Familial Cancer DOI 10.1007/s10689-015-9796-x
REVIEW ARTICLE
Germline mutations predisposing to non-small cell lung cancer Gerald H. Clamon1 • Aaron D. Bossler2 • Taher Abu Hejleh1 • Muhammad Furqan1
Ó Springer Science+Business Media Dordrecht 2015
Abstract Lung cancer in multiple first degree relatives had previously been attributed to smoking and to inherited enzymes associated with increased activation of carcinogens in smoke. There was not clear agreement on the significance of the testing methods for lung cancer susceptibility. More recent studies have identified germline mutations associated with lung cancer even in the absence of smoking and other mutations with plausible explanations for their association with lung cancer caused by smoking. At this time, the clinical significance of the various germline mutations for screening and the implications for therapy are not certain. This review summarizes the currently identified germline mutations associated with lung cancer, but this growing area of research will very likely identify further significant mutations as well. Keywords Germline mutations Non-small cell lung cancer Germline mutation Lung cancer
Introduction The majority of patients with non-small cell lung cancer have cancer attributable to smoking. In the past, attempts were made to predict which individuals who smoke might be predisposed to developing lung cancer. Recently,
& Gerald H. Clamon [email protected] 1
Department of Internal Medicine, University of Iowa College of Medicine, University of Iowa Hospitals, 200 Hawkins Drive, Iowa City, IA 52242, USA
2
Department of Pathology, University of Iowa Hospitals, Iowa City, IA, USA
families have been described in which germline mutations either predisposed to lung cancer in the absence of smoking or predisposed to lung cancer in smoking individuals [1–4]. The number of germline mutations associated with familial lung cancer has been small thus far. With increased use of exome or whole genome sequencing of lung cancer specimens, more mutations that may predispose the individual to lung cancer are likely to be discovered. The immediate clinical implication for such families would be that appropriate screening guidelines could be developed for affected individuals. Currently, screening is only recommended for active smokers who smoked 30 pack years or those who had smoked that much but quit with in the last 15 years. Younger individuals in affected families could be informed of their higher risk and urged to never smoke. Prior epidemiologic studies demonstrated a twofold to threefold increased risk of lung cancer in relatives of lung cancer cases [5, 6]. A study of genome wide association found a locus at 15q25.1 which was associated with increased risk for lung cancer. This SNP was in an area which encodes the nicotinic acetylcholine receptor subunit [7]. The increased risk was only demonstrated in individuals who smoked. SNPs were evaluated in 1154 current and former smokers of European ancestry with lung cancer and 1137 smoking controls from Houston, Texas. Two SNP’s (rs1051730 and rs8034191) mapping to the 15q25.1 region were associated with an increased susceptibility of developing lung cancer with a relative risk (RR) of 1.32. In a recent evaluation of 93 families with at least two first degree relatives with lung cancer, 444 lung cancers were detected and linkage analysis was performed from 1156 blood samples, 24 buccal cell samples, and 274 tissues blocks with normal tissue. A susceptibility locus on chromosome 6q was found which increased the risk of lung cancer in never smokers and light smokers [8]. For carriers
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of the germline mutation on 6q who smoked, the relative risk of lung cancer was 3.31. For family members who did not carry the germline mutation but who smoked, the relative risk of lung cancer was 2.95. The purpose of this review is to summarize the recent literature on germline mutations which predispose to lung cancer. In the development of future guidelines for low dose CAT scan screening, individuals with a high risk for lung cancer genetically rather than just by smoking history, should be evaluated to determine if they benefit from earlier screening.
Methods Studies of germline mutations predisposing to lung cancer were identified by a PUB-MED search, search of references in the PUB-MED identified studies, and search of the clinical literature in journals publishing studies of lung cancer such as Chest, Journal of Thoracic Oncology, Clinical Lung Cancer, Lung Cancer, Lancet Oncology, Familial Lung Cancer, and the Journal of the National Cancer Institute. References found in reviewing these studies were also evaluated. This method would not qualify however as a comprehensive review.
Germline mutations in the epidermal growth factor receptor gene NCCN guidelines recommend screening of lung cancer tissue for somatic mutations in EGFR, ALK and ROS1 in patients with adenocarcinoma of the lung, adenosquamous carcinoma of the lung, and large cell cancer of the lung. Somatic mutations in the tyrosine kinase domain, of the exons 19–21 of the EGFR (Epidermal growth factor receptor) gene have been described in about 8 % of adenocarcinoma of the lung patients, with never smokers, women, and Asian backgrounds having a higher incidence of such mutations. These mutations have been associated with susceptibility to tyrosine kinase inhibitors such as Erlotinib, Gefitinib, Afatinib. After treatment with such agents, resistance to these TKIs usually develops most often due to a second mutation with a threonine to methionine substitution at codone T790M and T79l. Thomas et al. [1] described two patients with T790M germ cell mutations; one case occurred in a family with multiple first degree relatives with lung cancer and several were never smokers, the second in an individual harboring both a T790M and a KRAS mutation. This paper also reviewed 10 previously described patients with T790M germline mutations. Eight of these individuals had an adenocarcinoma of the lung, 7 were never smokers, and one had bronchoalveolar lung cancer.
