Prevalence and Clinical Implications of Mismatch Repair-Proficient Colorectal Cancer in Patients With Lynch Syndrome.

PURPOSE: Lynch syndrome (LS)-associated colorectal cancer (CRC) is characterized by mismatch repair-deficiency (MMR-D) and/or microsatellite instability (MSI). However, with increasing utilization of germline testing, MMR-proficient (MMR-P) and/or microsatellite stable (MSS) CRC has also been observed. We sought to characterize MMR-P/MSS CRC among patients with LS. METHODS: Patients with solid tumors with germline MMR pathogenic/likely pathogenic (P/LP) variants were identified on a prospective matched tumor-normal next-generation sequencing (NGS) protocol. CRCs were evaluated for MMR-D via immunohistochemical (IHC) staining and/or MSI via NGS. Clinical variables were correlated with MMR status using nonparametric tests. RESULTS: Among 17,617 patients with solid tumors, 1.4% (n = 242) had LS. A total of 36% (86 of 242) of patients with LS had at least one CRC that underwent NGS profiling, amounting to 99 pooled CRCs assessed. A total of 10% (10 of 99) of CRCs were MMR-P, with 100% concordance between MSS status and retained MMR protein staining. A total of 89% (8 of 9) of patients in the MMR-P group had MSH6 or PMS2 variants, compared with 30% (23 of 77) in the MMR-D group (P = .001). A total of 46% (6 of 13) of PMS2+ patients had MMR-P CRC. The median age of onset was 58 and 43 years for MMR-P and MMR-D CRC, respectively (P = .07). Despite the later median age of onset, 40% (4 of 10) of MMR-P CRCs were diagnosed <50. A total of 60% (6 of 10) of MMR-P CRCs were metastatic compared with 13% (12 of 89) of MMR-D CRCs (P = .002). A total of 33% (3 of 9) of patients with MMR-P CRC did not meet LS testing criteria. CONCLUSION: Patients with LS remained at risk for MMR-P CRC, which was more prevalent among patients with MSH6 and PMS2 variants. MMR-P CRC was later onset and more commonly metastatic compared with MMR-D CRC. Confirmation of tumor MMR/MSI status is critical for patient management and familial risk estimation.

Measuring high-risk parents' opinions about direct-to-consumer genetic testing for adult-onset inherited cancer syndromes in their adolescent and young adult children.

Neither direct-to-consumer (DTC) genetic testing nor predictive genetic testing for adult-onset conditions is recommended for minor children due to ethical concerns and low clinical utility. However, parents with pathogenic variants (PVs) in disease-causing genes may be interested in pursuing genetic testing that includes the familial PV for their children. The Pediatric Testing Attitudes Scale (P-TAS) was previously developed to examine high-risk parents' opinions about pediatric BRCA genetic testing for adult-onset breast/ovarian cancer. Here, the psychometric properties of the P-TAS were examined in a new sample of N = 126 parents (M age = 47.2 years) with PVs in a more complete set of cancer risk genes represented on DTC panel tests. The mean score on the P-TAS was 44 out of a maximum score of 60, indicating that a majority of parents generally held favorable opinions about testing their children for adult-onset inherited cancer syndromes. The internal consistency of the full scale was high (α = 0.91). A factor analysis identified two-component scales, labeled Attitudes and Beliefs (α = 0.93) and Decision Making and Communication (α = 0.83). In a multivariable regression model, P-TAS co-factors accounted for 34% of variance in parental opinions, including the frequency of prior family communication about cancer and the likelihood of utilizing DTC genetic testing with children (R2  = 0.34, p < 0.001). Results suggest that the P-TAS remains a reliable measure to assess high-risk parents' opinions about pediatric DTC genetic testing for adult-onset conditions, with promising validity. Applications of the P-TAS include informing genetic counseling practice, pediatric medical care, and policy guidelines surrounding DTC genetic testing.

Clinical Impact of Pathogenic Variants in DNA Damage Repair Genes beyond BRCA1 and BRCA2 in Breast and Ovarian Cancer Patients.

Consensus guidelines for hereditary breast and ovarian cancer include management recommendations for pathogenic/likely pathogenic (P/LP) variants in ATM, CHEK2, PALB2, and other DNA damage repair (DDR) genes beyond BRCA1 or BRCA2. We report on clinical management decisions across three academic medical centers resulting from P/LP findings in DDR genes in breast/ovarian cancer patients. Among 2184 patients, 156 (7.1%) carried a P/LP variant in a DDR gene. Clinical follow-up information was available for 101/156 (64.7%) patients. Genetic test result-based management recommendations were made for 57.8% (n = 59) of patients and for 64.7% (n = 66) of patients' family members. Most recommendations were made for moderate-to-high risk genes and were consistent with guidelines. Sixty-six percent of patients (n = 39/59) implemented recommendations. This study suggests that P/LP variants in DDR genes beyond BRCA1 and BRCA2 can change clinical management recommendations for patients and their family members, facilitate identification of new at-risk carriers, and impact treatment decisions. Additional efforts are needed to improve the implementation rates of genetic-testing-based management recommendations for patients and their family members.

