Lung cancer is the most common cause of cancer death in the world, with 1.38 million deaths every year, accounting for 18.2% of the total number of cancer deaths5. It is also the cancer with the highest morbidity and mortality in China, with about 781,000 new cases and 626,000 deaths reported in 2014 6. Lung cancer has obvious familial aggregation, but it is not clear whether the same environment, similar habits and the inherent genetic factors that all contribute to familial aggregation of lung cancer.
A study involving 44,788 twins found that the heritability of lung cancer was about 26%2. This indicates that genetic factors only play a small part in the incidence of lung cancer, and most of the reasons can be attributed to environmental factors. The results of a genome-wide association study (GWAS) also confirmed that the penetrance rate of gene variation was in direct proportion to the genetic risk of cancer: common SNPs with low penetrance were associated with low genetic risk; infrequent moderate penetrance genetic variants were associated with moderate genetic risk, such as ataxia telangiectasia mutation (ATM) and checkpoint kinase 2 (CHEK2); rare genetic variants with high penetrance are associated with high genetic risk, such as BRCA1/2 are associated with hereditary breast and ovarian cancer, MLH1, MSH2 and other MMR pathway gene variants are associated with Lynch syndrome7. What is in common is that ATM, CHEK2, BRCA1/2, MLH1, MSH2 and so on are all belonged to DNA damage repair (DDR) pathway genes. This type of genetic variation causes errors in the DNA replication process to go uncorrected, so more genes are mutated and tumors eventually form. GWAS has shown that the genetic risk of most common cancers is mostly polygenic7, so the DDR pathway gene germline mutations become the strongest genetic factor in tumor formation. However, the incidence of DDR pathway variation in lung cancer is low, and only a few are germline mutations, so the role of genetic factors in the etiology of lung cancer remains to be fully elucidated8.
EGFR is the most common driver gene of NSCLC, suggesting that EGFR plays an important role in the occurrence of NSCLC. However, most of the pathogenic EGFR mutations are somatic mutations and are not passed on to the next generation. At present, very few EGFR germline mutations have been reported, including G724S, K757R, V786M, T790M, L792F, R831H, V843I, L844V and D1014N4, 9. Among those studies, only T790M has a significant family history, but the relationship between T790M germline mutation and the occurrence of lung cancer has not been determined through the family pedigree4. In another family with V843I germline mutation, only 1 developed lung cancer in 20 blood relatives from two generations, so the relationship between V843I germline mutation and the occurrence of lung cancer could not be confirmed either9. Very similar to this study, the V843I mutation was also resistant to erlotinib, and the protein structure analysis also found that the V843I mutation did not change the affinity of ATP pocket region to EGFR-TKIs, and the mechanism of resistance remains unknown9.
Germline mutation of EGFR p.V1010M was first identified in this family. This mutation has not been reported so far, and it is defined as variant of unknown significance (VOUS) according to American College of Medical Genetics (ACMG). In the Catalogue of Somatic Mutations in Cancer (COSMIC) web site, functional analysis through hidden Markov models (FATHMM) prediction of EGFR p.V1010M is pathogenic (score 0.72). In the pedigree (Figure 6), it can be seen that among the five generations of the proband's maternal relatives, seven are known to have developed into lung cancer, with significant familial aggregation characteristics. Six of the ten tested were found to be germline EGFR p.V1010M carrier. However, except for the proband (III3), no lung cancer was found in III1, IV1, IV2, IV4 and V1. Considering that IV1, IV2, IV4 and V1 are all under the age of 40, whether they will develop into lung cancer in the future still needs long-term observation. Therefore, current evidence does not confirm whether there is a causal relationship between germline EGFR p.V1010M and the incidence of lung cancer.
Somatic mutations of EGFR p.L858R and KRAS p.G12V (Figure 2D) were found in the proband and II4, respectively, which are obvious oncogenic driver gene variations. Since somatic variations is usually attributed to environmental influences in the later period, environmental factors are the main cause of lung cancer, which has been confirmed once again.
According to different EGFR mutation sites, the efficacy of EGFR-TKIs is also different, and mutation sites can be divided into sensitive sites and resistance sites1. In this case, somatic mutation of EGFR p.L858R was simultaneously detected beyond EGFR p.V1010M, which is a common sensitive mutation. However, after the use of geffitinib and afatinib, the optimal efficacy was SD as assessed by RECIST 1.1, and it showed a progression trend 4 months after the use of the drug, suggesting that EGFR p.V1010M may be the resistance site of EGFR-TKIs.
V1010 is located on exon 22 of EGFR gene, near the kinase binding domain and the C-terminal. The three-dimensional computer simulation of the structure of the mutant protein showed that V1010M had little effect on the spatial structure of the EGFR dimer, and did not affect the ATP pocket binding to the EGFR-TKIs molecule. Therefore, the biological mechanism of EGFR-TKIs resistance caused by V1010M is still unknown, and further study is needed in animal models and cell line experiments.
Somatic variation caused by environmental factors is usually not thought to be directly passed on to the next generation. However, the same environment, similar habits and even the same work content in the same family will all cause familial aggregation of cancer. Family history is still a risk factor for lung cancer. Although the risk of the disease may not be transmitted to offspring through DNA sequence changes of germline, the risk of the disease can also be increased through DNA methylation, histone modification and RNA regulation8. Therefore, the importance of family history assessment should not be underestimated, and the family we reported also confirmed that people with a family history of lung cancer have a higher risk of developing lung cancer.
In summary, this family is the first family to be analyzed by pedigree with EGFR p.V1010M germline mutation. Although it has not been proved that this mutation site is a genetic factor for the occurrence of lung cancer, it is found that it may be a potential drug-resistant mutation of EGFR-TKIs. Next, we will conduct cell line and animal model studies to explore the biological mechanism of EGFR p.V1010M for the development and treatment of disease resistance. At the same time, we will follow up this family for a long time to investigate the correlation between EGFR p.V1010M and the development of lung cancer, which will also improve the awareness of cancer prevention and health care in this family, help them diagnosis and intervene in time.