MLH1-methylated endometrial cancer under 60 years of age as the "sentinel" cancer in female carriers of high-risk constitutional MLH1 epimutation.

OBJECTIVE: Universal screening of endometrial carcinoma (EC) for mismatch repair deficiency (MMRd) and Lynch syndrome uses presence of MLH1 methylation to omit common sporadic cases from follow-up germline testing. However, this overlooks rare cases with high-risk constitutional MLH1 methylation (epimutation), a poorly-recognized mechanism that predisposes to Lynch-type cancers with MLH1 methylation. We aimed to determine the role and frequency of constitutional MLH1 methylation among EC cases with MMRd, MLH1-methylated tumors. METHODS: We screened blood for constitutional MLH1 methylation using pyrosequencing and real-time methylation-specific PCR in patients with MMRd, MLH1-methylated EC ascertained from (i) cancer clinics (n = 4, <60 years), and (ii) two population-based cohorts; "Columbus-area" (n = 68, all ages) and "Ohio Colorectal Cancer Prevention Initiative (OCCPI)" (n = 24, <60 years). RESULTS: Constitutional MLH1 methylation was identified in three out of four patients diagnosed between 36 and 59 years from cancer clinics. Two had mono-/hemiallelic epimutation (∼50% alleles methylated). One with multiple primaries had low-level mosaicism in normal tissues and somatic "second-hits" affecting the unmethylated allele in all tumors, demonstrating causation. In the population-based cohorts, all 68 cases from the Columbus-area cohort were negative and low-level mosaic constitutional MLH1 methylation was identified in one patient aged 36 years out of 24 from the OCCPI cohort, representing one of six (∼17%) patients <50 years and one of 45 patients (∼2%) <60 years in the combined cohorts. EC was the first/dual-first cancer in three patients with underlying constitutional MLH1 methylation. CONCLUSIONS: A correct diagnosis at first presentation of cancer is important as it will significantly alter clinical management. Screening for constitutional MLH1 methylation is warranted in patients with early-onset EC or synchronous/metachronous tumors (any age) displaying MLH1 methylation.

Developing a survivorship care plan (SCP) delivery process for patients and primary care providers serving poor, rural, and minority patients with cancer.

BACKGROUND: Survivorship care plans (SCPs) summarize patients' treatment and act as an education and communication tool between oncologists and primary care providers (PCPs). But creation and delivery of SCPs are challenging, labor intensive, and costly. The University of New Mexico Comprehensive Cancer Center (UNM CCC) treats a poor, rural, and minority patient population, and our purpose was to implement and evaluate a process to create and deliver SCPs to patients and PCPs. METHODS: Providers placed an electronic SCP order, basic information was imported, and staff compiled treatment details. Flagged SCPs were then ready for delivery, providers approved of and delivered the SCP at the next encounter, and the SCP was sent to the PCP. RESULTS: By April 2020, 283 SCPs were ordered, 241 (85.2%) were created by the designated staff, and 97 (34.2%) were given to patients after definitive therapy for breast cancer (59.1%), gynecological cancers (10.8%), prostate cancer (7.4%), colorectal cancer (5.1%), and lymphomas (4.8%). Of 97 SCPs eligible to be sent to PCPs, 75 (77.3%) were mailed or sent via EMR. Of the 41 (48.9%) SCPs sent via mail or fax, only 8 (8.3%) were received and 5 (5.2%) integrated. CONCLUSIONS: This study shows that SCPs can be delivered to patients in a poor, rural, and minority patient population but that PCP receipt and integration of SCPs are poor. Future efforts need to ensure that an oncologist to PCP education and communication tool is able reach and be integrated by PCPs.

Evaluation of an automated process for disclosure of negative noninvasive prenatal test results.

We designed and implemented a novel automated negative non-invasive prenatal test (NIPT) result disclosure process using a proprietary, HIPAA-compliant web-based portal. High-risk pregnant patients who opted for NIPT from 04/2017 to 12/2018 were given the option to receive their negative result through the automated process. Patients were required to watch a brief educational video and answer evaluative questions before downloading their result. After completing the process, patients completed a survey regarding their opinion of the efficiency and convenience of the process and their satisfaction. A total of 10,170 women registered online during the study period, and 8,965 completed the automated process (88%). Out of 8,965 women, 2,121 women responded to the survey (24%). Most (2,030 of 2,101) strongly agreed/agreed that they could easily navigate the patient portal (97%); 1,852 of 1,966 strongly agreed/agreed that disclosure was efficient and convenient (94%); 1,852 of 1,960 strongly agreed/agreed that they felt informed after watching a short educational video (94%); and 1,903 of 1,967 strongly agreed/agreed that they preferred downloading results rather than waiting for their next doctor's appointment (97%). This study demonstrates high patient satisfaction with this automated and scalable solution in a high-volume health system. As the utilization of genetic testing increases, we predict greater need for innovative healthcare delivery models.

Pancreatic neuroendocrine tumor in a patient with a TSC1 variant: case report and review of the literature.

The majority of pancreatic neuroendocrine tumors (PNETs) are sporadic while 10-15% are attributable to one of several familial cancer syndromes. Hereditary forms are more commonly associated with Multiple Endocrine Neoplasia Type I and von Hippel Lindau Syndrome. However, patients with Tuberous sclerosis complex also have an increased incidence of PNETs. More often this has been reported in patients with TSC2 variants. In this case report, we summarize the literature regarding PNETs associated with Tuberous sclerosis complex, as well as present a case of a patient with a TSC1 variant and a PNET. This case highlights the association of TSC1 gene variants with these tumors and emphasizes the importance of considering such diagnoses in this patient population.

Deep sequencing with intronic capture enables identification of an APC exon 10 inversion in a patient with polyposis.

PURPOSE: Single-exon inversions have rarely been described in clinical syndromes and are challenging to detect using Sanger sequencing. We report the case of a 40-year-old woman with adenomatous colon polyps too numerous to count and who had a complex inversion spanning the entire exon 10 in APC (the gene encoding for adenomatous polyposis coli), causing exon skipping and resulting in a frameshift and premature protein truncation. METHODS: In this study, we employed complete APC gene sequencing using high-coverage next-generation sequencing by ColoSeq, analysis with BreakDancer and SLOPE software, and confirmatory transcript analysis. RESULTS: ColoSeq identified a complex small genomic rearrangement consisting of an inversion that results in translational skipping of exon 10 in the APC gene. This mutation would not have been detected by traditional sequencing or gene-dosage methods. CONCLUSION: We report a case of adenomatous polyposis resulting from a complex single-exon inversion. Our report highlights the benefits of large-scale sequencing methods that capture intronic sequences with high enough depth of coverage-as well as the use of informatics tools-to enable detection of small pathogenic structural rearrangements.

Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features.

SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and, consequently, which of the three major SOX5 protein isoforms are affected. One intragenic deletion, involving only untranslated exons, was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene.