Inherited lung cancer: a review

Viviane Teixeira Loiola de Alencar, Maria Nirvana Formiga and Vladmir Cláudio Cordeiro de Lima

AC Camargo Cancer Center, R Prof Antônio Prudente, 211 São Paulo, SP 01509-010, Brazil

Abstract

Lung cancer is the most common cancer worldwide and has high rates of mortality. The major risk factor associated with this disease is tobacco smoke, but approximately 10%– 25% of all lung cancer cases occur in patients who have never smoked. Data suggest that lung cancer in never-smokers has a different molecular profile, tumour microenvironment and epidemiology than that in smokers. Several risk factors have been associated with its occurrence, and the possibility of inherited predisposition is becoming clearer. A bet- ter understanding of this disease is essential for the future development of personalised screening, diagnosis and treatment approaches, with consequent reduction of mortality. In this review, we discuss historical studies of lung cancer in never-smokers and the cur- rently available evidence of inherited predisposition to this disease.

Keywords: hereditary cancer, lung cancer, germline Review

Introduction

Lung cancer is the most commonly diagnosed cancer (accounting for 11.6% of all cases) and the leading cause of cancer death (accounting for 18.4% of all such deaths) in both sexes worldwide; it is responsible for more than 1.8 million deaths each year [1]. The high mortality rate associated with this disease is attributable in part to its diagnosis Correspondence to: Viviane Alencar at advanced stages, with regional or distant spread, in approximately 80% of cases; at Email: [email protected] such stages, treatment is less effective and survival rates are considerably lower (5-year survival, 57.4% in early stage versus 5.2% with distant metastasis at diagnosis) [2]. ecancer 2020, 14:1008 https://doi.org/10.3332/ecancer.2020.1008 Incidence rates of lung cancer vary among regions as a reflection of different historic Published: 29/01/2020 patterns of tobacco exposure, which includes exposure intensity and duration, cigarette Received: 15/10/2019 type and degree of inhalation and the evolution of these patterns over time, commonly Publication costs for this article were supported by called the ‘tobacco epidemic’. Recent statistics [1] show that incidence rates among men ecancer (UK Charity number 1176307). are the highest in Micronesia/Polynesia, Eastern Asia and much of Europe, especially Copyright: © the authors; licensee Eastern Europe. In Africa, the rates remain generally low, although they are intermediate ecancermedicalscience. This is an Open Access to high in several countries in the northern and southern regions of the continent, notably article distributed under the terms of the in Morocco (31.9/100,000) and South Africa (28.2/100,000). Among women, incidence Creative Commons Attribution License (http:// rates are highest in North America, Northern and Western Europe and Australia/New creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and Zealand. Interestingly, the rate among Chinese women is similar to those among women reproduction in any medium, provided the original in several Western European countries, such as France, despite substantial differences work is properly cited.

