Congenital Abnormalities; DNA; Fanconi Syndrome; Genetics; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Multiple Endocrine Neoplasia; Neoplastic Syndromes, Hereditary; Skin Neoplasms
Skin Diseases Research Center, Yale
My laboratory’s focus is hereditary cancer predisposition. One project in the laboratory arose from studies of the nevoid basal cell carcinoma syndrome (NBCCS), a human genetic disease characterized by skin cancer and brain tumors as well as a variety of birth defects. We isolated the NBCCS gene and showed that it is homologous to Drosophila "patched," a key gene in Drosophila embryonic development. We are now examining human homologs of other members
of the patched pathway and investigating their roles in human cancer. In addition, we have become involved in large molecular epidemiology studies, using high throughput sequencing to search in an unbiased way for novel skin cancer genes and the interaction between genes and environment in cancer causation.
Specialized Terms: Molecular Mechanisms of Cancer; Predisposition and Developmental Defects; DNA Diagnostics; Birth Defects; Cancer; Fanconi; Genetics; Hedgehog; Multiple Endocrine Neoplasia; Patched; Skin Cancer; Tumor Suppressor
Extensive Research Description
Genes involved in carcinogenesis often play a critical role in embryonic development and cellular differentiation. My laboratory focuses on analyzing the normal function of these genes and the mechanisms by which mutations lead to cancer. One emphasis of the laboratory is the gene underlying the nevoid basal cell carcinoma syndrome (NBCCS), an autosomal dominant disorder characterized by skin cancer, ovarian tumors, and brain tumors as well as developmental defects of the brain, bones, and teeth. We isolated the NBCCS gene by positional cloning and showed that it is homologous to Drosophila "patched". The Drosophila version of this gene encodes a cell surface protein that plays a role in segment polarity; i.e., distinguishing anterior from posterior in the developing fly. We are examining other segment polarity genes in human cancer. Other disease genes under study include MEN1 (multiple endocrine neoplasia type 1) and BRCA1 (the main gene responsible for hereditary breast cancer).
A second area of interest is the application of new molecular techniques, such as high throughput sequencing, to clinical diagnosis of cancer predispostion syndromes. Through collaboration with other investigators in the Department of Genetics and elsewhere in the medical school, we carry the most recent discoveries about genetic disorders and novel methodology from the research laboratory to the medical setting.
Characterization of DNA damage-dependent cell cycle checkpoints in a menin-deficient model.
Kottemann MC, Bale AE. Characterization of DNA damage-dependent cell cycle checkpoints in a menin-deficient model. DNA Repair 2009, 8:944-52.
MEN1 and FANCD2 mediate distinct mechanisms of DNA crosslink repair.
Marek LR, Kottemann MC, Glazer PM, Bale AE. MEN1 and FANCD2 mediate distinct mechanisms of DNA crosslink repair. DNA Repair 2008, 7:476-86.
Multiple endocrine neoplasia type 1 interacts with forkhead transcription factor CHES1 in DNA damage response.
Busygina V, Kottemann MC, Scott KL, Plon SE, Bale AE. Multiple endocrine neoplasia type 1 interacts with forkhead transcription factor CHES1 in DNA damage response. Cancer Research 2006, 66:8397-403.
Rhabdomyosarcoma, Wilms tumor, and deletion of the patched gene in Gorlin syndrome.
Cajaiba MM, Bale AE, Alvarez-Franco M, McNamara J, Reyes-Múgica M. Rhabdomyosarcoma, Wilms tumor, and deletion of the patched gene in Gorlin syndrome. Nature Clinical Practice. Oncology 2006, 3:575-80.
Cardiac and CNS defects in a mouse with targeted disruption of suppressor of fused.
Cooper AF, Yu KP, Brueckner M, Brailey LL, Johnson L, McGrath JM, Bale AE. Cardiac and CNS defects in a mouse with targeted disruption of suppressor of fused. Development (Cambridge, England) 2005, 132:4407-17.
