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1.
Breast Cancer Res Treat ; 204(1): 151-158, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38062336

ABSTRACT

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.


Subject(s)
Breast Neoplasms , Female , Humans , Biomarkers , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Genetic Predisposition to Disease , Germ-Line Mutation , Mutation
2.
J Genet Couns ; 2024 Aug 27.
Article in English | MEDLINE | ID: mdl-39189353

ABSTRACT

Hematologic malignancies (HMs) are a heterogeneous group of cancers impacting individuals of all ages that have been increasingly recognized in association with various germline predisposition syndromes. Given the myriad of malignancy subtypes, expanding differential diagnoses, and unique sample selection requirements, evaluation for hereditary predisposition to HM presents both challenges as well as exciting opportunities in the ever-evolving field of genetic counseling. This practice resource has been developed as a foundational resource for genetic counseling approaches to hereditary HMs and aims to empower genetic counselors who encounter individuals and families with HMs in their practice.

3.
Childs Nerv Syst ; 39(11): 3311-3315, 2023 11.
Article in English | MEDLINE | ID: mdl-37328659

ABSTRACT

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.


Subject(s)
Brain Neoplasms , Glioma , Humans , Glioma/complications , Glioma/diagnostic imaging , Glioma/genetics , Germ-Line Mutation , Mutation/genetics , Brain Neoplasms/complications , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/genetics , Isocitrate Dehydrogenase/genetics , DNA Helicases/genetics , Nuclear Proteins/genetics , Transcription Factors/genetics , Membrane Proteins/genetics , Proto-Oncogene Proteins/genetics , Apoptosis Regulatory Proteins/genetics
4.
JCO Precis Oncol ; 8: e2300466, 2024 May.
Article in English | MEDLINE | ID: mdl-38810171

ABSTRACT

PURPOSE: Somatic and germline testing are increasingly used to estimate risks for patients with cancer. Although both germline testing and somatic testing can identify genetic variants that could change a patient's care and eligible treatments, the aims of these tests and their technologies are fundamentally different and cannot be used interchangeably. This study examines the timing and results of somatic and germline genetic testing for patients with cancer at UW Health. METHODS: Eight hundred and seventy-seven participants underwent somatic genetic testing, which was reviewed by the Precision Medicine Molecular Tumor Board (PMMTB). Patients were diagnosed with cancers, including breast, colorectal, endometrial, pancreatic, or ovarian cancer, and met National Comprehensive Cancer Network criteria for germline genetic testing. Germline testing details were collected by medical record review. RESULTS: The results of this study found that only 310 patients (35%) had germline evaluation before PMMTB review. The percent of germline pathogenic/likely pathogenic variants identified in actionable genes was 28%. Most germline variants were identified in the BRCA1 (26%) and BRCA2 (28%) genes. In total, 65% (54/83) of germline variants were detected with both germline testing and somatic testing; however, 35% (29/83) of germline variants were not identified on somatic results. These results demonstrate the importance of combination germline and somatic testing. CONCLUSION: This study highlights the differences in genetic testing types and demonstrates that conducting germline testing at earlier stages of diagnoses is necessary to identify potentially actionable and treatment-specific variants in patients with cancer.


Subject(s)
Genetic Testing , Germ-Line Mutation , Neoplasms , Precision Medicine , Humans , Genetic Testing/methods , Female , Neoplasms/genetics , Male , Middle Aged , Adult , Aged , Aged, 80 and over , Young Adult
5.
JCO Precis Oncol ; 8: e2300518, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38848520

ABSTRACT

PURPOSE: Knowledge of an inherited predisposition to myelodysplastic syndrome (MDS) and AML has important clinical implications for treatment decisions, surveillance, and care of at-risk relatives. National Comprehensive Cancer Network (NCCN) guidelines recently incorporated recommendations for germline genetic evaluation of patients with MDS/AML on the basis of personal and family history features, but the practicality of implementing these recommendations has not been studied. METHODS: A hereditary hematology quality improvement (QI) committee was formed to implement these guidelines in a prospective cohort of patients diagnosed with MDS/AML. Referral for germline genetic testing was recommended for patients meeting NCCN guideline criteria. Referral patterns and genetic evaluation outcomes were compared with a historical cohort of patients with MDS/AML. Barriers to evaluation were identified. RESULTS: Of the 90 patients with MDS/AML evaluated by the QI committee, 59 (66%) met criteria for germline evaluation. Implementation of the QI committee led to more referrals for germline evaluation in accordance with NCCN guidelines (31% v 14%, P = .03). However, the majority of those meeting criteria were never referred due to high medical acuity or being deceased or in hospice at the time of QI committee recommendations. Despite this, two (17%) of the 12 patients undergoing genetic testing were diagnosed with a hereditary myeloid malignancy syndrome. CONCLUSION: Current NCCN guidelines resulted in two thirds of patients with MDS/AML meeting criteria for germline evaluation. A hereditary hematology-focused QI committee aided initial implementation and modestly improved NCCN guideline adherence. However, the high morbidity and mortality and prolonged inpatient stays associated with MDS/AML challenged traditional outpatient genetic counseling models. Further improvements in guideline adherence require innovating new models of genetic counseling and testing for this patient population.


Subject(s)
Genetic Testing , Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Humans , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Female , Male , Middle Aged , Aged , Practice Guidelines as Topic , Prospective Studies , Adult , Germ-Line Mutation , Aged, 80 and over , Quality Improvement
6.
Respir Med ; 220: 107464, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37951311

ABSTRACT

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.


Subject(s)
Lung Diseases, Interstitial , Lung Transplantation , Adult , Humans , Prospective Studies , Lung Diseases, Interstitial/diagnosis , Lung Diseases, Interstitial/genetics , Lung Diseases, Interstitial/surgery , Telomere/genetics , Biology
7.
Clin Case Rep ; 10(3): e05513, 2022 Mar.
Article in English | MEDLINE | ID: mdl-35251648

ABSTRACT

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.

8.
J Hematol ; 11(2): 71-76, 2022 Apr.
Article in English | MEDLINE | ID: mdl-35573754

ABSTRACT

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.

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