Improving our model of cascade testing for hereditary cancer risk by leveraging patient peer support: a concept report.

Consensus and evidence suggest that cascade testing is critical to achieve the promise of cancer genetic testing. However, barriers to cascade testing include effective family communication of genetic risk information and family members' ability to cope with genetic risk. These barriers are further complicated by the developmental needs of unaffected family members during critical windows for family communication and adaptation. Peer support could address these barriers. We provide two illustrative examples of ongoing BRCA1/2-related clinical trials that apply a peer support model to improve family communication and functioning. Peer support can augment currently available genetic services to facilitate adjustment to and effective use of cancer genetic risk information. Importantly, this scalable approach can address the presence of cancer risk within families across multiple developmental stages. This applies a family-centered perspective that accommodates all potentially at-risk relatives. This peer support model can be further applied to emerging topics in clinical genetics to expand reach and impact.

Prevalence and Characterization of Biallelic and Monoallelic NTHL1 and MSH3 Variant Carriers From a Pan-Cancer Patient Population.

NTHL1 and MSH3 have been implicated as autosomal recessive cancer predisposition genes. Although individuals with biallelic NTHL1 and MSH3 pathogenic variants (PVs) have increased cancer and polyposis risk, risks for monoallelic carriers are uncertain. We sought to assess the prevalence and characterize NTHL1 and MSH3 from a large pan-cancer patient population. MATERIALS AND METHODS: Patients with pan-cancer (n = 11,081) underwent matched tumor-normal sequencing with consent for germline analysis. Medical records and tumors were reviewed and analyzed. Prevalence of PVs was compared with reference controls (Genome Aggregation Database). RESULTS: NTHL1-PVs were identified in 40 patients including 39 monoallelic carriers (39/11,081 = 0.35%) and one with biallelic variants (1/11,081 = 0.009%) and a diagnosis of isolated early-onset breast cancer. NTHL1-associated mutational signature 30 was identified in the tumors of the biallelic patient and two carriers. Colonic polyposis was not identified in any NTHL1 patient. MSH3-PVs were identified in 13 patients, including 12 monoallelic carriers (12/11,081 = 0.11%) and one with biallelic MSH3 variants (1/11,081 = 0.009%) and diagnoses of later-onset cancers, attenuated polyposis, and abnormal MSH3-protein expression. Of the 12 MSH3 carriers, two had early-onset cancer diagnoses with tumor loss of heterozygosity of the wild-type MSH3 allele. Ancestry-specific burden tests demonstrated that NTHL1 and MSH3 prevalence was not significantly different in this pan-cancer population versus controls. CONCLUSION: NTHL1 and MSH3 germline alterations were not enriched in this pan-cancer patient population. However, tumor-specific findings, such as mutational signature 30 and loss of heterozygosity of the wild-type allele, suggest the potential contribution of monoallelic variants to tumorigenesis in a subset of patients.

Prevalence of germline variants in inflammatory breast cancer.

BACKGROUND: Inflammatory breast cancer (IBC) is an uncommon and aggressive subtype of breast cancer associated with early disease recurrence and short survival. The prevalence of germline variants in cancer predisposition genes has not been systematically evaluated in women with IBC. METHODS: Among 301 women enrolled in the clinical IBC registry at a single institution between 2010 and 2017, 168 had documented genetic testing. A second cohort of 200 IBC cases who had panel-based germline testing performed through a commercial testing laboratory from 2012 to 2017 was added to the analyses. Personal and family cancer histories and genetic testing results were evaluated when they were available for both cohorts. RESULTS: Among 501 IBC cases, 368 had documented genetic testing. Germline mutations (56 total) were identified in 53 cases (14.4%). BRCA1 or BRCA2 mutations were found in 7.3% of the subjects, 6.3% had a mutation in other breast cancer genes (PALB2, CHEK2, ATM, and BARD1), and 1.6% had mutations in genes not associated with breast cancer. The prevalence of mutations was 24% (22 of 92) among women with triple-negative IBC, 13% (13 of 99) among women with estrogen receptor- and/or progesterone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative disease, and 9.3% (10 of 108) among women with HER2-positive IBC. CONCLUSIONS: The prevalence and diversity of germline genetic mutations among patients with IBC suggest that further studies should be performed to assess the role of inherited mutations in IBC carcinogenesis in comparison with non-IBC breast cancer. Since IBC has a high metastatic potential associated with poor prognostic outcomes, proposed future studies may also inform targeted treatment options.

Trans-counseling: A case series of transgender individuals at high risk for BRCA1 pathogenic variants.

