TY - JOUR
T1 - Fanconi anemia and homologous recombination gene variants are associated with functional DNA repair defects in vitro and poor outcome in patients with advanced head and neck squamous cell carcinoma
AU - Verhagen, Caroline V. M.
AU - Vossen, David M.
AU - Borgmann, Kerstin
AU - Hageman, Floor
AU - Grénman, Reidar
AU - Verwijs-Janssen, Manon
AU - Mout, Lisanne
AU - Kluin, Roel J. C.
AU - Nieuwland, Marja
AU - Severson, Tesa M.
AU - Velds, Arno
AU - Kerkhoven, Ron
AU - O'Connor, Mark J.
AU - van der Heijden, Martijn
AU - van Velthuysen, Marie-Louise
AU - Verheij, Marcel
AU - Wreesmann, Volkert B.
AU - Wessels, Lodewyk F. A.
AU - van den Brekel, Michiel W. M.
AU - Vens, Conchita
AU - Verwijs-Jansen, M.
N1 - With supplementary files.
PY - 2018/4/6
Y1 - 2018/4/6
N2 - Mutations in Fanconi Anemia or Homologous Recombination (FA/HR) genes can cause DNA repair defects and could therefore impact cancer treatment response and patient outcome. Their functional impact and clinical relevance in head and neck squamous cell carcinoma (HNSCC) is unknown. We therefore questioned whether functional FA/HR defects occurred in HNSCC and whether they are associated with FA/HR variants. We assayed a panel of 29 patient-derived HNSCC cell lines and found that a considerable fraction is hypersensitive to the crosslinker Mitomycin C and PARP inhibitors, a functional measure of FA/HR defects. DNA sequencing showed that these hypersensitivities are associated with the presence of bi-allelic rare germline and somatic FA/HR gene variants. We next questioned whether such variants are associated with prognosis and treatment response in HNSCC patients. DNA sequencing of 77 advanced stage HNSCC tumors revealed a 19% incidence of such variants. Importantly, these variants were associated with a poor prognosis (p = 0.027; HR = 2.6, 1.1-6.0) but favorable response to high cumulative cisplatin dose. We show how an integrated in vitro functional repair and genomic analysis can improve the prognostic value of genetic biomarkers. We conclude that repair defects are marked and frequent in HNSCC and are associated with clinical outcome.
AB - Mutations in Fanconi Anemia or Homologous Recombination (FA/HR) genes can cause DNA repair defects and could therefore impact cancer treatment response and patient outcome. Their functional impact and clinical relevance in head and neck squamous cell carcinoma (HNSCC) is unknown. We therefore questioned whether functional FA/HR defects occurred in HNSCC and whether they are associated with FA/HR variants. We assayed a panel of 29 patient-derived HNSCC cell lines and found that a considerable fraction is hypersensitive to the crosslinker Mitomycin C and PARP inhibitors, a functional measure of FA/HR defects. DNA sequencing showed that these hypersensitivities are associated with the presence of bi-allelic rare germline and somatic FA/HR gene variants. We next questioned whether such variants are associated with prognosis and treatment response in HNSCC patients. DNA sequencing of 77 advanced stage HNSCC tumors revealed a 19% incidence of such variants. Importantly, these variants were associated with a poor prognosis (p = 0.027; HR = 2.6, 1.1-6.0) but favorable response to high cumulative cisplatin dose. We show how an integrated in vitro functional repair and genomic analysis can improve the prognostic value of genetic biomarkers. We conclude that repair defects are marked and frequent in HNSCC and are associated with clinical outcome.
KW - DNA repair; Fanconi anemia; HNSCC; gene variants; homologous recombination
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85045005759&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29719599
U2 - https://doi.org/10.18632/oncotarget.24797
DO - https://doi.org/10.18632/oncotarget.24797
M3 - Article
C2 - 29719599
SN - 1949-2553
VL - 9
SP - 18198
EP - 18213
JO - Oncotarget
JF - Oncotarget
IS - 26
ER -
