Kevin M. Zbuk
Cleveland Clinic
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Featured researches published by Kevin M. Zbuk.
Nature Clinical Practice Gastroenterology & Hepatology | 2007
Kevin M. Zbuk; Charis Eng
The hamartomatous polyposis syndromes are a heterogeneous group of disorders that share an autosomal-dominant pattern of inheritance and are characterized by hamartomatous polyps of the gastrointestinal tract. These syndromes include juvenile polyposis syndrome, Peutz–Jeghers syndrome and the PTEN hamartoma tumor syndrome. The frequency and location of the polyps vary considerably among syndromes, as does the affected patients predisposition to the development of gastrointestinal and other malignancies. Although the syndromes are uncommon, it is important for the clinician to recognize these disorders because they are associated with considerable morbidity and mortality, not only from malignancy but also from nonmalignant manifestations such as bleeding, intussusception, and bowel obstruction. Each hamartomatous polyposis syndrome has its own distinctive organ-specific manifestations and each requires a different surveillance strategy, which makes accurate diagnosis crucial for appropriate patient management. The availability of clinical genetic testing for these disorders means that appropriate recognition allows for timely referral for cancer genetic counseling, and often allows for predicative testing in at-risk family members. Promisingly, an understanding of the molecular pathogenesis of these disorders offers insights into the mechanisms underlying the development of sporadic malignancy, and enables rational selection of targeted therapies that warrant further investigation.
American Journal of Human Genetics | 2008
Ying Ni; Kevin M. Zbuk; Tammy Sadler; Attila Patócs; Glenn P. Lobo; Emily Edelman; Petra Platzer; Mohammed S. Orloff; Kristin A. Waite; Charis Eng
Individuals with PTEN mutations have Cowden syndrome (CS), associated with breast, thyroid, and endometrial neoplasias. Many more patients with features of CS, not meeting diagnostic criteria (termed CS-like), are evaluated by clinicians for CS-related cancer risk. Germline mutations in succinate dehydrogenase subunits SDHB-D cause pheochromocytoma-paraganglioma syndrome. One to five percent of SDHB/SDHD mutation carriers have renal cell or papillary thyroid carcinomas, which are also CS-related features. SDHB-D may be candidate susceptibility genes for some PTEN mutation-negative individuals with CS-like cancers. To address this hypothesis, germline SDHB-D mutation analysis in 375 PTEN mutation-negative CS/CS-like individuals was performed, followed by functional analysis of identified SDH mutations/variants. Of 375 PTEN mutation-negative CS/CS-like individuals, 74 (20%) had increased manganese superoxide dismutase (MnSOD) expression, a manifestation of mitochondrial dysfunction. Among these, 10 (13.5%) had germline mutations/variants in SDHB (n = 3) or SDHD (7), not found in 700 controls (p < 0.001). Compared to PTEN mutation-positive CS/CS-like individuals, those with SDH mutations/variants were enriched for carcinomas of the female breast (6/9 SDH versus 30/107 PTEN, p < 0.001), thyroid (5/10 versus 15/106, p < 0.001), and kidney (2/10 versus 4/230, p = 0.026). In the absence of PTEN alteration, CS/CS-like-related SDH mutations/variants show increased phosphorylation of AKT and/or MAPK, downstream manifestations of PTEN dysfunction. Germline SDH mutations/variants occur in a subset of PTEN mutation-negative CS/CS-like individuals and are associated with increased frequencies of breast, thyroid, and renal cancers beyond those conferred by germline PTEN mutations. SDH testing should be considered for germline PTEN mutation-negative CS/CS-like individuals, especially in the setting of breast, thyroid, and/or renal cancers.