ecancer 2020, 14:1008; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2020.1008 1 kinase inhibitors. For example, better prognoses,to due more the frequentoccurrence of actionable thatenable specifictreatments with receptor tyrosine Lung cancer innever-smokerscommonly isdiagnosedmost in women. Patients tend to be younger, respond better to treatment andhave alteration profiles andtumoral microenvironment compositions. that lung cancers insmokers andnever-smokers are twoentities, distinct which differ not only epidemiologically alsointheir but molecular 20%. Passive smoking, however, isassociated onlywith approximately 16%–24%of lungcancer casesinnon-smokers [12].Today,knowwe risk factorof insome has beendemonstratedas it cases, these to increase theriskof lungcancer development innon-smokers by at least worldwide,before cancers of thecervix, andprostate [11].Environmental tobacco smoke exposure (passive smoking)isaknown cancerlung innever-smokers (those consuming<100 cigarettes/lifetime) would rank astheseventh mostcommon causeof cancer death notattributable to smoking According to globalstatistics,however, onlyof10%–15% about allsmokers develop lungcancer [8],and10%–25%of alllungcancers are and squamouscell carcinoma, whereas adenocarcinoma common isthemost of type lungcancer inpatients who have never smoked [3]. related inadose–response manner the cumulativewith amountand duration of tobacco smoked [7].Smoking islinked moststrongly to SCLC populations,increases relative the of risk(RR) cancer lung 10–20-fold insmokers compared with never-smokers [1,6], with itsincidence cor and x-rays), asbestos andalcohol consumption [4,5]. Tobacco responsible smoking, for more than80%of alllungcancer casesin Western diseases (i.e.,tuberculosis,chronic bronchitis), occupational exposure to carcinogenic chemicals,ionisingradiation (i.e.,radon decay products [3]. Several environmental riskfactors are associated with itsdevelopment, passive includingsmoking, smoking,air pulmonarypollution, cell lungcancer (SCLC). NSCLC canbecategorised into three subtypes: squamouscell carcinoma, adenocarcinoma andlarge-cell carcinoma The two major histological forms of lungcancer arecell non-small lungcancer (NSCLC), which accounts for 85%of about cases,andsmall heating andcooking purposes in smokingprevalence betweenpopulations. these This rate may beexplained by continued exposure to smoke from charcoal burnedfor likely to contribute to diseasedevelopment [19]. tive genomic hybridisation arrays. They found that theproto- understandtumour growth,Park andcolleagues Squamouscell carcinoma, is usuallywhich more prevalent amongsmokers, alsomay have agenetic trigger innon-smokers. In 2017,to better cancer hasbeenlinked to ahereditary factor andshouldalsobeincludedinmore specificpatient follow-upprotocols [18]. least 30pack-year smoking histories hasbeenrecommended raphy (CT) for thescreening of individuals at highriskof the disease, screening of current and former smokers aged 55–74 years with at Lung Screening Trial Research [16], showedwhich a20%reduction inmortality from lungcancer with theuseof low-dose computed tomog- The essential role of theearly detectionof lungcancer inthesurvival rate is well established[2].Since thepublication in2011of The National to increase. Thus, abetter understanding of thedisease’s causalfactors, which includehereditary predisposition, isneeded. Withcurrent the application ofto policies control tobacco use worldwide, theproportion of lungcancer casesinnever-smokers isexpected types, correlated with worse prognoses, in samplesfrom smokers [15]. and CD4+ memory T cells, both associated with better prognoses, in tissue samples from never-smokers, and more activated cells of these were associated poorwith prognoses and were foundin greater numbers intumour samples. The authors observed more resting mastcells relative to thosefrom adjacentOn normaltissue. theother hand,activated mastcells (macrophages) andactivated CD4+memory T cells or restingstatus. Resting cellsmast were associated betterwith prognoses, andtheir number was found to bedecreased intumour samples genesis differ insmokers andnever-smokers due to differences in outcomes related to mast cells and CD4+memory T cells, and their active datasets fromsamples with adenocarcinomas1,111 lung and 200adjacent normaltissues. They found that thepathways involved incarcino- thelial cells andalterssystem thelocalimmune [13].In 2018,Liandcolleagues [15]performed astudy basedon11lungcancer microarray Tumoral microenvironmentsalso appear toin smokers bedistinct andnever-smokers, astobacco smokingcausesDNA damage inlungepi- methylations of TNFSF10C , BHLHB5andBOLL in never-smokers, as genome-wide association studies(GWASs) have demonstrated that EGFR, VTL1ATNFRSF10CC3ORF21 and hyper- orcinoma cell squamous carcinoma [13].Metabolicsyndrome alsohasbeenlinked to thedevelopment of lungadenocarcinoma, especially ecancer 2020, 14:1008; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1008 [9, 10]. The latter percentage iseven higher,to up 30%–40%,in Asian countries [10].If considered separately, [1]. ALK rearrangements are more common innon-smokers adenocarcinomawith thaninsmokers with adenocar are involved inboth pathways [13,14]. [19] analysed thegenetic profile of squamouscell carcinoma innon-smokers usingcompara- [17]. The development of multipleprimary malignanciesassociated lung with GAB2 (11q14.1) was frequently amplified in these patients and was 2 - -