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Oxnard et al. [9] pointed out that only about 1 % of patients have a T790M mutation at diagnosis prior to TKI therapy. They identified 11 unrelated patients with the T790M mutation in the tumor prior to exposure to any TKI therapy, five of whom also carried the mutation in the germline. In a separate trial reported by Vikis et al. [10], there were no cases of germline T790M mutation in 52 families with lung cancer. A study of 369 never smokers with lung adenocarcinoma found 2 cases of a germline T790M mutation [11] Reviewing the case histories in these reports of patients with germline T790M mutations, several never smoking individuals had more than one primary lung cancer and the cancer type was generally adenocarcinoma. A patient with a T790M mutation in the cancer (somatic) at diagnosis should have a blood study to determine if they carry a germline T790M mutation. The incidence of carrying such a germline mutation is likely very low but in those with the germline 790 mutation, other family members should be screened for this mutation. At this time, there are insufficient numbers of such individuals studied to know what their relative risk of lung cancer is. Another activating germline mutation in the EGFR, an arginine to histidine substitution in exon 20, R776H, has been associated with squamous cell lung cancer [12]. Squamous cell lung cancer developed in both a mother and daughter neither of whom smoked and whose cancer demonstrated this missense mutation (somatic). However, this mutation was also detectable in DNA from normal tissue from the lung, lymph node, skin and blood from the daughter (germline mutation). Analysis of a cytology specimen from the mother’s node revealed the R776H mutation was present in her tumor and as well as normal lymphoid cells. The mother’s tumor also had a second mutation at codon 719. Ceneno et al. [13] also identified a germline R776H substitution in the evaluation of tumor and blood samples from 912 patients with lung cancer, blood samples from 477 healthy unrelated blood donors, and 32 patients with other types of cancer. Tumor from 71 patients with adenocarcinoma was tested for an EGFR mutation at exons 18–21. Twelve patients had an EGFR mutation in the tumor and one had the R776G in both the tumor and germline tissues. This mutation was not found in the blood of 954 normal individuals without cancer nor in the blood of any other of 912 lung cancer patients. In vitro analysis demonstrated enhanced tyrosine kinase autophosphorylation in R776G mutant EGFR. Their conclusion was that the R776H germline mutation is rare. The relative risk it poses for lung cancer in affected individuals is not known because of the small number of cases identified. Ohtsuka et al. [14] detected a germline mutation in EGFR resulting in a valine to isoleucine substitution, V843I, in a family with multiple cases of adenocarcinoma
Germline mutations predisposing to non-small cell lung cancer
of the lung. The proband was a 48 year old woman who presented with widely disseminated adenocarcinoma of the lung. Her family history was significant for her mother having had a stage 1A lung adenocarcinoma resected at age 61 and a younger brother with a stage 1A lung cancer when he was 41. These three individuals with adenocarcinoma all had the germline V843I mutation in the cancer as well as an L858R mutation. The proband was treated with both gefitinib and erlotinib with no response. The V843I mutation may block the usual sensitivity of L858R to these tyrosine kinase inhibitors. This same group, Matsushima et al. [15], did further work showing that the V843I mutation was associated with increased tyrosine kinase phosphorylation and resistance to first generation TKI. Demierre et al. described a woman with a smoking history who had stage IV adenocarcinoma of the lung with both a tumor and germline mutation at exon 21 V843l. This patient’s tumor did not have any secondary activating mutation in EGFR [16]. Ikeda et al. [17] described a family with multiple cases of adenocarcinoma of the lung. The proband was a 70 year old woman with multiple lung adenocarcinomas who had the germline V843I but also a second mutation either L858R or L861Q in the tumors. Her father and brother had had lung cancer. Another brother and sister who had the germline EGFR V843I mutation had not yet developed lung cancer. Some of these patients with a germline V843I mutation in the blood also had a second somatic mutation in the cancer itself. However, there are too few cases to assess the relative risk for lung cancer with and without smoking in patients who carry the V843I germline mutation. Prim et al. [18] recently described two patients with germline mutations predisposing to lung adenocarcinoma One individual had a tumor with mutations at L858R and V843l and a germline mutation in V843l. This patient’s tumor did have stable disease on erlotinib. A second patient was described with a germline P848L mutation in exon 21. This report emphasized that germline mutations in EGFR are described in \1 in 1000 patients with EGFR somatic mutations. One family from Japan has been described by Yamamoto et al. [19] with a germline HER2-G660D mutation. This substitution is not in the area of the tyrosine kinase domain but rather in the transmembrane domain. This family had approximately nine members with lung cancer over three generations. The proband had only smoked 1.2 pack years and her mother was a never smoker. Although there were 9 family members with lung cancer, the report by Yamamoto does not indicate that any other family members were tested except the proband and her mother. No additional cases of this germline mutation were found through sequencing of 315 other patients with nonsmall cell lung cancers. The above family history suggests
that carriers of the germline HER-2G660D mutation are at risk for lung cancer, even in the absence of smoking but again there are too few cases known to determine the relative risk for these carriers. With no other cases found in searching 315 other lung cancer patients, this may be an uncommon mutation.
