Fanconi anemia and homologous recombination gene variants are associated with functional DNA repair defects and poor outcome in patients with advanced head and neck squamous cell carcinoma

TY - JOUR

T1 - Fanconi anemia and homologous recombination gene variants are associated with functional DNA repair defects 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

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 - Journal Article

U2 - 10.18632/oncotarget.24797

DO - 10.18632/oncotarget.24797

M3 - SCORING: Journal article

C2 - 29719599

VL - 9

SP - 18198

EP - 18213

JO - ONCOTARGET

JF - ONCOTARGET

SN - 1949-2553

IS - 26

ER -