Review ecancer 2020, 14:1008; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1008 estimationthe of risksbasedonpopulationrates ofcancer, lung theresearchers usedrates of individuals nofamilywith history of this to estimate individuals’ RRs of lungcancer basedontheir family histories of thedisease.In contrast to theIceland study, which involved More recently, Cannon-Albright etal for relatives of patients with early-onset disease[27]. it although was significantly higher thanexpected inthelatter groups. For allgroups of relatives analysed, theriskof lungcancer was greater 95% CI1.77–2.23)andchildren (λ=1.96,95%CI1.53–2.39),andlesser amongsecond-degree (λ carcinomalung between 1955and2002[27]. The familialrisk was greater amongparents (λ=2.69,95%CI2.20–3.23),siblings λ =2.02, Another study was performed usingdata from theIcelandic Cancer Registry onall2,756patients intheIcelandic population diagnosed with with different exposures [26]. tors,environmental the but influence wasSwedishin the minimised cohort, which includedindividualsfrom differentgenerations andthus colon (λ=1.9)cancers. This of type study doesnotenable determination of whether theclustering isdueto genetic or environmental fac byCI 1.6–2.4),similar(95% 1.9times to thatof other commoncancers with well-known genetic components, includingbreast (λ=1.5)and probands with genetic susceptibility. The authors also reported a greater for RR female relatives of female probands than for malerelatives of male cancers,as cancers such ofand cervix,lip larynx, lung, the which was attributable to shared environmental factors potentially associated significantly high [λ = 2.55, 95% confidence interval (CI) 2.08–3.08]. The study identified significant familial clustering among tobacco-related cancer registry, 1,283,047 cancerincluded which between cases 1958and1997[26].In theUtah study, thefamilial riskof lungcancer was from theUtah cancer registry study, approximatelyincluded which 125,000 individualsbetween 1952and1992[25],theSwedish Twoof studies familialclustering thathave provided importantinformation specificcancers about were based ontheUtah family database, without theinfluence of smoking,althoughtheriskof lung cancer development was higher amongsmokers. among smokingrelativesthan of controls. The Baltimore study [18]alsoshowed that familial aggregation for lungcancer existed with or Tokuhata andLilienfeld cancerlung [5,22]. The firsttostudies suggesta genetic component for lungcancer were theBaltimore andBuffalo studiesperformed by The literature contains several importantof studies familial aggregation that hasraised theinferred possibility of genetic susceptibility to relatives to theexpected frequency, calledlambda( of common cancers. To assessthegenetic effect,many researchers calculate theratio of theobserved incidence of cancer amongfirst-degree (SNPs).polymorphisms GWASs, for example, are effective for thedetection of common allelesthat contribute to the inherited components explained by shared environmental factors, inherited mutation of moderate- andhigh-penetrance genes and/or inherited singlenucleotide of affected controland inasuitable subjects group,typically therelatives of healthy subjects[21,22].Familial clustering of cancer may be enhanced by theexistence of relatives illness. Itsame the with may beinferred by comparing theincidence of agiven diseaseamongrelatives are usually first steps intheidentification of hereditary diseases. The inherent ideaisto determine whether anindividual’s riskof adiseaseis to infectiousagents. It isanecessary,not although sufficient, condition for theinference of genetic susceptibility, assessingit andstudies Familial aggregation istheclustering of adisease families,within which may beattributable to genetics, environmental causesor exposure of which are associated with known hereditary cancer syndromes [20]. penetrance andenvironmental factors [4]. We estimate today that 5%–10% of allcancers are causedby inherited germline mutations, many be attributableto inheritablegene mutations. Theexpression clinical of thedisorder isinfluenced by hereditary predisposition, variable gene Familial clustering of cancer ischaracterised by theoccurrence of thesametypeof cancer intwo or more first-degree relatives, which may Familial aggregation inlungcancer possibly with new therapeutic targets. iopathology ofcancers these may leadto thedevelopmentof additionalpreventive strategies andmore accurate approaches to treatment, developmentand application of broader screeningcould guidelines impactthesurvival of theseindividuals.Better elucidation of the phys- Witha better understandingof non-smokerswhich are atgreater riskfor lungcancer (e.g., those with inherited susceptibility ), the [11, 19]. The Swedish study showed that therisk of lungcancer infirst-degree relatives of 88,589lungcancer cases was increased [23, 24]. They found a 2.5-fold greater risk of mortality among smoking first-degree relatives of lung cancer probands [28] publishedtheresultsof another analysis basedon the Utah population database, performed λ). = 1.4)andthird-degree (λ = 1.2)relatives, 3 -