Transgender individuals comprise a growing patient population in genetic counseling practice. The identification of a pathogenic variant in a cancer susceptibility gene may impact a transgender person's decisions regarding hormonal and/or surgical transition. Limited scientific literature exists on specific genetic counseling needs and medical management strategies for transgender individuals. In addition, most genetic counselors have had limited experience and training in conducting genetic counseling sessions with transgender patients. In this report, we describe three cases of transgender individuals who underwent genetic counseling and testing in our clinic. All were at ≥50% risk to carry a familial BRCA1 pathogenic variant. Case 1 is a 20-year-old transgender female initiating hormonal agents. Case 2 is a 19-year-old transgender male considering surgical decisions who has a BRCA1 pathogenic variant on both sides of the family. Case 3 is a 24-year-old transgender male who had previously undergone gender-affirming mastectomy (top surgery) and is taking androgen therapy. Unique aspects of genetic testing, psychosocial counseling, and medical management of transgender individuals have arisen in the course of their care. In this report, we discuss our experiences and practices of case preparation, case management, appropriate genetic testing, and medical management such as screening, surgical decisions, and coordination of care. There is a need for more research in this area and more transgender-specific training for genetic counselors.

Association of airway abnormalities with 22q11.2 deletion syndrome.

INTRODUCTION: 22q11.2 deletion syndrome (22q11.2DS) presents with complex but variable symptoms, including cardiac, immune, palatal, endocrine, cognitive, and psychiatric issues. However, an association of 22q11.2DS with structural airway abnormalities has not been formally described. The aim of this study was to document the frequency of this association. METHODS: We retrospectively reviewed medical records of patients with 22q11.2DS evaluated in the 22q and You Center at the Children's Hospital of Philadelphia between 1999 and 2015 referred to otolaryngology for an airway assessment. Type of airway abnormality and presence of comorbidities, such as congenital heart disease, tracheostomy, and association with prenatal symptomatology such as polyhydramnios, were noted. RESULTS: Of the 104 patients who underwent an otolaryngology procedure (microlaryngoscopy or bronchoscopy), 71% (n = 74) had airway abnormalities. Patients with airway abnormalities ranged in age from 5 months to 37 years, with similar prevalence among males and females. Observed airway abnormalities included tracheomalacia (36%), subglottic stenosis (28%), laryngomalacia (26%), glottic web (21%), and bronchomalacia (16%). Most patients with airway abnormalities (91%) had an associated congenital heart defect, with ventricular septal defect and Tetralogy of Fallot being the most prevalent. Importantly, 30% of patients required a tracheostomy, and overall polyhydramnios was noted in 16% of pregnancies. CONCLUSION: Airway abnormalities are a common feature of 22q11.2DS, leading to substantial morbidity, particularly when combined with complex cardiac disease. Polyhydramnios may be an important prenatal clue to both the diagnosis of 22q11.2DS and airway anomalies. Postnatal assessment of airway structure and function among patients with 22q11.2DS is an important component of overall evaluation and will help guide long-term management.

Genetically engineered mouse models in drug discovery research.

Genetically modified mouse models have been proven to be a powerful tool in drug discovery. The ability to genetically modify the mouse genome by removing or replacing a specific gene has enhanced our ability to identify and validate target genes of interest. In addition, many human diseases can be mimicked in the mouse and signaling pathways have been shown to be conserved. In spite of these advantages the technology has limitations. In transgenic animals there may be significant heterogeneity among different founders. In knock-out animals the predicted phenotypes are not always readily observed and occasionally a completely novel and unexpected phenotype emerges. To address the latter and ensure that a deep knowledge of the target of interest is obtained, we have developed a comprehensive phenotyping program which has identified novel phenotypes as well as any potential safety concerns which may be associated with a particular target. Finally we continue to explore innovative technologies as they become available such as RNAi for temporal and spatial gene knock-down and humanized models that may better simulate human disease states.

Knockout of striatal enriched protein tyrosine phosphatase in mice results in increased ERK1/2 phosphorylation.

STriatal Enriched protein tyrosine Phosphatase (STEP) is a brain-specific protein that is thought to play a role in synaptic plasticity. This hypothesis is based on previous findings demonstrating a role for STEP in the regulation of the extracellular signal-regulated kinase1/2 (ERK1/2). We have now generated a STEP knockout mouse and investigated the effect of knocking out STEP in the regulation of ERK1/2 activity. Here, we show that the STEP knockout mice are viable and fertile and have no detectable cytoarchitectural abnormalities in the brain. The homozygous knockout mice lack the expression of all STEP isoforms, whereas the heterozygous mice have reduced STEP protein levels when compared with the wild-type mice. The STEP knockout mice show enhanced phosphorylation of ERK1/2 in the striatum, CA2 region of the hippocampus, as well as central and lateral nuclei of the amygdala. In addition, the cultured neurons from KO mice showed significantly higher levels of pERK1/2 following synaptic stimulation when compared with wild-type controls. These data demonstrate more conclusively the role of STEP in the regulation of ERK1/2 activity.