BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair
TLDR
Two tumor suppressor genes, familial mutations in which account for approximately 5% of breast cancer cases in the USA annually, and how they function in maintaining genome integrity after the onset of DNA damage will be the focus of this review.Abstract:
BRCA1 and BRCA2 are tumor suppressor genes, familial mutations in which account for approximately 5% of breast cancer cases in the USA annually. Germ line mutations in BRCA1 that truncate or inactivate the protein lead to a cumulative risk of breast cancer, by age 70, of up to 80%, whereas the risk of ovarian cancer is 30-40%. For germ line BRCA2 mutations, the breast cancer cumulative risk approaches 50%, whereas for ovarian cancers, it is between 10 and 15%. Both BRCA1 and BRCA2 are involved in maintaining genome integrity at least in part by engaging in DNA repair, cell cycle checkpoint control and even the regulation of key mitotic or cell division steps. Unsurprisingly, the complete loss of function of either protein leads to a dramatic increase in genomic instability. How they function in maintaining genome integrity after the onset of DNA damage will be the focus of this review.read more
Citations
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Book ChapterDOI
The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer.
TL;DR: Current understanding of the organization and functions of the ATM-Chk2 and ATR- Chk1 pathways are reviewed and the prospects for targeting DNA damage signaling processes for therapeutic purposes are reviewed.
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Molecular mechanisms of micronucleus, nucleoplasmic bridge and nuclear bud formation in mammalian and human cells
Michael Fenech,Micheline Kirsch-Volders,Adayapalam T. Natarajan,Jordi Surrallés,J. W. Crott,James M. Parry,Hannu Norppa,David A. Eastmond,James D. Tucker,Philip Thomas +9 more
TL;DR: The wealth of knowledge currently available that best explains the formation of these important nuclear anomalies that are commonly seen in cancer and are indicative of genome damage events that could increase the risk of developmental and degenerative diseases are summarized.
Journal ArticleDOI
Association Between BRCA1 and BRCA2 Mutations and Survival in Women with Invasive Epithelial Ovarian Cancer
Kelly L. Bolton,Kelly L. Bolton,Georgia Chenevix-Trench,Cindy Goh,Siegal Sadetzki,Susan J. Ramus,Beth Y. Karlan,Diether Lambrechts,Evelyn Despierre,Daniel Barrowdale,Lesley McGuffog,Sue Healey,Douglas F. Easton,Olga M. Sinilnikova,Javier Benitez,María Jesús Gómez García,Susan L. Neuhausen,Mitchell H. Gail,Patricia Hartge,Susan Peock,Debra Frost,D. Gareth Evans,Rosalind A. Eeles,Andrew K. Godwin,Mary B. Daly,Ava Kwong,Ava Kwong,Edmond S. K. Ma,Conxi Lázaro,Ignacio Blanco,Marco Montagna,Emma D'Andrea,Maria Ornella Nicoletto,Sharon E. Johnatty,Susanne K. Kjaer,Allan Jensen,Estrid Høgdall,Ellen L. Goode,Brooke L. Fridley,Jennifer T. Loud,Mark H. Greene,Phuong L. Mai,Angela Chetrit,Flora Lubin,Galit Hirsh-Yechezkel,Gord Glendon,Irene L. Andrulis,Irene L. Andrulis,Amanda E. Toland,Leigha Senter,Martin Gore,Charlie Gourley,Caroline O. Michie,Honglin Song,Jonathan Tyrer,Alice S. Whittemore,Valerie McGuire,Weiva Sieh,Ulf Kristoffersson,Håkan Olsson,Åke Borg,Douglas A. Levine,Linda Steele,Mary S. Beattie,Salina Chan,Robert L. Nussbaum,Kirsten B. Moysich,Jenny Gross,Ilana Cass,Christine Walsh,Andrew J. Li,R.S. Leuchter,Ora Gordon,Montserrat Garcia-Closas,Simon A. Gayther,Stephen J. Chanock,Antonis C. Antoniou,Paul D.P. Pharoah +77 more
TL;DR: Among patients with invasive EOC, having a germline mutation in BRCA1 or BRC a2 was associated with improved 5-year overall survival and BRCa2 carriers had the best prognosis.
