M6P/IGF2R loss of heterozygosity in head and neck cancer associated with poor patient prognosis.
BACKGROUND
The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) encodes for a multifunctional receptor involved in lysosomal enzyme trafficking, fetal organogenesis, cytotoxic T cell-induced apoptosis and tumor suppression. The purpose of this investigation was to determine if the M6P/IGF2R tumor suppressor gene is mutated in human head and neck cancer, and if allelic loss is associated with poor patient prognosis.


METHODS
M6P/IGF2R loss of heterozygosity in locally advanced squamous cell carcinoma of the head and neck was assessed with six different gene-specific nucleotide polymorphisms. The patients studied were enrolled in a phase 3 trial of twice daily radiotherapy with or without concurrent chemotherapy; median follow-up for surviving patients is 76 months.


RESULTS
M6P/IGF2R was polymorphic in 64% (56/87) of patients, and 54% (30/56) of the tumors in these informative patients had loss of heterozygosity. M6P/IGF2R loss of heterozygosity was associated with a significantly reduced 5 year relapse-free survival (23% vs. 69%, p = 0.02), locoregional control (34% vs. 75%, p = 0.03) and cause specific survival (29% vs. 75%, p = 0.02) in the patients treated with radiotherapy alone. Concomitant chemotherapy resulted in a better outcome when compared to radiotherapy alone only in those patients whose tumors had M6P/IGF2R loss of heterozygosity.


CONCLUSIONS
This study provides the first evidence that M6P/IGF2R loss of heterozygosity predicts for poor therapeutic outcome in patients treated with radiotherapy alone. Our findings also indicate that head and neck cancer patients with M6P/IGF2R allelic loss benefit most from concurrent chemotherapy.
Jamieson
Timothy A
TA
Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA. voll002@duke.edu
Brizel
David M
DM
Killian
J Keith
JK
Oka
Yoshihiko
Y
Jang
Hong-Seok
HS
Fu
Xiaolong
X
Clough
Robert W
RW
Vollmer
Robin T
RT
Anscher
Mitchell S
MS
Jirtle
Randy L
RL
D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D005260:Female; D020022:Genetic Predisposition to Disease; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D017527:Receptor, IGF Type 2 / Q000235:genetics*; D016019:Survival Analysis; D017211:Treatment Failure; D016896:Treatment Outcome
D017527:Receptor, IGF Type 2