Full List of PubMed Publications
- Umano GR, Caprio S, Di Sessa A, Chalasani N, Dykas DJ, Pierpont B, Bale AE, Santoro N: The rs626283 Variant in the MBOAT7 Gene is Associated with Insulin Resistance and Fatty Liver in Caucasian Obese Youth. Am J Gastroenterol. 2018 Mar; 2018 Feb 27. PMID: 29485130
- Couto PP, Bastos-Rodrigues L, Schayek H, Melo FM, Lisboa RGC, Miranda DM, Vilhena A, Bale AE, Friedman E, De Marco L: Spectrum of germline mutations in smokers and non-smokers in Brazilian non-small-cell lung cancer (NSCLC) patients. Carcinogenesis. 2017 Oct 26. PMID: 28968711
- Lee EJ, Dykas DJ, Leavitt AD, Camire RM, Ebberink E, García de Frutos P, Gnanasambandan K, Gu SX, Huntington JA, Lentz SR, Mertens K, Parish CR, Rezaie AR, Sayeski PP, Cromwell C, Bar N, Halene S, Neparidze N, Parker TL, Burns AJ, Dumont A, Yao X, Chaar CIO, Connors JM, Bale AE, Lee AI: Whole-exome sequencing in evaluation of patients with venous thromboembolism. Blood Adv. 2017 Jul 11; 2017 Jun 29. PMID: 29296762
- Brownstein AJ, Ziganshin BA, Kuivaniemi H, Body SC, Bale AE, Elefteriades JA: Genes Associated with Thoracic Aortic Aneurysm and Dissection: An Update and Clinical Implications. Aorta (Stamford). 2017 Feb; 2017 Feb 1. PMID: 28868310
- Zhang Y, Cartmel B, Choy CC, Molinaro AM, Leffell DJ, Bale AE, Mayne ST, Ferrucci LM: Body mass index, height and early-onset basal cell carcinoma in a case-control study. Cancer Epidemiol. 2017 Feb; 2016 Dec 28. PMID: 28039770
- Seidelmann SB, Smith E, Subrahmanyan L, Dykas D, Abou Ziki MD, Azari B, Hannah-Shmouni F, Jiang Y, Akar JG, Marieb M, Jacoby D, Bale AE, Lifton RP, Mani A: Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults. Circ Cardiovasc Genet. 2017 Feb. PMID: 28087566
- Kim J, Liao YH, Ionita C, Bale AE, Darras B, Acsadi G: Mitochondrial Membrane Protein-Associated Neurodegeneration Mimicking Juvenile Amyotrophic Lateral Sclerosis. Pediatr Neurol. 2016 Nov; 2016 Aug 24. PMID: 27671242
- Melo FM, Couto PP, Bale AE, Bastos-Rodrigues L, Passos FM, Lisboa RG, Ng JM, Curran T, Dias EP, Friedman E, De Marco L: Whole-exome identifies RXRG and TH germline variants in familial isolated prolactinoma. Cancer Genet. 2016 Jun; 2016 May 4. PMID: 27245436
- Ziai J, Matloff E, Choi J, Kombo N, Materin M, Bale AE: Defining the polyposis/colorectal cancer phenotype associated with the Ashkenazi GREM1 duplication: counselling and management recommendations. Genet Res (Camb). 2016 Mar 7; 2016 Mar 7. PMID: 26947005
- Goffredo M, Caprio S, Feldstein AE, D'Adamo E, Shaw MM, Pierpont B, Savoye M, Zhao H, Bale AE, Santoro N: Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: A multiethnic study. Hepatology. 2016 Jan; 2015 Nov 16. PMID: 26457389
- Berlin NL, Cartmel B, Leffell DJ, Bale AE, Mayne ST, Ferrucci LM: Family history of skin cancer is associated with early-onset basal cell carcinoma independent of MC1R genotype. Cancer Epidemiol. 2015 Dec; 2015 Sep 14. PMID: 26381319