Journal ArticleDOI
Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma
Sergey Nikolaev,Donata Rimoldi,Christian Iseli,Christian Iseli,Armand Valsesia,Armand Valsesia,Armand Valsesia,Daniel Robyr,Corinne Gehrig,Keith Harshman,Michel Guipponi,Olesya Bukach,Vincent Zoete,Olivier Michielin,Olivier Michielin,Olivier Michielin,Katja Muehlethaler,Daniel E. Speiser,Jacques S. Beckmann,Jacques S. Beckmann,Ioannis Xenarios,Thanos D. Halazonetis,C. Victor Jongeneel,Brian Stevenson,Brian Stevenson,Stylianos E. Antonarakis +25 more
TL;DR: Exome sequencing detected somatic mutations in protein-coding regions in seven melanoma cell lines and donor-matched germline cells, which showed the hallmark of UV-induced DNA repair, but such a hallmark was absent in tumor sample–specific mutations in two metastases derived from the same individual.
Journal ArticleDOI
Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: the molecular choreography.
TL;DR: This review strives to integrate the information about the molecular mechanisms of DSB repair that has emerged over the last two decades with a focus on DSBs produced by the prototype agent ionizing radiation (IR), and links molecular abnormalities to cellular pathology as much a possible and provides a framework of temporal relationships.
References
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Journal ArticleDOI
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
Hannah Farmer,Nuala McCabe,Christopher J. Lord,Andrew Tutt,Andrew Tutt,Damian A. Johnson,Tobias B. Richardson,Manuela Santarosa,Krystyna J. Dillon,Ian Hickson,Charlotte Knights,Niall M. B. Martin,Stephen P. Jackson,Graeme C. M. Smith,Alan Ashworth +14 more
TL;DR: BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis, illustrating how different pathways cooperate to repair damage.
Journal ArticleDOI
The DNA-damage response in human biology and disease
Stephen P. Jackson,Jiri Bartek +1 more
TL;DR: The authors' improving understanding of DNA-damage responses is providing new avenues for disease management, and these responses are biologically significant because they prevent diverse human diseases.
Journal ArticleDOI
Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies
Antonis C. Antoniou,Paul D.P. Pharoah,Steven A. Narod,Harvey A. Risch,Jorunn E. Eyfjord,John L. Hopper,Niklas Loman,Håkan Olsson,Oskar T. Johannsson,Åke Borg,Barbara Pasini,Paolo Radice,Siranoush Manoukian,Diana Eccles,Nelson L.S. Tang,E. Olah,Hoda Anton-Culver,Ellen Warner,Jan Lubinski,Jacek Gronwald,Bohdan Górski,Hrafn Tulinius,Steinunn Thorlacius,Hannaleena Eerola,Heli Nevanlinna,Kirsi Syrjäkoski,Olli Kallioniemi,Deborah J. Thompson,Christopher H. Evans,Julian Peto,Julian Peto,Fiona Lalloo,D G R Evans,Douglas F. Easton +33 more
TL;DR: Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age and for variation in risk by mutation position for both genes, and some evidence for a reduction in risk in women from earlier birth cohorts is found.
Journal ArticleDOI
Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers
Peter C.C. Fong,D. S. Boss,Timothy A. Yap,Andrew Tutt,Peijun Wu,Marja Mergui-Roelvink,Peter S. Mortimer,Helen Swaisland,Alan Lau,Mark J. O'Connor,Alan Ashworth,James Carmichael,Stan B. Kaye,Jan H.M. Schellens,Jan H.M. Schellens,Johann S. de Bono +15 more
TL;DR: Olaparib has few of the adverse effects of conventional chemotherapy, inhibits PARP, and has antitumor activity in cancer associated with the BRCA1 or BRCa2 mutation.
Journal ArticleDOI
DNA double-strand breaks: signaling, repair and the cancer connection.
TL;DR: Recent progress is described in understanding of how cells detect and signal the presence and repair of one particularly important form of DNA damage induced by ionizing radiation—the DNA double-strand break (DSB).
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