Germline mutations other than EGFR which predispose to lung carcinoma The overall incidence of mutations in genes other than EGFR genes could potentially be of greater significance than those described for the EGFR mutations as they may be more common. The BRCA2 mutation may affect about 0.1–2 % of the population. Wang et al. [2] examined 4 genome-wide association studies of lung cancer in population of European ancestry. There were 11,348 cases with lung cancer and 15,861 controls. They found that a rare variant of BRCA2 (L3326X) was associated with a relative risk of 2.47 for lung cancer. They also reported an association between BRCA2 and CHK2 germline mutations and squamous cell lung cancer and a mutation at 3q28 and adenocarcinoma of the lung. They concluded that about 25 % of smokers with a germline mutation in BRCA2 will develop lung cancer compared with all smokers who have about a 13 % risk of lung cancer Studies have been performed examining the prognostic implications of BRCA1 mutation in the tumor of patients with non-small cell lung cancer. These have been summarized [20] but the conclusion at this time is that germline BRCA1 mutation is not involved in the development of non-small cell lung cancer. In families with inherited melanoma, 5–20 % carry a germline mutation of the CDKN2A gene on chromosome 9p21 (involving the tumor suppressor p16-INK4A and p14ARF). A familial CDKN2A mutation, R112dup associated with melanoma and pancreatic cancer has been associated with an increased risk of lung, head and neck cancer and gastroesophageal cancer in patients who smoke [3]. The relative risk for CDKN2A R112dup mutation carriers was estimated to be 15.6 for respiratory tract cancer compared to individuals who were not carriers of the mutation. They were able to obtain smoking histories in about 60 % of the CDKN2A mutation carriers. Those with the mutation who smoked had an odds ratio of 9.3 for lung cancer or upper digestive cancer compared with never smokers and the same mutation. The hypothesis is that this mutation increases the carcinogenic effect of smoking. Potrony et al. [21] reported on Spanish patients with CDKN2A mutations. Among families with two members with melanoma, the CDKN2A mutation was found in 10.9 % of cases, and for 3,4, or 5 family members involved the CDKN2A mutation was found in 23,36 and 66 % of
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cases respectively. In families in which at least one member had a CDKN2A, the relative risk for lung cancer in other family members was found to be 3.04. This study did not demonstrate that the other family members with lung cancer actually had the germline CDKN2A mutation and did it provide any smoking history. Therefore it is difficult to interpret this reported increase in risk for lung cancer. Abdel-Rahman et al. [4] described a family with a germline mutation in BAP1 which is associated with uveal melanoma. They found one patient with a germline BAP1 mutation by screening 53 patients who had uveal melanoma. The proband had both uveal melanoma and lung adenocarcinoma. Other relatives of the proband with the BAP1 germline mutation or obligate carriers suffered from cutaneous melanoma, meningioma, uveal melanoma, a neuroendocrine cancer, and abdominal adenocarcinoma possibly of ovarian primary, and mesothelioma. With just this one family, it is difficult to discern the relative risk of lung cancer. Muir-Torre syndrome is a variant of Lynch syndrome or hereditary non polyposis colon cancer with sebaceous cancer of the skin. Other neoplasms associated with HNPCC (hereditary non polyposis colon cancer which is also called Lynch Syndrome) are endometrial, bladder, and upper gastrointestinal cancer. Nolan et al. [22] reported a patient with Muir-Torre syndrome who had a deficiency in hMSH-2 by immunohistochemistry (this mutation can be detected in tumor tissue and confirmed by blood tests as a germline mutation). The patient had had two colon cancers and later developed bilateral adenocarcinoma of the lung. These were lung primaries as evidenced by the fact that they were CK7 positive, TTF positive and CK20 negative. One of the lung tumors was deficient in hMSH2 but the contralateral tumor was not. The patient had a 20 pack year history of smoking. Canney et al. [23] described a very similar case of a patient with a germline mutation of MSH2 who had colon cancer and later lung cancers with both adenocarcinoma and bronchoalveolar features. With only these two cases, it will require further studies to determine if HNPCC is associated with an increased risk of lung adenocarcinoma. In a systematic review of cancer risk in patients with Peutz-Jeghers syndrome (PJS), there was a marked increase in risk of colorectal, breast, small bowel and pancreatic cancers. There was also a likely increased risk of lung cancer but in the absence of data on smoking history, it may be difficult to assess the magnitude of the risk [24]. However, there is a specific mutation in LKB1 associated with Peutz–Jeghers (PJS) syndrome described in the lung adenocarcinomas of such patients. The LKB1 mutation is also associated with adenocarcinoma of the lung in the absence of PJS [25]. This would be a plausible explanation for the possibly increased risk of lung cancer in those with PJS.
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Using a Dutch tumor registry, Marees et al. [26] were able to follow up on 668 patients with retinoblastoma (bilateral or hereditary and unilateral or non-hereditary). Bilateral eye involvement is associated with a germline mutation in the retinoblastoma gene. From the time of diagnosis, the risk of secondary cancers with hereditary retinoblastoma was 36 % after 50 years of follow up. Most secondary tumors are soft tissue sarcoma, osteosarcoma or melanoma. Those individuals with hereditary retinoblastoma had a relative risk of 16.8 for other cancers compared with the general population. Wang et al. [27] described two families with interstitial fibrosis (IF) and adenocarcinoma of the lung. In one family, the proband was a 51 year old man who had 10 relatives with IF and 5 had died before age 50. Four of these cases also had adenocarcinoma of the lung (what was then termed bronchoalveolar carcinoma) and 3 other relatives had adenocarcinoma or bronchoalveolar lung cancer without fibrosis. This family had a rare missense mutation in SFTPA2 within the interval coding for the surfactant protein A2. A different mutation in SFTPA2 was found in another family with IPF and lung cancer. These families were identified from 59 kindreds with pulmonary fibrosis and no detected mutations in TERT or TERC which is associated with about 15 % of IPF families. Extensive literature exists that single nucleotide polymorphisms (SNP’s) are associated with lung cancer via genome wide association studies [28]. Three separate susceptibility loci in particular at 5p15, 6p21 and 15q25 have been described. A further analysis of just the genetic variants on chromosome 5p15 have significant effect on lung cancer risk and these are rs2736100 (OR 1.20), rs401681 (OR 0.88), rs40270 (OR 1.15) and rs31489 (OR1.10) [29]. The risk varied among different ethnicities. Two important candidate genes in that area are cleft lip and palate transmembrane 1-like gene (CLPTM1L) and human telomerase reverse transcriptase gene (TERT). Hung et al. [30] described SNP’s on 15q25 which they indicated were associated with 14 % of lung cancer cases. This locus is the site of nicotinic acetylcholine receptor subunit genes CHRNA5, CHRNA3 and CHRNB4. This area may also be associated with increased propensity for smoking. The fact that SNP’s in this area were associated with lung cancer but not head and neck cancer suggested that the risk of lung cancer was not attributable to only increased smoking exposure. Most notable of these SNPs in this area with their odds ratios are rs1051730 (OR 1.32), rs803419 (OR 1.32) and rs16969968 (OR 1.3). The initial studies of SNP’s on 15q25.1 were carried out in Asian and Caucasian populations only, however studies that included African-Americans also suggested that multiple SNP’s in this region were associated with risk of lung cancer [31, 32]. In white individuals, some SNPs were associated with more
