6月15日，Cancer Research雜志在線(xiàn)報(bào)道了BRCA1基因突變攜帶者的乳腺癌研究的最新進(jìn)展。生殖細(xì)胞系BRCA1基因突變攜帶者的乳腺癌常顯示基底樣分子亞型的典型特征。然而，BRCA1功能失調(diào)導(dǎo)致哪些基因反復(fù)突變尚不清楚,。
在這項(xiàng)研究中，研究者利用基因表達(dá)譜對(duì)577例乳腺腫瘤進(jìn)行分子亞型分類(lèi)，其中包括72例乳腺腫瘤BRCA1/2突變基因攜帶者,。以RB1位點(diǎn)為重點(diǎn),研究者使用覆蓋RB1基因的自定義設(shè)計(jì)高密度寡聚微陣列,分析了33 例BRCA1基因突變,，36 例BRCA2基因突變和48 例non-BRCA1/2-mutated的乳腺腫瘤患者。
他們發(fā)現(xiàn)在基底樣亞型和BRCA1基因突變的乳腺腫瘤和管腔B亞型以及BRCA2基因突變的乳腺腫瘤之間存在強(qiáng)烈關(guān)聯(lián),。在BRCA1基因突變攜帶者乳腺腫瘤患者和散發(fā)BRCA1基因啟動(dòng)子甲基化乳腺腫瘤患者中,，RB1被確定為一個(gè)基因組破壞的主要目標(biāo)。但這很少發(fā)生在其他類(lèi)型乳腺癌,。
研究者發(fā)現(xiàn),，在33％的BRCA1基因突變?nèi)橄倌[瘤，36％的BRCA1基因啟動(dòng)子甲基化的基底細(xì)胞樣腫瘤,，13％的非BRCA1基因缺陷的基底細(xì)胞樣腫瘤,，3％的BRCA2基因突變腫瘤中，RB1的存在純合性缺失,，基因內(nèi)斷裂,，或微缺失。
總之,，廣泛基因破壞導(dǎo)致的RB1失活經(jīng)常發(fā)生在BRCA1基因相關(guān)的遺傳性乳腺癌基因的破壞和BRCA1基因甲基化的散發(fā)基底樣乳腺癌,，但很少在BRCA2基因遺傳性乳腺癌和非BRCA1基因缺陷的散發(fā)性乳腺癌?？傊?，研究結(jié)果表明在基底樣亞型乳腺癌中的遺傳異質(zhì)性取決于BRCA1基因狀態(tài)。(生物谷bioon.com)
doi:10.1016/j.cell.2011.10.017
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The retinoblastoma gene undergoes rearrangements in BRCA1-deficient basal-like breast cancer
Gran Jnsson1,2,§, Johan Staaf1,2,§, Johan Vallon-Christersson1,2,§, Markus Ringnér1,2, Sofia K Gruvberger-Saal1,2, Lao H Saal1,2, Karolina Holm1,2, Cecilia Hegardt1,2, Adalgeir Arason3,4, Rainer Fagerholm5, Camilla Persson1,2, Dorthe Grabau6, Ellinor Johnsson1,2, Kristina L?vgren1, Linda Magnusson7, P?ivi Heikkil?8, Bjarni A Agnarsson3,4, Oskar T Johannsson3, Per Malmstr?m1,9, M?rten Fern?1, H?kan Olsson1,
Niklas Loman1,9, Heli Nevanlinna5, Rosa B Barkardottir3,4, ?ke Borg1,2Breast tumors from BRCA1 germ line mutation carriers typically exhibit features of the basal-like molecular subtype. However, the specific genes recurrently mutated as a consequence of BRCA1 dysfunction have not been fully elucidated. In this study, we utilized gene expression profiling to molecularly subtype 577 breast tumors, including 72 breast tumors from BRCA1/2 mutation carriers. Focusing on the RB1locus, we analyzed 33 BRCA1-mutated, 36 BRCA2-mutated and 48 non-BRCA1/2-mutated breast tumors using a custom-designed high-density oligomicroarray association between the basal-like subtype and BRCA1-mutated breast tumors and the luminal B subtype and BRCA2-mutated breast tumors. RB1 was identified as a major target for genomic disruption in tumors arising in BRCA1 mutation carriers and in sporadic tumors with BRCA1 promoter-methylation, but rarely in other breast cancers. Homozygous deletions, intragenic breaks, or microdeletions were found in 33% of BRCA1-mutant tumors, 36% of BRCA1 promoter-methylated basal-like tumors, 13% of non-BRCA1 deficient basal-like tumors, and 3% of BRCA2-mutated tumo rs. In conclusion, RB1 was frequently inactivated by gross gene disruption in BRCA1-related hereditary breast cancer and BRCA1-methylated sporadic ba sal-like breast cancer, but rarely in BRCA2-hereditary breast cancer and non-BRCA1-deficient sporadic breast cancers. Together, our findings demonstrate the existence of genetic heterogeneity within the basal-like breast cancer subtype that is based upon BRCA1-status.
