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BRCA1 mutation and neuronal migration defect:
implications for chemoprevention
D Eccles, D Bunyan, S Barker and B Castle J. Med. Genet.
doi:10.1136/jmg.2004.028084 Updated information and services can be found at: References
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Articles on similar topics can be found in the following collections To order reprints of this article go to: J Med Genet 2005;42:e42 (http://www.jmedgenet.com/cgi/content/full/42/7/e42). doi: 10.1136/jmg.2004.028084 39 years, breast magnetic resonance imaging as well as conventional breast mammography (MIM 251200), in which biallelic mutations led to primary microcephaly, contains three Multiplex ligation dependent probe ampli- fication eventually revealed that exons 9–12 possible prenatal insults that could give rise of the BRCA1 gene in twin 1 were deleted.
Predictive testing confirmed that this multi- include infection and an early vascular event exonic deletion was also present in twin 2.
leading to hypoperfusion, however the loca- Previously we described a BRCA1 carrier with Closer attention to the neurological pro- lised nature of the abnormality in this case a neuronal migration defect and postulated blems and history of twin 2 revealed that the makes these explanations less likely than the twins were born at home to non-consangui- second hit hypothesis postulated here.
neous parents after an uneventful pregnancy, describe another family in which a similar trant with a lifetime cumulative breast cancer prenatally. Both twins were healthy at birth risk of 70–80% and a median age at onset of occurred in one of female identical twins and had an uneventful neonatal period. At 11 around 43 years. Penetrance is likely to be with a BRCA1 gene mutation (MIM 113705).
months of age twin 2 developed focal right affected by modifying genes and by environ- sided seizures usually progressing to grand mal mental factors. In identical twins the effect of multiple primary breast cancers while the seizures for which she required anti-convul- Environmental factors presumably therefore school with her sister. Twin 1 was right handed standing epilepsy and focal subcortical het- whereas twin 2 was left handed. Anti-con- free 10 years after her sister developed the erotopia. We hypothesise that the neuronal vulsant treatment initially was with sodium first of three unusually early onset primary migration defect is due to focal nullisomy of valproate, and phenobarbitone was added at age 5 years and phenytoin at age 21 years, cancer risk is due to the anti-oestrogenic Sodium valproate was stopped 3 years later.
effects of long term anticonvulsant therapy.
9 years compared to 4 years for twin 2.
Thirty three year old identical twins were but mild right sided motor weakness in upper There is some evidence suggesting that oral referred for genetic counselling. Twin 1 had contraceptive pill use increases breast cancer developed breast cancer aged 29 years and a extensor plantar reflex on the right hand risk in BRCA1 gene carriers.7 Twin 1 took second primary breast cancer aged 33 years.
side with no gross sensory abnormality. The 6 months of clomiphene for primary inferti- MRI brain scan (fig 2) demonstrates focal lity just prior to the diagnosis of her first subcortical heterotopia and reduced volume breast cancer, but this is less likely to be family history (fig 1) suggested an inherited implicated as it is a synthetic anti-oestrogen and was taken probably after the first cancer lial developmental anomalies incompatible had started to develop. Her only full term from twin 1 using the protein truncation test pregnancy occurred after her second breast and denaturing high performance liquid chro- life. They exhibit structural disorganisation cancer was diagnosed and is unlikely to have matography failed to reveal any abnormality in and in particular the neuroepithelium shows influenced either of the first two cancers. A signs of rapid proliferation and excessive cell more compelling modifying factor, however, markers spread across chromosomes 6, 11, and death.2 A second somatic hit affecting the X were used to compare DNA from twin 1 with wild type BRCA1 allele in an early neuronal taken by twin 2 since infancy. Many anti- stem cell would result in focal nullisomy for convulsant drugs, including phenytoin and concordant making it highly unlikely that they BRCA1 and would mimic focally the situation phenobarbitone, act as potent liver inducing were not identical. Annual ovarian and breast in a BRCA1 null developing brain. Although enzymes that reduce the bioavailability of screening was established for both twins.
both exogenous oestrogen and progesterone.