Germline mutations predisposing to non-small cell lung cancer
smoking and other SNP were not associated with more smoking., The haplotypes associated with lung cancer were assessed for smoking behavior such as pack years smoked, cigarettes per day, and maximum cigarettes per day as measured by a test called the Fagerstrom Test for Nicotine Dependence. African-Americans carried some of the same haplotypes observed in Caucasian patients. With the rs1051730 haplotype the odds ratio for lung cancer was 1.59 and with the rs931794 haplotypes the odds ratio for lung cancer was 1.39 in ever smoking African-Americans. Renieri et al. studied non-smoking individuals with adenocarcinoma of the lung prior to age 60 who had a sibling who did not have lung cancer at the time of their analysis. They did whole exome sequencing in germline DNA on 4 of the pairs and found 8 cancer related genes involved in one patient with lung cancer and 5 in another patient, but not in their matched siblings without lung cancer [33]. In one of the sib pairs (both case and control), they found the 15q25 risk alleles of rs1051730 and rs16969968. In the other sib pair they found the risk allele rs 402710 in the 5p15.33 region. In a study from China [34], coke oven workers were found to have 25 lung cancer risk related SNPs which correlated with polycyclic hydrocarbon induced genetic damage. In a study of variants of the nicotinic receptor genes and the association with both smoking dependence and adenocarcinoma of the lung, two CHRNA3 SNPs were most associated with nicotine dependence and adenocarcinoma of the lung [35]. They demonstrated that variations in these genes significantly affect the risk for adenocarcinoma of the lung. Nicotine dependence accounts for 15 % of the relationship between these genetic variants and lung adenocarcinoma Schwartz and Ruckdeschel [36] in 2006 and again in 2012 [37] examined the data for genetic factors related to familial lung cancer. Their studies focused on a possible genetic susceptibility to COPD and lung cancer. Data was cited for a susceptibility locus at 6q23–25 [38] reported from a study of 52 families with multiple cases of lung cancer in the family. However, in that trial, the association was only significant after dropping the number of families included from 52 to 23. Twenty nine studies were cited in which different loci possibly associated with COPD and lung cancer were cited [36]. Lung diseases associated with inflammation such as emphysema, chronic bronchitis, prior pneumonia, prior tuberculosis are associated with an increased risk of lung cancer with relative risk 2.44, 1.47, 1.57 and 1.48 respectively. Never smokers were also found to be at elevated risk of lung cancer though lower than smokers if they had any of these diseases, indicating that these diseases are an independent risk factor for lung cancer. How much is related to genetic susceptibility and how much is related to inflammation is not clear. In these studies, former smokers and smokers had
a very similar relative risk but never smokers had a lower relative risk [39]. As there is the potential for multiple interactions of combinations of SNPs, it may be difficult to assess the extent of increased risk in any patient with one or more of these SNPs.
Discussion The identification of somatic mutations in adenocarcinomas of the lung such as EGFR mutation, ALK mutations, and ROS 1 mutations has led to the discovery of specific agents to treat pateints with these mutations. These new agents which are tyrosine kinase inhibitors (erlotinib, gefinitinb, afitinib, crizotinib, ceritinib) have improved therapy and prognosis compared with standard chemotherapy regimens for lung cancer. After treatment with these targeted agents, secondary somatic mutations develop which lead to resistance to these agents and progression of the cancer. With the secondary resistance mutation T790M, lung cancers previously sensitive to first line agents such as erlotinibor become resistant. However, a very small number of cases have been reported in which patients had the T790M mutation in the cancer at diagnosis, before ever being exposed to one of the targeted agents. In some these patients, with T790M at diagnosis, they have had a germline mutation with T790M as well. This T790M germline mutation is associated with familial lung cancer. The clinical implication for a patient with a germline T790M mutation and a T790M mutation at diagnosis in the lung cancer is that while standard tyrosine kinase inhibitors are not apt to be effective, new tyrosine kinase inhibitors are under development which overcomes the T790M mutation such as AZD9291 [40]. The implication for family members who have this T790M germline mutation but who do not yet have lung cancer is still being worked out. It is possible that these affected family members might benefit from never smoking, from being screened for lung cancer even if they never smoke, and that agents that could prevent their developing lung cancer could be found. This review is intended to outline the new but growing knowledge of new mutations which may lead to lung cancer without smoking or increase the risk of lung cancer with smoking. Families who carry germline mutations such as the EGFR T790M1 or other SNP’s such as those at 15q25 appear to have increased risk of lung cancer development. The number of associations with various SNP suggests that unlike germline mutations (BRCA2, T790M mutations) they are not likely ready to be used to select patients for lung cancer screening. In the past, attempts were made to predict which smoking individuals might be predisposed to developing lung cancer. The conjecture had been made that increased
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aryl hydrocarbon hydroxylase (AHH) led to greater activation of polycyclic hydrocarbons to active carcinogens. Cigarette smoke contains some carcinogens which can bind to DNA directly and other carcinogens which require metabolism to bind to and damage DNA. This literature is vast but with prior methodology, the relationship between AHH and lung cancer remained controversial [41]. At one time the debrisoquin metabolic phenotype was considered as a potential means to predict which individuals might be more apt to develop lung cancer with smoking. This also remained controversial [42]. With the recent genetic investigations, more specific biomarkers are being identified that may help to improve the risk calculation for familial lung cancer. New screening guidelines will need to be developed for families based on the age of onset of the cancer in the affected family and the specific mutation identified. It is possible that for families with germline mutations which increase the risk for lung cancer, earlier screening with low dose CAT scans might be useful However, there is not yet evidence that demonstrates that testing for lung cancer susceptibility will lead to improved survival for affected individuals who are screened. Further, germline mutations may suggest improved therapy for affected individuals. For example, patients with a BRCA2 mutation may have improved response to therapy which includes a PARP inhibitor and for those with a T790M mutation, therapy with AZD9291 may help. While much clinical investigation remains to be carried out, the identification of germline mutations predisposing to lung cancer has to the potential for translational research to benefit patients and their families who carry such a mutation. Conflict of interest
None.
