title: Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents.
abstract: DNA repair competency is one determinant of sensitivity to certain chemotherapy drugs, such as cisplatin. Cancer cells with intact DNA repair can avoid the accumulation of genome damage during growth and also can repair platinum-induced DNA damage. We sought genomic signatures indicative of defective DNA repair in cell lines and tumors and correlated these signatures to platinum sensitivity. The number of subchromosomal regions with allelic imbalance extending to the telomere (N(tAI)) predicted cisplatin sensitivity in vitro and pathologic response to preoperative cisplatin treatment in patients with triple-negative breast cancer (TNBC). In serous ovarian cancer treated with platinum-based chemotherapy, higher levels of N(tAI) forecast a better initial response. We found an inverse relationship between BRCA1 expression and N(tAI) in sporadic TNBC and serous ovarian cancers without BRCA1 or BRCA2 mutation. Thus, accumulation of telomeric allelic imbalance is a marker of platinum sensitivity and suggests impaired DNA repair.
  
  
  CONCLUSIONS
  Mutations in BRCA genes cause defects in DNA repair that predict sensitivity to DNA damaging agents, including platinum; however, some patients without BRCA mutations also benefit from these agents. NtAI, a genomic measure of unfaithfully repaired DNA, may identify cancer patients likely to benefit from treatments targeting defective DNA repair.
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, DK-2800 Lyngby, Denmark.|Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215 USA.
authors.forename: Nicolai J
authors.initials: NJ
authors.lastname: Birkbak
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215 USA.|Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 USA.
authors.forename: Zhigang C
authors.initials: ZC
authors.lastname: Wang
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 USA.|CHA University School of Medicine, Seoul, Republic of Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, DK-2800 Lyngby, Denmark.
authors.forename: Aron C
authors.initials: AC
authors.lastname: Eklund
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, DK-2800 Lyngby, Denmark.|Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215 USA.
authors.forename: Qiyuan
authors.initials: Q
authors.lastname: Li
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215 USA.
authors.forename: Ruiyang
authors.initials: R
authors.lastname: Tian
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215 USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Bowman-Colin
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215 USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215 USA.
authors.forename: April
authors.initials: A
authors.lastname: Greene-Colozzi
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215 USA.|Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 USA.
authors.forename: J Dirk
authors.initials: JD
authors.lastname: Iglehart
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Tung
authors.affiliation: Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111.
authors.forename: Paula D
authors.initials: PD
authors.lastname: Ryan
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215 USA.
authors.forename: Judy E
authors.initials: JE
authors.lastname: Garber
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215 USA.|Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Silver
authors.affiliation: Center for Biological Sequence Analysis, Technical University of Denmark, DK-2800 Lyngby, Denmark.|Children's Hospital Informatics Program at the Harvard-MIT Division of Health Sciences and Technology (CHIP@HST), Harvard Medical School, Boston, MA, 02115 USA.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szallasi
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215 USA.|Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
mesh_terms: D022981:Allelic Imbalance; D000970:Antineoplastic Agents; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D019398:Genes, BRCA1; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D016615:Telomere / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger; D002945:Cisplatin