with screening millions of humans remain prohibitive. New methods for population genetic testing that lower the costs of NGS without compromising diagnostic power are needed.

Methods: We developed double batched sequencing where DNA samples are batch-sequenced twice - directly pinpointing individuals with rare variants.

RosettaDDGPrediction for high-throughput mutational scans: From stability to binding.

Reliable prediction of free energy changes upon amino acid substitutions (ΔΔGs) is crucial to investigate their impact on protein stability and protein-protein interaction. Advances in experimental mutational scans allow high-throughput studies thanks to multiplex techniques. On the other hand, genomics initiatives provide a large amount of data on disease-related variants that can benefit from analyses with structure-based methods.

Redefining germline predisposition in children with molecularly characterized ependymoma: a population-based 20-year cohort.

Ependymoma is the second most common malignant brain tumor in children. The etiology is largely unknown and germline DNA sequencing studies focusing on childhood ependymoma are limited. We therefore performed germline whole-genome sequencing on a population-based cohort of children diagnosed with ependymoma in Denmark over the past 20 years (n = 43).

Clinical implications of genetic testing in familial intermediate and late-onset colorectal cancer.

The genetic background of familial, late-onset colorectal cancer (CRC) (i.e., onset > age 50 years) has not been studied as thoroughly as other subgroups of familial CRC, and the proportion of families with a germline genetic predisposition to CRC remains to be defined.