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REVIEW ARTICLE
Germline mutations predisposing to non-small cell lung cancer Gerald H. Clamon1 • Aaron D. Bossler2 • Taher Abu Hejleh1 • Muhammad Furqan1
Ó Springer Science+Business Media Dordrecht 2015
Abstract Lung cancer in multiple first degree relatives had previously been attributed to smoking and to inherited enzymes associated with increased activation of carcinogens in smoke. There was not clear agreement on the significance of the testing methods for lung cancer susceptibility. More recent studies have identified germline mutations associated with lung cancer even in the absence of smoking and other mutations with plausible explanations for their association with lung cancer caused by smoking. At this time, the clinical significance of the various germline mutations for screening and the implications for therapy are not certain. This review summarizes the currently identified germline mutations associated with lung cancer, but this growing area of research will very likely identify further significant mutations as well. Keywords Germline mutations Non-small cell lung cancer Germline mutation Lung cancer
Introduction The majority of patients with non-small cell lung cancer have cancer attributable to smoking. In the past, attempts were made to predict which individuals who smoke might be predisposed to developing lung cancer. Recently,
& Gerald H. Clamon [email protected] 1
Department of Internal Medicine, University of Iowa College of Medicine, University of Iowa Hospitals, 200 Hawkins Drive, Iowa City, IA 52242, USA
2
Department of Pathology, University of Iowa Hospitals, Iowa City, IA, USA
families have been described in which germline mutations either predisposed to lung cancer in the absence of smoking or predisposed to lung cancer in smoking individuals [1–4]. The number of germline mutations associated with familial lung cancer has been small thus far. With increased use of exome or whole genome sequencing of lung cancer specimens, more mutations that may predispose the individual to lung cancer are likely to be discovered. The immediate clinical implication for such families would be that appropriate screening guidelines could be developed for affected individuals. Currently, screening is only recommended for active smokers who smoked 30 pack years or those who had smoked that much but quit with in the last 15 years. Younger individuals in affected families could be informed of their higher risk and urged to never smoke. Prior epidemiologic studies demonstrated a twofold to threefold increased risk of lung cancer in relatives of lung cancer cases [5, 6]. A study of genome wide association found a locus at 15q25.1 which was associated with increased risk for lung cancer. This SNP was in an area which encodes the nicotinic acetylcholine receptor subunit [7]. The increased risk was only demonstrated in individuals who smoked. SNPs were evaluated in 1154 current and former smokers of European ancestry with lung cancer and 1137 smoking controls from Houston, Texas. Two SNP’s (rs1051730 and rs8034191) mapping to the 15q25.1 region were associated with an increased susceptibility of developing lung cancer with a relative risk (RR) of 1.32. In a recent evaluation of 93 families with at least two first degree relatives with lung cancer, 444 lung cancers were detected and linkage analysis was performed from 1156 blood samples, 24 buccal cell samples, and 274 tissues blocks with normal tissue. A susceptibility locus on chromosome 6q was found which increased the risk of lung cancer in never smokers and light smokers [8]. For carriers
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of the germline mutation on 6q who smoked, the relative risk of lung cancer was 3.31. For family members who did not carry the germline mutation but who smoked, the relative risk of lung cancer was 2.95. The purpose of this review is to summarize the recent literature on germline mutations which predispose to lung cancer. In the development of future guidelines for low dose CAT scan screening, individuals with a high risk for lung cancer genetically rather than just by smoking history, should be evaluated to determine if they benefit from earlier screening.
Methods Studies of germline mutations predisposing to lung cancer were identified by a PUB-MED search, search of references in the PUB-MED identified studies, and search of the clinical literature in journals publishing studies of lung cancer such as Chest, Journal of Thoracic Oncology, Clinical Lung Cancer, Lung Cancer, Lancet Oncology, Familial Lung Cancer, and the Journal of the National Cancer Institute. References found in reviewing these studies were also evaluated. This method would not qualify however as a comprehensive review.
Germline mutations in the epidermal growth factor receptor gene NCCN guidelines recommend screening of lung cancer tissue for somatic mutations in EGFR, ALK and ROS1 in patients with adenocarcinoma of the lung, adenosquamous carcinoma of the lung, and large cell cancer of the lung. Somatic mutations in the tyrosine kinase domain, of the exons 19–21 of the EGFR (Epidermal growth factor receptor) gene have been described in about 8 % of adenocarcinoma of the lung patients, with never smokers, women, and Asian backgrounds having a higher incidence of such mutations. These mutations have been associated with susceptibility to tyrosine kinase inhibitors such as Erlotinib, Gefitinib, Afatinib. After treatment with such agents, resistance to these TKIs usually develops most often due to a second mutation with a threonine to methionine substitution at codone T790M and T79l. Thomas et al. [1] described two patients with T790M germ cell mutations; one case occurred in a family with multiple first degree relatives with lung cancer and several were never smokers, the second in an individual harboring both a T790M and a KRAS mutation. This paper also reviewed 10 previously described patients with T790M germline mutations. Eight of these individuals had an adenocarcinoma of the lung, 7 were never smokers, and one had bronchoalveolar lung cancer.