- Ziganshin BA, Bailey AE, Coons C, Dykas D, Charilaou P, Tanriverdi LH, Liu L, Tranquilli M, Bale AE, Elefteriades JA: Routine Genetic Testing for Thoracic Aortic Aneurysm and Dissection in a Clinical Setting. Ann Thorac Surg. 2015 Nov; 2015 Jul 15. PMID: 26188975
- Zheng C, Dalla Man C, Cobelli C, Groop L, Zhao H, Bale AE, Shaw M, Duran E, Pierpont B, Caprio S, Santoro N: A common variant in the MTNR1b gene is associated with increased risk of impaired fasting glucose (IFG) in youth with obesity. Obesity (Silver Spring). 2015 May. PMID: 25919927
- Cartmel B, Dewan A, Ferrucci LM, Gelernter J, Stapleton J, Leffell DJ, Mayne ST, Bale AE: Novel gene identified in an exome-wide association study of tanning dependence. Exp Dermatol. 2014 Oct. PMID: 25041255
- Troche JR, Ferrucci LM, Cartmel B, Leffell DJ, Bale AE, Mayne ST: Systemic glucocorticoid use and early-onset basal cell carcinoma. Ann Epidemiol. 2014 Aug; 2014 May 22. PMID: 24958637
- Ferrucci LM, Cartmel B, Molinaro AM, Leffell DJ, Bale AE, Mayne ST: Tea, coffee, and caffeine and early-onset basal cell carcinoma in a case-control study. Eur J Cancer Prev. 2014 Jul. PMID: 24841641
- Carneiro JG, Couto PG, Bastos-Rodrigues L, Bicalho MA, Vidigal PV, Vilhena A, Amaral NF, Bale AE, Friedman E, De Marco L: Spectrum of somatic EGFR, KRAS, BRAF, PTEN mutations and TTF-1 expression in Brazilian lung cancer patients. Genet Res (Camb). 2014; 2014 Mar 5. PMID: 24594201
- Cartmel B, Ferrucci LM, Spain P, Bale AE, Pagoto SL, Leffell DJ, Gelernter J, Mayne ST: Indoor tanning and tanning dependence in young people after a diagnosis of basal cell carcinoma. JAMA Dermatol. 2013 Sep. PMID: 23824273
- Hofstatter EW, Bale AE: The promise and pitfalls of genomics-driven cancer medicine. Virtual Mentor. 2013 Aug 1; 2013 Aug 1. PMID: 23937784
- Ferrucci LM, Cartmel B, Molinaro AM, Leffell DJ, Bale AE, Mayne ST: Indoor tanning and risk of early-onset basal cell carcinoma. J Am Acad Dermatol. 2012 Oct; 2011 Dec 9. PMID: 22153793
- Ferrucci LM, Cartmel B, Molinaro AM, Gordon PB, Leffell DJ, Bale AE, Mayne ST: Host phenotype characteristics and MC1R in relation to early-onset basal cell carcinoma. J Invest Dermatol. 2012 Apr; 2011 Dec 8. PMID: 22158557
- Santoro N, Zhang CK, Zhao H, Pakstis AJ, Kim G, Kursawe R, Dykas DJ, Bale AE, Giannini C, Pierpont B, Shaw MM, Groop L, Caprio S: Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology. 2012 Mar; 2011 Dec 18. PMID: 22105854
- Lostritto K, Ferrucci LM, Cartmel B, Leffell DJ, Molinaro AM, Bale AE, Mayne ST: Lifetime history of indoor tanning in young people: a retrospective assessment of initiation, persistence, and correlates. BMC Public Health. 2012 Feb 10; 2012 Feb 10. PMID: 22324969
- Williams SA, Wilson JB, Clark AP, Mitson-Salazar A, Tomashevski A, Ananth S, Glazer PM, Semmes OJ, Bale AE, Jones NJ, Kupfer GM: Functional and physical interaction between the mismatch repair and FA-BRCA pathways. Hum Mol Genet. 2011 Nov 15; 2011 Aug 24. PMID: 21865299
- Santoro N, Kursawe R, D'Adamo E, Dykas DJ, Zhang CK, Bale AE, Calí AM, Narayan D, Shaw MM, Pierpont B, Savoye M, Lartaud D, Eldrich S, Cushman SW, Zhao H, Shulman GI, Caprio S: A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents. Hepatology. 2010 Oct. PMID: 20803499