Review to identify acandidate gene. These studies were importantto raisepossibility the of ageneticpredisposition to lungcancer andto point to theneedfor further analysis at theage of 70 years, possibly asa reflectionof an increasing proportion of tobacco exposure-related lungcancer in non-carriers [17,30]. cancerlung predispositioncouldlocus be responsible for of 69% lungcancer casesat theage of 50 years, at 47% theage of 60 years and22% is consistent Mendelianwith co-dominant inheritance of arare autosomal gene. Sellers et al ability of inheritance of amajor gene forcancer lung predisposition, andboth showed thatthe pattern of lungcancer occurrence infamilies predispositiongene, adifferent of type study,as asegregation such analysis, isneeded[12].Twostudies To better validate whether thefamilial pattern of a disease is consistent a geneticwith modelof inheritance due to the existence of a major on tumour microenvironments andprognosis mentioned above [15]. distantwith metastasis,consistent poorwith prognoses. These findingsare controversial when considered together with thoseof thestudy of cancer among women, frequentmost the with histology of adenocarcinoma; andthetendency to have other cancer histories and present lung cancer onthe Yunnan-GuizhouPlateau inChina.Unique characteristics of thesesubjects were earlier diseaseonset; greater frequency In 2018,Ding andcolleagues [29]performed anobservational study of theclinicopathological characteristics of 152patients with thefamilial diagnosis at anearlier age (50–60 years). A limitation of thisstudy isthat data ontobacco use were not available. or more such relatives) to 1.55 (for four or more such relatives). The authors also found a greater riskassociated a first-degreewith relative’s more relatives).such For third-degree relatives, in the absence of affected first- and second-degree relatives, RRs ranged from 1.18 (for one For second-degree relatives,absence inthe of first-degree relatives, RRs ranged from 1.41(for oneor more relatives) such to 4.76(for four or degree relatives. For first-degree relatives, they ranged from2.57 (for oneor more relatives) such to 4.24(for three or more relatives). such than twice aslikely to bediagnosed lung cancerwith as were those with nofamily history. RRs were significant for first-, second- andthird- malignancy. They identified a total of 5,048 lung cancer cases and estimated that individuals with any family history of lung cancer were more ecancer 2020, 14:1008; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1008 (50%), followed by TP53,BRCA2, EGFR genes a frequencywith of 2.5%. These mutationsoccurred more frequently ingenes associated with theDNA repair pathway, asATM such gene (TERT), thetumour protein p53gene (TP53)andthe YES-associated protein 1gene (YAP1). They found 14pathogenic mutations infive the checkpoint kinase 2 gene (CHEK2), EGFR Atlas to evaluate possiblerisks associated the with ATMserine/threonine kinasegene (ATM A candidate gene studyin 2017employed published germline sequence data from 555lungadenocarcinoma casesfrom The Cancer Genome [32], which may point to agreater contribution of genetic predisposition inpatients with NSCLC thaninthose with SCLC. were moderate (CHRNA5rs16969968, rs4646903 CYP1A1 andNQO1(rs1800566) and weak (GSTM1 present/nullrs2228001)and XPC strated strong cumulative epidemiologicalevidence. Five variants intheSCLC groupshowed significantassociations, theseassociations but rs402710, CYP2E1rs6413432, ERCC1 rs11615, FGFR4rs351855, HYKKrs931794, MIR146A rs2910164 and TERT rs2736098) demon- ofcal type cancer revealed significant associations for 25 variants intheNSCLC group,eight of which (CHRNA5 rs16969968, CLPTM1L rs10937405, WWOX CNV-67048 andXRCC1 rs3213255) were moderately associated with thisrisk. An analysis basedonthehistologi- rs189037, CD3EAP rs967591,rs1801272, CYP2A6 HIF1A rs11549467, PDCD5rs1862214, PROM1 rs2240688, TP53 rs12951053, TP63 rs931794,HYKK rs662 PON1 andREV3L rs462779) were strongly associated with theriskof lungcancer development, andten (ATM gested thateight genetic variantsrs1760944,(APEX1 rs2240308,AXIN2 rs6495309, CHRNA3 CXCR2 rs1126579, CYP2E1rs6413432, common variants cancerlung with [32].Credibility assessmentof theaccumulated epidemiological evidence from 246eligible variants sug- A meta-analysis of 1,018 publications describing2,910 variants in 754 genes and loci was conducted to interpret genetic associations of 1,000 candidate gene studieshave beenpublishedinthepast25 years, are studies assuch cost effective andrelatively easy to perform. In recent decades,manyhave studies beenperformedto gather evidence of agenetic predisposition to lungcancer. Findings from more than Candidate genes associated with lungcancer Inheritable predisposition genes associated withlungcancer andPARK2 [33]. , the parkin RBR E3 ubiquitin proteinE3 ubiquitin , the parkinRBR ligase gene (PARK2), the telomerase reverse transcriptase ), theBRCA2 DNA repair-associated gene (BRCA2), [30] estimated that segregation at thispresumed [30, 31]have investigated theprob- 4