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Oxnard et al. [9] pointed out that only about 1 % of patients have a T790M mutation at diagnosis prior to TKI therapy. They identified 11 unrelated patients with the T790M mutation in the tumor prior to exposure to any TKI therapy, five of whom also carried the mutation in the germline. In a separate trial reported by Vikis et al. [10], there were no cases of germline T790M mutation in 52 families with lung cancer. A study of 369 never smokers with lung adenocarcinoma found 2 cases of a germline T790M mutation [11] Reviewing the case histories in these reports of patients with germline T790M mutations, several never smoking individuals had more than one primary lung cancer and the cancer type was generally adenocarcinoma. A patient with a T790M mutation in the cancer (somatic) at diagnosis should have a blood study to determine if they carry a germline T790M mutation. The incidence of carrying such a germline mutation is likely very low but in those with the germline 790 mutation, other family members should be screened for this mutation. At this time, there are insufficient numbers of such individuals studied to know what their relative risk of lung cancer is. Another activating germline mutation in the EGFR, an arginine to histidine substitution in exon 20, R776H, has been associated with squamous cell lung cancer [12]. Squamous cell lung cancer developed in both a mother and daughter neither of whom smoked and whose cancer demonstrated this missense mutation (somatic). However, this mutation was also detectable in DNA from normal tissue from the lung, lymph node, skin and blood from the daughter (germline mutation). Analysis of a cytology specimen from the mother’s node revealed the R776H mutation was present in her tumor and as well as normal lymphoid cells. The mother’s tumor also had a second mutation at codon 719. Ceneno et al. [13] also identified a germline R776H substitution in the evaluation of tumor and blood samples from 912 patients with lung cancer, blood samples from 477 healthy unrelated blood donors, and 32 patients with other types of cancer. Tumor from 71 patients with adenocarcinoma was tested for an EGFR mutation at exons 18–21. Twelve patients had an EGFR mutation in the tumor and one had the R776G in both the tumor and germline tissues. This mutation was not found in the blood of 954 normal individuals without cancer nor in the blood of any other of 912 lung cancer patients. In vitro analysis demonstrated enhanced tyrosine kinase autophosphorylation in R776G mutant EGFR. Their conclusion was that the R776H germline mutation is rare. The relative risk it poses for lung cancer in affected individuals is not known because of the small number of cases identified. Ohtsuka et al. [14] detected a germline mutation in EGFR resulting in a valine to isoleucine substitution, V843I, in a family with multiple cases of adenocarcinoma
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of the lung. The proband was a 48 year old woman who presented with widely disseminated adenocarcinoma of the lung. Her family history was significant for her mother having had a stage 1A lung adenocarcinoma resected at age 61 and a younger brother with a stage 1A lung cancer when he was 41. These three individuals with adenocarcinoma all had the germline V843I mutation in the cancer as well as an L858R mutation. The proband was treated with both gefitinib and erlotinib with no response. The V843I mutation may block the usual sensitivity of L858R to these tyrosine kinase inhibitors. This same group, Matsushima et al. [15], did further work showing that the V843I mutation was associated with increased tyrosine kinase phosphorylation and resistance to first generation TKI. Demierre et al. described a woman with a smoking history who had stage IV adenocarcinoma of the lung with both a tumor and germline mutation at exon 21 V843l. This patient’s tumor did not have any secondary activating mutation in EGFR [16]. Ikeda et al. [17] described a family with multiple cases of adenocarcinoma of the lung. The proband was a 70 year old woman with multiple lung adenocarcinomas who had the germline V843I but also a second mutation either L858R or L861Q in the tumors. Her father and brother had had lung cancer. Another brother and sister who had the germline EGFR V843I mutation had not yet developed lung cancer. Some of these patients with a germline V843I mutation in the blood also had a second somatic mutation in the cancer itself. However, there are too few cases to assess the relative risk for lung cancer with and without smoking in patients who carry the V843I germline mutation. Prim et al. [18] recently described two patients with germline mutations predisposing to lung adenocarcinoma One individual had a tumor with mutations at L858R and V843l and a germline mutation in V843l. This patient’s tumor did have stable disease on erlotinib. A second patient was described with a germline P848L mutation in exon 21. This report emphasized that germline mutations in EGFR are described in \1 in 1000 patients with EGFR somatic mutations. One family from Japan has been described by Yamamoto et al. [19] with a germline HER2-G660D mutation. This substitution is not in the area of the tyrosine kinase domain but rather in the transmembrane domain. This family had approximately nine members with lung cancer over three generations. The proband had only smoked 1.2 pack years and her mother was a never smoker. Although there were 9 family members with lung cancer, the report by Yamamoto does not indicate that any other family members were tested except the proband and her mother. No additional cases of this germline mutation were found through sequencing of 315 other patients with nonsmall cell lung cancers. The above family history suggests
that carriers of the germline HER-2G660D mutation are at risk for lung cancer, even in the absence of smoking but again there are too few cases known to determine the relative risk for these carriers. With no other cases found in searching 315 other lung cancer patients, this may be an uncommon mutation.
