Mutation Linked to Poor Prognosis in Head & Neck Cancer

SAN FRANCISCO—A single nucleotide polymorphism at codon 388 in the transmembrane domain of FGFR4 is linked to poor survival in patients with head and neck squamous cell carcinoma. The mutation (Arg388) involves the substitution of an arginine molecule for glycine at this position on the gene. It occurs in 45% to 50% of all humans.

Since the mutation occurs in the germ line, it is not connected to disease initiation, said Axel Ullrich, PhD, director of the Molecular Biology Department at the Max Planck Institute for Biochemistry, Martinsried, Germany. But, he said, "when the patient gets cancer, it is directly connected, and statistically highly significant, with an aggressive disease progression."

Dr. Ullrich reported the results at a news briefing at the 93rd Annual Meeting of the American Association for Cancer Research. Dr. Sylvia Streit, also of the Max Planck Institute, presented the paper at a minisymposium at the meeting (abstract 4116).

Possible Protective Effect

The German researchers studied samples from 104 tumors of patients with squamous cell head and neck cancer, using archival tissue. The tissue samples were analyzed for the FGFR4 genotype using a method based on restriction fragment length polymorphism.

The arginine mutation was found in 59 of the tumors, 46 heterozygous (in one chromosome), 13 homozygous (in both chromosomes). Patients with the FGFR4 Arg388 polymorphism experienced a significantly worse overall survival, compared with those with FGFR4 Gly388 (P = .02).

There were not enough subjects to determine if patients who were homozygous for FGFR4 Arg388 did worse than those who were heterozygous. "We are trying to determine that right now with another study," Dr. Ullrich said, adding that "there’s a good possibility" that this would turn out to be the case.

The researchers also investigated the relationship between overexpression of FGFR4 and survival. Seventeen of the samples were rated as being "high" for FGFR4 expression, 59 were "intermediate," and 28 were "low."

Overall survival rates were not related to FGFR4 expression. However, of the 17 individuals with high expression of FGFR4, only those with the FGFR4 Arg388 polymorphism died during the follow-up period (P = .035). Dr. Ullrich suggested that high expression of FGFR4 Gly388 might have a protective effect.

Breast and Colon Cancer

The German researchers demonstrated in a recently published study (Cancer Res 62:840-847, 2002) that FGFR4 Arg388 is also linked to poorer prognosis in patients with breast and colon cancer. As in the head and neck cancer investigation, approximately 50% of the individuals were heterozygous or homozygous for FGFR4 Arg388.

Disease-free survival was significantly reduced in those breast cancer patients with FGR4 Arg388 (P = .01) while it was associated with earlier lymph node metastasis and advanced TNM stage in colon cancer patients.

Possible Mechanisms

The researchers have not determined the mechanism by which FGFR4 Arg388 promotes a more aggressive disease development. However, Dr. Ullrich noted that "this gene apparently is involved in regulating motility and possibly invasion of cells."

He suggested that FGFR4 Gly388 may act as a negative control on motility and cell invasion, and that "introduction of this arginine codon . . . releases this negative control and therefore allows activation of the signaling system that promotes motility."

The researchers will be continuing their research on FGFR4 using samples of tumors taken from 300 head and neck squamous cell cancer patients with better clinical data.