- Kottemann MC, Bale AE: Characterization of DNA damage-dependent cell cycle checkpoints in a menin-deficient model. DNA Repair (Amst). 2009 Aug 6; 2009 Jul 15. PMID: 19608464
- Marek LR, Kottemann MC, Glazer PM, Bale AE: MEN1 and FANCD2 mediate distinct mechanisms of DNA crosslink repair. DNA Repair (Amst). 2008 Mar 1; 2008 Feb 6. PMID: 18258493
- Busygina V, Bale AE: Multiple endocrine neoplasia type 1 (MEN1) as a cancer predisposition syndrome: clues into the mechanisms of MEN1-related carcinogenesis. Yale J Biol Med. 2006 Dec. PMID: 17940620
- Marek LR, Bale AE: Drosophila homologs of FANCD2 and FANCL function in DNA repair. DNA Repair (Amst). 2006 Nov 8; 2006 Jul 21. PMID: 16860002
- Klein RD, Thorland EC, Gonzales PR, Beck PA, Dykas DJ, McGrath JM, Bale AE: A multiplex assay for the detection and mapping of complex glycerol kinase deficiency. Clin Chem. 2006 Oct; 2006 Aug 3. PMID: 16887896
- Cajaiba MM, Bale AE, Alvarez-Franco M, McNamara J, Reyes-Múgica M: Rhabdomyosarcoma, Wilms tumor, and deletion of the patched gene in Gorlin syndrome. Nat Clin Pract Oncol. 2006 Oct. PMID: 17019435
- Risch HA, Bale AE, Beck PA, Zheng W: PGR +331 A/G and increased risk of epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2006 Sep. PMID: 16985038
- Busygina V, Kottemann MC, Scott KL, Plon SE, Bale AE: Multiple endocrine neoplasia type 1 interacts with forkhead transcription factor CHES1 in DNA damage response. Cancer Res. 2006 Sep 1. PMID: 16951149
- Klein RD, Dykas DJ, Bale AE: Clinical testing for the nevoid basal cell carcinoma syndrome in a DNA diagnostic laboratory. Genet Med. 2005 Nov-Dec. PMID: 16301862
- Cooper AF, Yu KP, Brueckner M, Brailey LL, Johnson L, McGrath JM, Bale AE: Cardiac and CNS defects in a mouse with targeted disruption of suppressor of fused. Development. 2005 Oct. PMID: 16155214
- Klein RD, Salih S, Bessoni J, Bale AE: Clinical testing for multiple endocrine neoplasia type 1 in a DNA diagnostic laboratory. Genet Med. 2005 Feb. PMID: 15714081
- Busygina V, Suphapeetiporn K, Marek LR, Stowers RS, Xu T, Bale AE: Hypermutability in a Drosophila model for multiple endocrine neoplasia type 1. Hum Mol Genet. 2004 Oct 15; 2004 Aug 27. PMID: 15333582
- Choi DH, Lee MH, Bale AE, Carter D, Haffty BG: Incidence of BRCA1 and BRCA2 mutations in young Korean breast cancer patients. J Clin Oncol. 2004 May 1. PMID: 15117986
- Suphapeetiporn K, Greally JM, Walpita D, Ashley T, Bale AE: MEN1 tumor-suppressor protein localizes to telomeres during meiosis. Genes Chromosomes Cancer. 2002 Sep. PMID: 12203793
- Haffty BG, Harrold E, Khan AJ, Pathare P, Smith TE, Turner BC, Glazer PM, Ward B, Carter D, Matloff E, Bale AE, Alvarez-Franco M: Outcome of conservatively managed early-onset breast cancer by BRCA1/2 status. Lancet. 2002 Apr 27. PMID: 11988246
- Bale AE: Hedgehog signaling and human disease. Annu Rev Genomics Hum Genet. 2002; 2002 Apr 15. PMID: 12142354