Germline Mutation Predisposes Women Who Never Smoked? - 1262911

doubletime
Posts:18

A new study done recently that leaves me wondering, snippet below

1. Why Lung cancer development is much less common among smokers and men?
2. Should non-smoking siblings and children be tested for T790M even without knowing if their lung cancer relative carried gene but passed away from BAC in their 40's?

"Researchers at UT Southwestern Medical Center suggest that people who have an inherited mutation of a certain gene have a high chance of getting lung cancer than heavy smokers with or without the inherited mutation.

Although both genders have an equal risk of inheriting the mutation, those who develop lung cancer are mostly women and have never smoked, the researchers found.

People with the rare inherited T790M mutation of the epidermal growth factor receptor (EGFR) gene who have never smoked have a one-in-three chance of developing lung cancer, researchers found."

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Reply # - March 23, 2014, 12:03 PM

catdander
Posts:

Thanks doubletime, interesting new info. I had to look it up so... I pasted the abstract from the J of thoracic onc below.

"Introduction:

Hereditary lung cancer syndromes are rare, and T790M germline mutations of the epidermal growth factor receptor (EGFR) gene predispose to the development of lung cancer. The goal of this study was to determine the clinical features and smoking status of lung cancer cases and unaffected family members with this germline mutation and to estimate its incidence and penetrance.

Methods:

We studied a family with germline T790M mutations over five generations (14 individuals) and combined our observations with data obtained from a literature search (15 individuals).

Results:

T790M germline mutations occurred in approximately 1% of non–small-cell lung cancer cases and in less than one in 7500 subjects without lung cancer. Both sporadic and germline T790M mutations were predominantly adenocarcinomas, favored female gender, and were occasionally multifocal. Of lung cancer tumors arising in T790M germline mutation carriers, 73% contained a second activating EGFR gene mutation. Inheritance was dominant. The odds ratio that T790M germline carriers who are smokers will develop lung cancer compared with never smoker carriers was 0.31 (p = 6.0E-05). There was an overrepresentation of never smokers with lung cancer with this mutation compared with the general lung cancer population (p = 7.4E-06).

Conclusion:

Germline T790M mutations result in a unique hereditary lung cancer syndrome that targets never smokers, with a preliminary estimate of 31% risk for lung cancer in never smoker carriers, and this risk may be lower for heavy smokers. The resultant cancers share several features and differences with lung cancers containing sporadic EGFR mutations." http://journals.lww.com/jto/Abstract/2014/04000/Hereditary_Lung_Cancer_…

Reply # - March 23, 2014, 12:08 PM

catdander
Posts:

Penetrance is a new word for me so wiki'd

"Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene (allele or genotype) that also expresses an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms. For example, if a mutation in the gene responsible for a particular autosomal dominant disorder has 95% penetrance, then 95% of those with the mutation will develop the disease, while 5% will not."
http://en.wikipedia.org/wiki/Penetrance

Reply # - March 23, 2014, 01:08 PM

Dr West
Posts: 4735

Lung cancer isn't less common among smokers. Smoking is an overwhelming risk factor that increases the risk of developing lung cancer, but never-smokers aren't risk-free. Women are at higher risk of developing lung cancer than men with the same degree of tobacco exposure, for reasons we don't understand. You can read more about this issue here:

http://cancergrace.org/lung/2010/10/26/gender-differences-in-risk-for-l…

As for testing for T790M mutations, we are just beginning to learn about this. At the present time, I'd say that inherited. germline T790M mutations are too rare to make recommendations for routine testing of family members of never-smokers with lung cancer. Those germline muttions are clearly not the main mechanism by which most lung cancer in never-smokers develops.

There is certainly some new exciting work going on about this topic, Within the next few days, I'm planning to write a new post on the subject of T790M germline mutations and the implications for genetic screening of lung cancer.

Good luck.

-Dr. West

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