A rare truncating BRCA2 variant and genetic susceptibility to upper aerodigestive tract cancer

Abstract

Deleterious BRCA2 genetic variants markedly increase risk of developing breast cancer. A rare truncating BRCA2 genetic variant, rs11571833 (K3326X), has been associated with a 2.5-fold risk of lung squamous cell carcinoma but only a modest 26% increase in breast cancer risk. We analyzed the association between BRCA2 SNP rs11571833 and upper aerodigestive tract (UADT) cancer risk with multivariable unconditional logistic regression adjusted by sex and combinations of study and country for 5942 UADT squamous cell carcinoma case patients and 8086 control patients from nine different studies. All statistical tests were two-sided. rs11571833 was associated with UADT cancers (odds ratio = 2.53, 95% confidence interval = 1.89 to 3.38, P = 3x10(-10)) and was present in European, Latin American, and Indian populations but extremely rare in Japanese populations. The association appeared more apparent in smokers (current or former) compared with never smokers (P het = .026). A robust association between a truncating BRCA2 variant and UADT cancer risk suggests that treatment strategies orientated towards BRCA2 mutations may warrant further investigation in UADT tumors.

Figure 1.

Association between BRCA2 SNP rs11571833 and upper aerodigestive tract cancer risk. Squares represent odds ratios, size of the square represents the inverse of the variance of the log odds ratios; horizontal lines represent 95% confidence intervals. The solid vertical line indicates an odds ratio of 1 and the dashed vertical line the overall odds ratio. The arrow indicates that the confidence interval of this particular estimate exceeds the scale of the plot. Results derived from a two-sided multivariable unconditional logistic regression adjusted by sex and study-specific country. All statistical tests were two-sided. ACTREC = Advanced Centre for Treatment, Research and Education in Cancer oral cancer study; CI = confidence interval; HNI = Rome (Italy) head and neck cancer study; OR = odds ratio; ORC = IARC multicentre oral cancer case control study; SA = South America.