Loss of heterozygosity of chromosome 3p21 is associated with mutant TP53 and better patient survival in non-small-cell lung cancer

Our plain-English summary of Loss of heterozygosity of chromosome 3p21 is associated with mutant TP53 and better patient survival in non-small-cell lung cancer, by C.J. Marsit, M. Hasegawa, T. Hirao, et al (Cancer Research, 2004).

The study

• Authors: C.J. Marsit, M. Hasegawa, T. Hirao, D.H. Kim, K. Aldape, P.W. Hinds, J.K. Wiencke, H.H. Nelson, K.T. Kelsey
• Journal: Cancer Research
• Published: 2004;64(23):8702-7
• Cited by: 34 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Allelic loss of chromosome region 3p21.3 occurs early and frequently in non-small-cell lung cancer, and numerous tumor suppressor genes at this locus may be targets of inactivation. Using an incident case series study of non-small-cell lung cancer, we sought to determine the prevalence of loss of heterozygosity (LOH) in the 3p21.3 region and to examine the associations between this alteration and patient outcome, exposure to tobacco smoke, occupational asbestos exposure, and additional molecular alterations in these tumors. We examined LOH at 7 microsatellite markers in the chromosome 3p21.3 region, and LOH was present in at least one of the loci examined in 60% (156 of 258) of the tumors, with the prevalence of LOH at individual loci ranging from 15 to 56%. Occupational asbestos exposure and TP53 mutation were significantly associated with more extensive 3p21 LOH. In squamous cell carcinomas, measures of cumulative smoking dose were significantly lower in patients with LOH at 3p21, particularly in TP53 mutant tumors. Examining patient outcome, we found that in squamous cell carcinomas, having any LOH in this region was associated with a better overall survival (log-rank test, P < 0.04). Together, these results indicate that allelic loss at 3p21 can affect patient outcome, and that this loss may initially be related to carcinogen exposure, but that extension of this loss is related to TP53 mutation status and occupational asbestos exposure.

In plain English

This study examined tumors from a random subset of 260 patients with surgically removable non-small-cell lung cancer treated at Massachusetts General Hospital from November 1992 through December 1996. The authors looked for loss of genetic material (loss of heterozygosity) at seven markers in chromosome region 3p21. They compared it with smoking, self-reported occupational asbestos exposure (no fiber type was given), TP53 gene mutations and survival. Loss was found in 60% (156 of 258) of tumors. Any loss occurred in 75% of tumors from asbestos-exposed patients and 58% from unexposed patients. The authors reported that extensive loss was about twice as common in exposed patients, but the article's table for this comparison is internally inconsistent. After accounting for TP53 mutation, histology and gender, asbestos exposure was no longer significantly linked to extensive loss (odds ratio 1.30, 95% confidence interval 0.55 to 3.09), while TP53 mutation was (odds ratio 3.36, 1.72 to 6.55). In squamous cell carcinoma, any loss was associated with better survival (hazard ratio 0.53, 0.30 to 0.94). The authors said larger studies including asbestos-exposed individuals are needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Case series of surgically resected lung tumors, with laboratory analysis of tumor DNA (loss of heterozygosity at 7 microsatellite markers on 3p21, TP53 mutation testing) linked to questionnaire data and survival
• Who was studied: Newly diagnosed patients with resectable lung cancer treated at the Massachusetts General Hospital Thoracic Surgery Service, November 1992 through December 1996. A random subset of 260 was analyzed, and 258 tumors were informative at one or more markers.
• Exposure: Occupational asbestos exposure (fiber type not specified) and tobacco use (ever or never smoking, pack-years, cigarettes per day), gathered from a self-administered questionnaire reviewed by an interviewer. Table 2 classes 36 patients as asbestos-exposed and 221 as unexposed.
• Main results:
  • Loss of heterozygosity at one or more 3p21 markers was found in 60% (156 of 258) of informative tumors.
  • Any 3p21 loss occurred in 59 of 81 (73%) squamous cell carcinomas compared with 83 of 145 (57%) adenocarcinomas (reported P value 0.02).
  • Any 3p21 loss was significantly associated with occupational asbestos exposure. It was found in 27 (75%) of exposed patients' tumors and 128 (58%) of unexposed patients' tumors (reported P value 0.05).
  • The authors reported that extensive 3p21 loss (fractional allelic loss score above the median of 0.2) was about twice as prevalent in asbestos-exposed patients as in unexposed patients (reported P value 0.02). The supporting table (Table 3) is internally inconsistent, so no reliable percentages can be given.
  • In a multivariate model of 214 adenocarcinoma or squamous cell tumors adjusting for TP53 mutation, gender and histology, occupational asbestos exposure was not significantly associated with extensive 3p21 loss (odds ratio 1.30, 95% CI 0.55 to 3.09).
  • In the same model, TP53 mutation was significantly associated with extensive 3p21 loss (odds ratio 3.36, 95% CI 1.72 to 6.55).
  • No statistically significant association was observed between TP53 mutation status and occupational asbestos exposure.
  • In squamous cell carcinoma, patients whose tumors retained 3p21 smoked a median of 40 cigarettes per day, compared with 30 per day for patients whose tumors had loss (reported P value 0.04).
  • In squamous cell carcinoma (n = 79), any 3p21 loss was associated with better survival after adjustment for age, gender and stage (hazard ratio 0.53, 95% CI 0.30 to 0.94).
• The authors' conclusion: The authors concluded that 3p21 loss may serve as a marker of response to treatment and of early carcinogenesis. On asbestos, they stated that larger studies including asbestos-exposed individuals will be needed to clarify the relationship between asbestos, TP53 and 3p21 loss.
• Limitations the authors state:
  • Statistical power for the stage-stratified survival analyses was low because of small numbers of samples.
  • Many factors affecting survival were not measured or controlled, so the survival hazard ratio may be influenced by uncontrolled confounding.
  • The authors noted that asbestos acted as a confounder in the multivariate model, and that larger studies are needed to clarify the relationships.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Lung Cancer, Tumor Suppressor Gene, Asbestos Exposure, Squamous Cell Carcinoma, Overall Survival.

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