Nature Reviews Clinical Oncology | 2007
Kevin M. Zbuk; Attila Patócs; Amy Shealy; Heather Sylvester; Susan Miesfeldt; Charis Eng
Background A 43-year-old woman presented to a cancer genetics clinic for a genetic risk assessment because of her personal history of multiple neoplasias. At 37 years of age, she was diagnosed with multifocal papillary thyroid cancer, and within a year was further diagnosed with a paraganglioma of the left common carotid artery. Two years later, she was diagnosed with a paraganglioma of the right carotid body. All three tumors were treated with surgical resection. There was no family history of malignancy. Past medical history includes uterine leiomyoma and fibrocystic breast disease. Physical examination revealed macrocephaly and papillomatous papules.Investigations CT scan of the neck and thorax, 24-hour urine collection for measurement of metanephrines and catecholamines, MRI of the neck, thorax, and abdomen, metaiodobenzylguanidine scan, germline mutation analysis of PTEN, SDHB, SDHC and SDHD.Diagnosis Cowden syndrome due to a germline mutation of PTEN, and pheochromocytoma–paraganglioma syndrome due to a germline mutation of SDHC.Management Clinical surveillance for breast, endometrial, thyroid, and renal cell carcinoma risks associated with Cowden syndrome according to the National Comprehensive Cancer Network guidelines, annual MRI of the neck, thorax, abdomen and pelvis, annual metabolic screening, and where available, annual 18-fluorodopamine PET scanning, predictive genetic testing of both PTEN and SDHC for the patients daughter and parents.
Nature Reviews Clinical Oncology | 2007
Brandie Heald; Joanne M. Hilden; Kevin M. Zbuk; Alice Norton; Paresh Vyas; Karl S. Theil; Charis Eng
Background A 34-year-old woman was referred for evaluation of a recent stillborn male fetus, gestational age 27 6/7 weeks, found to have congenital myeloid leukemia at autopsy. Autopsy findings included high weight for gestational age, hepatomegaly, and extensive intravascular leukemic infiltrates in the placenta, heart, liver, thymus, lung, kidneys, and brain. Genetic consultation and examination of photographs of the fetus revealed dysmorphic features.Investigations Immunoperoxidase staining of placental tissue, fluorescence in situ hybridization of paraffin-embedded sections of the placenta using probes for t(12;21)(p13;q22), t(8;21)(q22;q22) and t/del(11q23), cytogenetic analysis of fetal tissue (tendon), sequence analysis of GATA1 in placental leukemic cells, and parental chromosome studies.Diagnosis Down syndrome with in utero onset of GATA1 mutation-positive severe transient myeloproliferative disorder/acute megakaryoblastic leukemia.Management Genetic counseling for the recurrence risk of Down syndrome on the basis of maternal age.
The New England Journal of Medicine | 2008
Sharon E. Plon; Michael L. Pirics; Jed G. Nuchtern; John Hicks; Heidi V. Russell; Shipra Agrawal; Kevin M. Zbuk; Charis Eng; Madhuri Hegde; Ephrem L.H. Chin
To the Editor: TP53, a tumor-suppressor gene, is frequently inactivated by somatic mutations in cancer. Inheritance of a heterozygous TP53 mutation results in the Li–Fraumeni syndrome of a heredita...
Cancer Biology & Therapy | 2007
Kevin M. Zbuk; Charis Eng
Commentary to: EGFR Intron 1 Polymorphism in Asian Populations and its Correlation with EGFR Gene Expression and Amplification in Breast Tumor Tissues Qingyu Zhou, Yin Bun Cheung, Srinivasa Rao Jada, Wan Teck Lim, Wen-Lin Kuo, Joe Gray, Ann SG Lee and Balram Chowbay Volume: 5 | Issue: 11 | Pages: 1445 - 1449
Nature Reviews Cancer | 2007
Kevin M. Zbuk; Charis Eng
American Journal of Human Genetics | 2007
Rosemary E. Teresi; Kevin M. Zbuk; Marcus G. Pezzolesi; Kristin A. Waite; Charis Eng
Human Molecular Genetics | 2007
Marcus G. Pezzolesi; Kevin M. Zbuk; Kristin A. Waite; Charis Eng
Archive | 2008
Sharon E. Plon; Michael L. Pirics; Jed Nuchtern; John Hicks; Heidi Russell; Shipra Agrawal; Kevin M. Zbuk; Charis Eng; Madhuri R. Hegde