Breast cancers in monoallelic MUTYH germline mutation carriers have clinicopathological features overlapping with those in BRCA1 germline mutation carriers.

PURPOSE: Breast cancer patients referred to genetic counseling often undergo genetic testing with broad panels that include both breast cancer susceptibility genes as well as genes more specific for extramammary sites. As a result, patients are often incidentally found to have germline mutations in genes that are not necessarily related to breast cancer risk. One such gene is MUTYH. To understand the role MUTYH may play in breast cancer, the clinicopathological features of patients with monoallelic MUTYH germline mutation and breast cancer were examined. METHODS: The clinicopathological characteristics of the breast cancers from patients with monoallelic MUTYH mutation were compared to breast cancer patients with other germline mutations in known breast cancer susceptibility genes, including ATM, BRCA1/2, CHEK2, and PALB2. The breast cancer patients who received genetic counseling but tested negative for the aforementioned gene mutations were used as a control group. RESULTS: Histologic characteristics of the breast cancers arising in monoallelic MUTYH mutation carriers had significantly larger tumor size, higher tumor grade, and more high-risk biomarker profiles (i.e., Her2-positive and triple-negative) than breast cancer patients with susceptibility genes, except for BRCA1. MUTYH mutation carriers also showed a trend of more frequent intratumoral divergency in terms of tumor grade and biomarker profiles. CONCLUSION: Although germline monoallelic MUTYH mutation is not thought to confer a meaningfully increased risk of breast cancer development, it may contribute to pathological aggressiveness and diversity of breast cancers when they sporadically arise in MUTYH carriers.

Implementation of a prospective screening strategy to identify adults with a telomere biology disorder among those undergoing lung transplant evaluation for interstitial lung disease.

INTRODUCTION: Patients with interstitial lung disease (ILD) secondary to telomere biology disorders (TBD) experience increased morbidity after lung transplantation. Identifying patients with TBD may allow for personalized management to facilitate better outcomes. However, establishing a TBD diagnosis in adults is challenging. METHODS: A TBD screening questionnaire was introduced prospectively into the lung transplant evaluation. Patients with ILD screening positive were referred for comprehensive TBD phenotyping and concurrent telomere length measurement and germline genetic testing. RESULTS: Of 98 patients, 32 (33%) screened positive. Eight patients (8% of total; 25% of patients with a positive screen) met strict TBD diagnostic criteria, requiring either critically short lymphocyte telomeres (<1st percentile) (n = 4), a pathogenic variant in a TBD-associated gene (n = 1), or both (n = 3) along with a TBD clinical phenotype. Additional patients not meeting strict diagnostic criteria had histories consistent with TBD along with telomere lengths <10th percentile and/or rare variants in TBD-associated genes, highlighting a critical need to refine TBD diagnostic criteria for this patient population. CONCLUSION: A TBD phenotype screening questionnaire in patients with ILD undergoing lung transplant evaluation has a diagnostic yield of 25%. Additional gene discovery, rare variant functional testing, and refined TBD diagnostic criteria are needed to realize the maximum benefit of testing for TBD in patients undergoing lung transplantation.

Concurrent high-grade glioma with cavernous malformations and pathogenic variants in PDCD10 and SMARCA4.

The co-occurrence of multiple disease processes can pose diagnostic challenges. We report an unusual case of a patient found to have co-occurrences of an IDH1-mutant high-grade glioma along with cerebral cavernous malformations and pathogenic germline variants in PDCD10 and SMARCA4. Somatic testing was done on the tumor and identified a SMARCA4 and two TP53 variants. Within the literature, little is known about the association of high-grade gliomas with these germline variants. Such findings furthermore not only inform complex diagnoses, but have the potential to play a crucial role in the ongoing care of a patient.

A Case of Isolated Myeloid Sarcoma Associated With Germline EGFR T790M Variant: The Importance of Recognizing Potential Germline Variants on Somatic Tumor Sequencing Panels.

Isolated myeloid sarcoma is an uncommon subtype of acute myeloid leukemia associated with variable prognosis. We present the case of a previously healthy 30-year-old man presenting with chest pain and weight loss who was found to have a large mediastinal mass. Biopsy of the mass was consistent with isolated myeloid sarcoma. A somatic tumor sequencing panel revealed an EGFR T790M variant, which was later confirmed to be of germline origin. Germline EGFR T790M variants are associated with a hereditary predisposition to lung cancer, though myeloid malignancies have not yet been described. To our knowledge, this is the first reported case of myeloid sarcoma in a patient with an underlying germline EGFR T790M mutation. As somatic tumor sequencing panels become more commonplace, it is important to recognize potential germline variants in order to facilitate appropriate referral for genetic counseling, perform confirmatory genetic testing, and to develop a personalized treatment and surveillance plan for patients and their families.

Rare variant in the fumarate hydratase gene found in patients with clinical features of hereditary leiomyomatosis and renal cell cancer (HLRCC): A case series.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an inherited cancer predisposition syndrome caused by autosomal dominant heterozygous pathogenic variants in the fumarate hydratase (FH) gene. FH pathogenic variant carriers are at an increased risk for cutaneous leiomyomas, renal cell cancer, and uterine fibroids. We present a case series of patients identified at two different medical institutions with clinically diagnostic features of HLRCC and a shared rare variant in the FH gene.