have been described, there are no reported In addition, most categories of anti-convul- breast carcinoma 10 years after the initial cases of viable homozygous BRCA1 mutation sant cause an increase in serum sex hormone diagnosis. At her most recent screen, age carriers in any species. Given that the carrier binding globulin (SHBG).8 This increase in Ashkenazi Jewish population is around 1% in oestrogens including tamoxifen and clomi- zygote mutation carriers would be expected bioavailability of endogenous sex steroid were compatible with life.3–5 BRCA1 has few oestrogen receptor positive breast cancer over homologies, but interestingly another gene a 5 year treatment period in older women but Breast cancer at 29Breast cancer at 33Breast cancer at 38 Figure 1 Family history. The early onset, high grade, oestrogen receptor negative breast cancer with multiple new primaries in the index case are typical for BRCA1. The young onset breast and ovarian cancer cases in immediate Figure 2 Coronal inversion recovery (A) and axial T2 (B) MRI images show a small left cerebral relatives in the previous generation are also hemisphere with a nodular mass of grey matter in the left parieto-occipital region extending down to and around the lateral ventricle.
current trials start recruitment only after 5 Struewing JP, Abeliovich D, Peretz T, Avishai N, Wessex Neurological Centre, Southampton General Kaback MM, Collins FS, Brody LC. The carrier frequency of the BRCA1 185delAG mutation isapproximately 1 percent in Ashkenazi Jewish gene carriers clearly reduces breast cancer individuals. Nat Genet 1995;11:198–200.
risk so there does appear to be a role for long 6 Jackson AP, Eastwood H, Bell SM, Adu J, term reduction in endogenous oestrogen in Wessex Clinical Genetics Service, Princess Anne Toomes C, Carr IM, Roberts E, Hampshire DJ, modifying risk.10 The earlier the age at which Crow YJ, Mighell AJ, Karbani G, Jafri H, Rashid Y, Identification of microcephalin, a protein Professor Diana M Eccles, MD, FRCP, Wessex Clinical implicated in determining the size of the human Genetics Service, Princess Anne Hospital, Coxford brain. Am J Hum Genet 2002;71:136–42.
options for individuals with a genetic predis- Road, Southampton SO16 5YA, UK; [email protected].
7 Narod SA, Dube MP, Klijn J, Lubinski J, Lynch HT, position to cancer and a better understanding Ghadirian P, Provencher D, Heimdal K, Moller P, Robson M, Offit K, Isaacs C, Weber B, Friedman E, Gershoni-Baruch R, Rennert G, Pasini B, Wagner T, Furthermore, since long standing epilepsy Daly M, Garber JE, Neuhausen SL, Ainsworth P, without any change in clinical status may not prompt investigation in adults, any localised Foulkes WD, Warner E, Kim-Sing C, Olopade O,Tung N, Saal HM, Weitzel J, Merajver S, Gauthier- neurological signs or symptoms in a BRCA1 Villars M, Jernstrom H, Sun P, Brunet JS. Oral gene carrier may warrant more detailed inves- 1 Eccles DM, Barker S, Pilz DT, Kennedy C.
contraceptives and the risk of breast cancer in tigation including an MRI brain scan although Neuronal migration defect in a BRCA1 gene BRCA1 and BRCA2 mutation carriers. J Natl this is likely to be a rare phenomenon.
carrier: possible focal nullisomy? J Med Genet 8 Murialdo G, Galimberti CA, Gianelli MV, 2 Gowen LC, Johnson BL, Latour AM, Sulik KK, Rollero A, Polleri A, Copello F, Magri F, Ferrari E, Koller BH. Brca1 deficiency results in early Sampaolo P, Manni R, Tartara A. Effects of Hilary Bullman, Margaret Connarty, and Julie valproate, phenobarbital, and carbamazepine on Sillibourne in the Wessex Regional Genetics NHS sex steroid setup in women with epilepsy. Clin Laboratory contributed to the molecular genetic 3 Gal I, Sadetzki S, Gershoni-Baruch R, Oberman B, 9 Cuzick J, Powles T, Veronesi U, Forbes J, analyses described. We are grateful to the family Edwards R, Ashley S, Boyle P. Overview of the members for permission to report this case.
Eisenberg-Barzilai S, Friedman E. Offspring main outcomes in breast-cancer prevention trials.
spontaneous miscarriages in Jewish women at 10 Rebbeck TR, Friebel T, Lynch HT, Neuhausen SL, Wessex Clinical Genetics Service, Princess Anne high risk for breast/ovarian cancer. Am J Hum van’t Veer L, Garber JE, Evans GR, Narod SA, Hospital, Coxford Road, Southampton SO16 5YA, UK Isaacs C, Matloff E, Daly MB, Olopade OI, 4 Roa BB, Boyd AA, Volcik K, Richards CS.
Weber BL. Bilateral prophylactic mastectomy Ashkenazi Jewish population frequencies for reduces breast cancer risk in BRCA1 and BRCA2 Wessex Regional Genetics Laboratory, Salisbury mutation carriers: the PROSE Study Group. J Clin District Hospital, Odstock, Salisbury, UK

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