Review 9p21 [44]. histology-specificeffects for first the two variants ing approximatelycancer 14,900lung and 29,485controls cases of European descentidentified risklociat 5p15,6p21and15q25 with Other variants associated lung cancerwith susceptibility inGWASs are 6p21and5p15[42,43] . A meta-analysis of 16GWASs includ- tion processing andsignallingmoleculesinteractions congenital diseasesandnicotine dependence, consists mainly of agroupof neuroreceptor genes andisinvolved inenvironmental informa- activationof theneuroactive ligandreceptor interactionpathway. This pathway, which isalso associated with neuropsychiatric disorders, A study in2018showed published that chromosome15q25 modifieslungcancer riskand isinvolved inthepathogenesis of thisdisease via rs13314271; OR=1.13, ecancer 2020, 14:1008; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1008 susceptibility. thatsignificant gene linkage for familialcancerlung exists,suggesting that somerare genetic variants play important roles inlungcancer theydisease; same identifieda major susceptibilityrelated locus to lungcancer riskinthe6q23–25chromosomic region. This study proved performed usinganautosomal-dominant model,of 52families of probands with lungcancer who hadseveral first-degree relatives with the genes may beresponsible for asimilar or identicalphenotype oftype studyto helps identify whether adiseasephenotypeis causedby themutation inonegene alone,or whether mutations inother These analyses are based on the rationale that somegenetic traits are attributable to genes that are linked, and thus inherited together. This risk of lung cancer small number of commonrisk allelesconfer smallto moderate risksof disease), they have explained only asmallportionof thehereditary As GWASs tend to identify common riskallelesof low penetrance, basedonthecommon disease–common variant hypothesis (i.e.,that a Linkage analysis studies carcinomadevelopment rarewith variantsof BRCA2-K3326X[rs11571833; odds ratio(OR) = 2.47,p4.74×10 In 2014,aGWAS of data from more than20,000casesand40,000controls revealed astrong association of theriskof squamouscell effect was similar amongnever-smokers andever-smokers and was independent of sex [39]. risk of lungcancer associated fourwith other SNPs in15q25(rs2036534C > T, rs667282C > T, rs12910984G > A andrs6495309T >C). This of populations Caucasian mentioned above [34–36] were foundto berare inthe Asian population, thestudy but demonstrated anincreased two-stage case–control studies (3,500 lung cancer cases and 3,300 controls) were [39]. published The three allelesidentified in the studies viduals who inherittwo alleles[5], is probablywhich not duesolely to theinfluence of tobacco. In 2009,findingsof ananalysis of Chinese The associationbetween cancer 15q25andlung to seems bestrong with an80%increase intheriskof lungcancer developmentfor indi- linked to genetic susceptibility to lungcancer inaEuropean cohort of never-smokers. et al some 15that was associated smoking quantity,with indirectly andthus to elevated cancer risk[34–36].In aGWAS reported in2019,Hung geneticregions directly to lungcancerdeCODE risk,andthe study identified asequence variantin thecluster of nAChR genes onchromo - thatincludes [34–36]. The IARC study was later expanded,leading to discovery the of anadditionalsusceptibility locusonchromosomein aregion 5p, that acluster includes of nicotinic acetylcholinereceptor genes CHRNA5andCHRNB4)isassociated (CHRNA3, strongly with lungcancer MD Anderson Cancer Center, anddeCODEGenetics], in 2008,identified published thesame locus inchromosome region 15q25,anarea alleles, arewhich usually of low penetrance [12]. Three GWASs for lungcancer [from theInternational Agency for Research onCancer (IARC), throughgenotypingthe of to up 1,000,000genetic variantsor SNPs [5]. They are highly powered to enabletheidentification of common risk More recently, GWASs have beendeveloped asalternatives to candidate gene studies,asthey provide broader coverage of genetic variation GWASs (rs17879961; OR= 0.38, [38] detected three SNPs (rs31490, rs380286 andrs4975616), to alsomapped CLPTM1-like the5p15.33 TERT region, which were TERTcleft andthe and palatelip transmembrane 1-like gene) ( CLPTMIL [45]. With theaimof identifyinghigh-penetrance genes with stronger effects, linkage analyses have also been performed. p =7.22×10 p = 1.27 × 10 -10 -13 ) previously associated with cancer only among Asians. ) [40]. For adenocarcinoma histology, the authors described a common variation at 3q28 (TP63; [44]. The researchers alsoidentified alocusfor squamouscell carcinoma susceptibility at [41]. [46]. In 2004,Bailey-Wilson et al [37]. The IARC andMD Anderson studieslinked these published agenome-wide[47] published linkage study, -20 ] and CHEK2-I157 ] andCHEK2-I157 5

