Approximately 1 in 5 individuals diagnosed with CRC at age younger than 50 years carries a germline mutation associated with cancer; nearly half of these do not have clinical histories typically associated with the identified syndrome. Germline testing with multigene cancer panels should be considered for all young patients with CRC.

Microdeletions of 1q43q44 result in a recognizable clinical disorder characterized by moderate to severe intellectual disability (ID) with limited or no expressive speech, characteristic facial features, hand and foot anomalies, microcephaly (MIC), abnormalities (agenesis/hypogenesis) of the corpus callosum (ACC), and seizures (SZR). Critical regions have been proposed for some of the more prominent features of this disorder such as MIC and ACC, yet conflicting data have prevented precise determination of the causative genes. In this study, the largest of pure interstitial and terminal deletions of 1q43q44 to date, we characterized 22 individuals by high-resolution oligonucleotide microarray-based comparative genomic hybridization. We propose critical regions and candidate genes for the MIC, ACC, and SZR phenotypes associated with this microdeletion syndrome. Three cases with MIC had small overlapping or intragenic deletions of AKT3, an isoform of the protein kinase B family. The deletion of only AKT3 in two cases implicates haploinsufficiency of this gene in the MIC phenotype. Likewise, based on the smallest region of overlap among the affected individuals, we suggest a critical region for ACC that contains ZNF238, a transcriptional and chromatin regulator highly expressed in the developing and adult brain. Finally, we describe a critical region for the SZR phenotype which contains three genes (FAM36A, C1ORF199, and HNRNPU). Although ~90% of cases in this study and in the literature fit these proposed models, the existence of phenotypic variability suggests other mechanisms such as variable expressivity, incomplete penetrance, position effects, or multigenic factors could account for additional complexity in some cases.

Cancer genetics professionals face a new opportunity and challenge in adapting to the availability of cancer genetic testing panels, now available as a result of Next Generation Sequencing (NGS) technology. While cancer panels have been available for over a year, we believe that there is not yet enough data to create practice guidelines. Despite this, a year of experience allows us to provide our opinion on points to consider as cancer genetic counselors incorporate this testing technology into genetic counseling practice models. NGS technology offers the ability to potentially diagnose hereditary cancer syndromes more efficiently by testing many genes at once for a fraction of what it would cost to test each gene individually. However, there are limitations and additional risks to consider with these tests. Obtaining informed consent for concurrent testing of multiple genes requires that genetics professionals modify their discussions with patients regarding the potential cancer risks and the associated implications to medical management. We propose dividing the genes on each panel into categories that vary by degree of cancer risk (e.g. penetrance of the syndrome) and availability of management guidelines, with the aim to improve patient understanding of the range of information that can come from this testing. The increased risk for identifying variants of uncertain significance (VUS) when testing many genes at once must be discussed with patients. Pretest genetic counseling must also include the possibility to receive unexpected results as well as the potential to receive a result in the absence of related medical management guidelines. It is also important to consider whether a single gene test remains the best testing option for some patients. As panels expand, it is important that documentation reflects exactly which genes have been analyzed for each patient. While this technology holds the promise of more efficient diagnosis for many of our patients, it also comes with new challenges that we must recognize and address.

Purpose Prostate cancer has a significant heritable component, and rare deleterious germline variants in certain genes can increase the risk of prostate cancer. Our aim was to describe the prevalence of pathogenic germline variants in cancer predisposing genes in men with prostate cancer and at least one additional primary cancer. Patients and Methods Using a multi-gene panel, we sequenced germline DNA from 102 men with prostate cancer and at least one additional primary cancer who also met one or more of the following criteria: 1) age ≤ 55 at diagnosis of first malignancy, 2) rare tumor type or atypical presentation of a common tumor, and/or 3) three or more primary malignancies. Cancer family history and clinicopathologic data were independently reviewed by a clinical genetic counselor to determine if the patient met established criteria for testing for a hereditary cancer syndrome. Results Sequencing identified ~3500 variants. Nine protein truncating deleterious mutations were found across six genes including BRCA2, ATM, MLH1, BRIP1, PALB2, and FGFR3. Likely pathogenic missense variants were identified in CHEK2 and HOXB13. In total, 11/102 (10.8%) subjects were found to have pathogenic or likely pathogenic mutations in cancer predisposing genes. The majority of these men (64%) did not meet current clinical criteria for germline testing. Conclusion Men with prostate cancer and at least one additional primary cancer are enriched for harboring a germline deleterious mutation in a cancer predisposing gene that may impact cancer prognosis and treatment, but most do not meet current criteria for clinical genetic testing.