Germline mutations other than EGFR which predispose to lung carcinoma The overall incidence of mutations in genes other than EGFR genes could potentially be of greater significance than those described for the EGFR mutations as they may be more common. The BRCA2 mutation may affect about 0.1–2 % of the population. Wang et al. [2] examined 4 genome-wide association studies of lung cancer in population of European ancestry. There were 11,348 cases with lung cancer and 15,861 controls. They found that a rare variant of BRCA2 (L3326X) was associated with a relative risk of 2.47 for lung cancer. They also reported an association between BRCA2 and CHK2 germline mutations and squamous cell lung cancer and a mutation at 3q28 and adenocarcinoma of the lung. They concluded that about 25 % of smokers with a germline mutation in BRCA2 will develop lung cancer compared with all smokers who have about a 13 % risk of lung cancer Studies have been performed examining the prognostic implications of BRCA1 mutation in the tumor of patients with non-small cell lung cancer. These have been summarized [20] but the conclusion at this time is that germline BRCA1 mutation is not involved in the development of non-small cell lung cancer. In families with inherited melanoma, 5–20 % carry a germline mutation of the CDKN2A gene on chromosome 9p21 (involving the tumor suppressor p16-INK4A and p14ARF). A familial CDKN2A mutation, R112dup associated with melanoma and pancreatic cancer has been associated with an increased risk of lung, head and neck cancer and gastroesophageal cancer in patients who smoke [3]. The relative risk for CDKN2A R112dup mutation carriers was estimated to be 15.6 for respiratory tract cancer compared to individuals who were not carriers of the mutation. They were able to obtain smoking histories in about 60 % of the CDKN2A mutation carriers. Those with the mutation who smoked had an odds ratio of 9.3 for lung cancer or upper digestive cancer compared with never smokers and the same mutation. The hypothesis is that this mutation increases the carcinogenic effect of smoking. Potrony et al. [21] reported on Spanish patients with CDKN2A mutations. Among families with two members with melanoma, the CDKN2A mutation was found in 10.9 % of cases, and for 3,4, or 5 family members involved the CDKN2A mutation was found in 23,36 and 66 % of
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cases respectively. In families in which at least one member had a CDKN2A, the relative risk for lung cancer in other family members was found to be 3.04. This study did not demonstrate that the other family members with lung cancer actually had the germline CDKN2A mutation and did it provide any smoking history. Therefore it is difficult to interpret this reported increase in risk for lung cancer. Abdel-Rahman et al. [4] described a family with a germline mutation in BAP1 which is associated with uveal melanoma. They found one patient with a germline BAP1 mutation by screening 53 patients who had uveal melanoma. The proband had both uveal melanoma and lung adenocarcinoma. Other relatives of the proband with the BAP1 germline mutation or obligate carriers suffered from cutaneous melanoma, meningioma, uveal melanoma, a neuroendocrine cancer, and abdominal adenocarcinoma possibly of ovarian primary, and mesothelioma. With just this one family, it is difficult to discern the relative risk of lung cancer. Muir-Torre syndrome is a variant of Lynch syndrome or hereditary non polyposis colon cancer with sebaceous cancer of the skin. Other neoplasms associated with HNPCC (hereditary non polyposis colon cancer which is also called Lynch Syndrome) are endometrial, bladder, and upper gastrointestinal cancer. Nolan et al. [22] reported a patient with Muir-Torre syndrome who had a deficiency in hMSH-2 by immunohistochemistry (this mutation can be detected in tumor tissue and confirmed by blood tests as a germline mutation). The patient had had two colon cancers and later developed bilateral adenocarcinoma of the lung. These were lung primaries as evidenced by the fact that they were CK7 positive, TTF positive and CK20 negative. One of the lung tumors was deficient in hMSH2 but the contralateral tumor was not. The patient had a 20 pack year history of smoking. Canney et al. [23] described a very similar case of a patient with a germline mutation of MSH2 who had colon cancer and later lung cancers with both adenocarcinoma and bronchoalveolar features. With only these two cases, it will require further studies to determine if HNPCC is associated with an increased risk of lung adenocarcinoma. In a systematic review of cancer risk in patients with Peutz-Jeghers syndrome (PJS), there was a marked increase in risk of colorectal, breast, small bowel and pancreatic cancers. There was also a likely increased risk of lung cancer but in the absence of data on smoking history, it may be difficult to assess the magnitude of the risk [24]. However, there is a specific mutation in LKB1 associated with Peutz–Jeghers (PJS) syndrome described in the lung adenocarcinomas of such patients. The LKB1 mutation is also associated with adenocarcinoma of the lung in the absence of PJS [25]. This would be a plausible explanation for the possibly increased risk of lung cancer in those with PJS.
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Using a Dutch tumor registry, Marees et al. [26] were able to follow up on 668 patients with retinoblastoma (bilateral or hereditary and unilateral or non-hereditary). Bilateral eye involvement is associated with a germline mutation in the retinoblastoma gene. From the time of diagnosis, the risk of secondary cancers with hereditary retinoblastoma was 36 % after 50 years of follow up. Most secondary tumors are soft tissue sarcoma, osteosarcoma or melanoma. Those individuals with hereditary retinoblastoma had a relative risk of 16.8 for other cancers compared with the general population. Wang et al. [27] described two families with interstitial fibrosis (IF) and adenocarcinoma of the lung. In one family, the proband was a 51 year old man who had 10 relatives with IF and 5 had died before age 50. Four of these cases also had adenocarcinoma of the lung (what was then termed bronchoalveolar carcinoma) and 3 other relatives had adenocarcinoma or bronchoalveolar lung cancer without fibrosis. This family had a rare missense mutation in SFTPA2 within the interval coding for the surfactant protein A2. A different mutation in SFTPA2 was found in another family with IPF and lung cancer. These families were identified from 59 kindreds with pulmonary fibrosis and no detected mutations in TERT or TERC which is associated with about 15 % of IPF families. Extensive literature exists that single nucleotide polymorphisms (SNP’s) are associated with lung cancer via genome wide association studies [28]. Three separate susceptibility loci in particular at 5p15, 6p21 and 15q25 have been described. A further analysis of just the genetic variants on chromosome 5p15 have significant effect on lung cancer risk and these are rs2736100 (OR 1.20), rs401681 (OR 0.88), rs40270 (OR 1.15) and rs31489 (OR1.10) [29]. The risk varied among different ethnicities. Two important candidate genes in that area are cleft lip and palate transmembrane 1-like gene (CLPTM1L) and human telomerase reverse transcriptase gene (TERT). Hung et al. [30] described SNP’s on 15q25 which they indicated were associated with 14 % of lung cancer cases. This locus is the site of nicotinic acetylcholine receptor subunit genes CHRNA5, CHRNA3 and CHRNB4. This area may also be associated with increased propensity for smoking. The fact that SNP’s in this area were associated with lung cancer but not head and neck cancer suggested that the risk of lung cancer was not attributable to only increased smoking exposure. Most notable of these SNPs in this area with their odds ratios are rs1051730 (OR 1.32), rs803419 (OR 1.32) and rs16969968 (OR 1.3). The initial studies of SNP’s on 15q25.1 were carried out in Asian and Caucasian populations only, however studies that included African-Americans also suggested that multiple SNP’s in this region were associated with risk of lung cancer [31, 32]. In white individuals, some SNPs were associated with more