Review and G719R,1L861Q, 2H773Rand1 V774M. Patients who were treated with osimertinibpresented nounexpected toxicity [57]. static disease. Tumour genotyping revealed somatic EGFR co-mutations in94% of probands: 6exon 19 del,12L858R,6G719X,1exon 19del advanced stage andimaging analysis (IV); suggested anindolent multifocal nodular phase,progressing to lymph-nodeandthenremote meta- cancer diagnosisof 57(range 28–82) years; 81% were white and19% were black;52% were never-smokers; 65%of cases were diagnosedat of 27)and44%(4of 9)of first- andsecond-degree relatives of germline carriers, respectively. The affected individualshadamedianage at lung pants, germline EGFR mutations were found in63%of patients with EGFR T790M detected inlung cancer tissueat diagnosis,andin62%(16 Recently, theDana-Farber Institute performed theINHERIT EGFR Study, which investigated families with this variant. Among the105partici- ation germline T790M the opacities andpulmonary nodules with anindolent diseasecourse [51]. The screening of unselected populations hasno proven benefit, but,as are associated more frequently with female sex and non-smoking status. The mostfrequent presentation in CT scans is bilateral ground-glass germline T790M prevalence of germline mutations inlungcancer casesin Japan was lower thanthat inNorth America [51],and,to our knowledge, nocaseof the mostcommon histology isadenocarcinoma. Although somatic mutations inEGFR are more common amongpatients from East Asia, the germline T790M The most commonly theL858Rmutation [49]. three percentof patients lung cancerwith germline andthe mutationT790M have beenfound to carry asecond activating mutation [51], activating EGFRmutation, however, theoncogenic potential issignificantly enhanced, possibly contributing to earlier diseaseonset. Seventy- to induce tumour formation inmousemodels[56], this mutation is characterised as weakly oncogenic. When associated a commonwith risk ofcancer lung developmentcarriersin non-smoking [52]. Although thepresence of the EGFR T790M mutation seemsto besufficient ecancer 2020, 14:1008; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1008 in never-smokers confer agreater riskof cancer development. Amongthese, seemstoT790M beassociated with aspecificlungcancer syndrome targeting Case reportshave germline described mutations kinase domainofin the theEGFR asR776G,R776H, , such T790M, V843I andP848L, which EGFR T790M Genes associated with inherited lungcancer syndromes these two techniques. In thefollowingparagraphs, we exploregenesmain the thatare possibly related to hereditary lungcancer, discovered basedon instudies reduced cost, timeandlabour thanrequired for Sanger sequencing. multi-gene panelsisnow performedhas beenadopted [45].NGS widely and canbeusedto sequence more target genes with lessDNA and for of thesequencing individualgenes,due to but, itshighcost, ‘second-generation sequencing’ or next-generation sequencing(NGS) with also knownsequencing, as‘first-generation sequencing’, was thefirst technique to used sequence genome. thehuman It isstillused widely To explorehypothesis, this direct betteris the sequencing option, asitenablestheidentification of allrare allelesinapopulation. Sanger loci containrare multiple independent risk alleles across populations, each with moderate to high penetrance (high allelic heterogeneity). Based onthesefindings,another hypothesis becomes thecommon appealing: disease–rare variant hypothesis, according to which risk Sanger sequencingand whole-genome sequencing the age of 30 years with lifetime risksof upto in 70%inmenand100% women [58]. occurrence of cancersorgans, inmultiple usually with early onset. Statistics show that approximately 50%of carriers will develop cancer by Li-FraumeniSyndrome (LFS) is arare hereditary conditionassociated with a germline mutation of TP53that predisposes thepatient to the TP53 (Li-Fraumeni syndrome) EGFR [52], someauthors have suggested that thesepatients shouldbereferred for routine germline genotyping to identify carriers [42,44].

[49–56]. This mutationis rare, but [48]. In variousSanger studies, sequencinghascorrelated familial clustering of lungcancer with agermline T790M mutation EGFR EGFR mutation ispresent inapproximately 50%of patients with baseline T790M EGFR identified inpre-treatment evalu- EGFR mutation ispresent inapproximately 1%of NSCLC cases [52] with amedianage at diagnosisof 40 years, and mutation inEast Asia hasbeenreported intheliterature. