Editors' ChoiceCancer

Genes and lung cancer: Stop YAPping!

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Science Translational Medicine  24 Jun 2015:
Vol. 7, Issue 293, pp. 293ec107
DOI: 10.1126/scitranslmed.aac7162

The majority of lung cancers are caused by smoking. In nonsmokers, genetic susceptibility may partly explain the development of lung cancer. Knowledge of genetic susceptibility might motivate individuals at high risk to reduce harmful exposures, increase surveillance, and seek preventive measures. Although a number of genetic variants that underlie inherited susceptibility to lung cancer are known, the majority have a high prevalence in the general population and low penetrance precluding their use as a screening tool to identify individuals at high risk. Identification of highly penetrant cancer susceptibility alleles (similar to BRCA1 or BRCA2 mutations in breast and ovarian cancers) offers an opportunity to screen carriers of such alleles, but only a handful of germline mutations that predispose to lung cancer have been described.

Chen et al. report the identification and characterization of a missense mutation in YAP1, a key component of the Hippo pathway, as a germline risk allele for lung adenocarcinoma. The starting point of their investigations was a family with an unusually high frequency of lung adenocarcinoma affecting a mother and four out of her five children. Whole-genome sequencing of germline DNA from affected and nonaffected family members identified over 200 nonsynonymous alleles that were shared by the affected individuals. Variants that were found in ethnically comparable individuals without cancer were excluded to zero in on the germline mutation in YAP1 as the risk allele. In the extended family of the proband, YAP1 mutation carriers had overwhelmingly higher frequencies of lung adenocarcinoma or ground-glass opacity lung lesions than those who did not carry the mutation. In an external validation cohort of over 1300 individuals without cancer and a similar number with lung adenocarcinoma, the YAP1 mutant allele carrier frequency was 0.18% and 1.1%, respectively. After adjusting for other risk factors including smoking, the odds ratio for lung cancer was 5.9 in YAP1 mutant allele carriers.

Although of low prevalence, the highly penetrant YAP1 germline mutation has obvious implications in lung cancer prevention because mutation carriers will likely benefit from increased surveillance and early detection measures, such as low-dose computed tomography. As with a number of other heritable cancer genes, further studies on YAP1-mediated lung carcinogenesis might shed light on molecular regulatory pathways important in sporadic tumor development as well.

H.-Y. Chen et al., R331W missense mutation of oncogene YAP1 is a germline risk allele for lung adenocarcinoma with medical actionability. J. Clin. Oncol. 10.1200/JCO.2014.59.3590 (2015). [Abstract]

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