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smoking and other SNP were not associated with more smoking., The haplotypes associated with lung cancer were assessed for smoking behavior such as pack years smoked, cigarettes per day, and maximum cigarettes per day as measured by a test called the Fagerstrom Test for Nicotine Dependence. African-Americans carried some of the same haplotypes observed in Caucasian patients. With the rs1051730 haplotype the odds ratio for lung cancer was 1.59 and with the rs931794 haplotypes the odds ratio for lung cancer was 1.39 in ever smoking African-Americans. Renieri et al. studied non-smoking individuals with adenocarcinoma of the lung prior to age 60 who had a sibling who did not have lung cancer at the time of their analysis. They did whole exome sequencing in germline DNA on 4 of the pairs and found 8 cancer related genes involved in one patient with lung cancer and 5 in another patient, but not in their matched siblings without lung cancer [33]. In one of the sib pairs (both case and control), they found the 15q25 risk alleles of rs1051730 and rs16969968. In the other sib pair they found the risk allele rs 402710 in the 5p15.33 region. In a study from China [34], coke oven workers were found to have 25 lung cancer risk related SNPs which correlated with polycyclic hydrocarbon induced genetic damage. In a study of variants of the nicotinic receptor genes and the association with both smoking dependence and adenocarcinoma of the lung, two CHRNA3 SNPs were most associated with nicotine dependence and adenocarcinoma of the lung [35]. They demonstrated that variations in these genes significantly affect the risk for adenocarcinoma of the lung. Nicotine dependence accounts for 15 % of the relationship between these genetic variants and lung adenocarcinoma Schwartz and Ruckdeschel [36] in 2006 and again in 2012 [37] examined the data for genetic factors related to familial lung cancer. Their studies focused on a possible genetic susceptibility to COPD and lung cancer. Data was cited for a susceptibility locus at 6q23–25 [38] reported from a study of 52 families with multiple cases of lung cancer in the family. However, in that trial, the association was only significant after dropping the number of families included from 52 to 23. Twenty nine studies were cited in which different loci possibly associated with COPD and lung cancer were cited [36]. Lung diseases associated with inflammation such as emphysema, chronic bronchitis, prior pneumonia, prior tuberculosis are associated with an increased risk of lung cancer with relative risk 2.44, 1.47, 1.57 and 1.48 respectively. Never smokers were also found to be at elevated risk of lung cancer though lower than smokers if they had any of these diseases, indicating that these diseases are an independent risk factor for lung cancer. How much is related to genetic susceptibility and how much is related to inflammation is not clear. In these studies, former smokers and smokers had
a very similar relative risk but never smokers had a lower relative risk [39]. As there is the potential for multiple interactions of combinations of SNPs, it may be difficult to assess the extent of increased risk in any patient with one or more of these SNPs.
Discussion The identification of somatic mutations in adenocarcinomas of the lung such as EGFR mutation, ALK mutations, and ROS 1 mutations has led to the discovery of specific agents to treat pateints with these mutations. These new agents which are tyrosine kinase inhibitors (erlotinib, gefinitinb, afitinib, crizotinib, ceritinib) have improved therapy and prognosis compared with standard chemotherapy regimens for lung cancer. After treatment with these targeted agents, secondary somatic mutations develop which lead to resistance to these agents and progression of the cancer. With the secondary resistance mutation T790M, lung cancers previously sensitive to first line agents such as erlotinibor become resistant. However, a very small number of cases have been reported in which patients had the T790M mutation in the cancer at diagnosis, before ever being exposed to one of the targeted agents. In some these patients, with T790M at diagnosis, they have had a germline mutation with T790M as well. This T790M germline mutation is associated with familial lung cancer. The clinical implication for a patient with a germline T790M mutation and a T790M mutation at diagnosis in the lung cancer is that while standard tyrosine kinase inhibitors are not apt to be effective, new tyrosine kinase inhibitors are under development which overcomes the T790M mutation such as AZD9291 [40]. The implication for family members who have this T790M germline mutation but who do not yet have lung cancer is still being worked out. It is possible that these affected family members might benefit from never smoking, from being screened for lung cancer even if they never smoke, and that agents that could prevent their developing lung cancer could be found. This review is intended to outline the new but growing knowledge of new mutations which may lead to lung cancer without smoking or increase the risk of lung cancer with smoking. Families who carry germline mutations such as the EGFR T790M1 or other SNP’s such as those at 15q25 appear to have increased risk of lung cancer development. The number of associations with various SNP suggests that unlike germline mutations (BRCA2, T790M mutations) they are not likely ready to be used to select patients for lung cancer screening. In the past, attempts were made to predict which smoking individuals might be predisposed to developing lung cancer. The conjecture had been made that increased
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aryl hydrocarbon hydroxylase (AHH) led to greater activation of polycyclic hydrocarbons to active carcinogens. Cigarette smoke contains some carcinogens which can bind to DNA directly and other carcinogens which require metabolism to bind to and damage DNA. This literature is vast but with prior methodology, the relationship between AHH and lung cancer remained controversial [41]. At one time the debrisoquin metabolic phenotype was considered as a potential means to predict which individuals might be more apt to develop lung cancer with smoking. This also remained controversial [42]. With the recent genetic investigations, more specific biomarkers are being identified that may help to improve the risk calculation for familial lung cancer. New screening guidelines will need to be developed for families based on the age of onset of the cancer in the affected family and the specific mutation identified. It is possible that for families with germline mutations which increase the risk for lung cancer, earlier screening with low dose CAT scans might be useful However, there is not yet evidence that demonstrates that testing for lung cancer susceptibility will lead to improved survival for affected individuals who are screened. Further, germline mutations may suggest improved therapy for affected individuals. For example, patients with a BRCA2 mutation may have improved response to therapy which includes a PARP inhibitor and for those with a T790M mutation, therapy with AZD9291 may help. While much clinical investigation remains to be carried out, the identification of germline mutations predisposing to lung cancer has to the potential for translational research to benefit patients and their families who carry such a mutation. Conflict of interest
None.
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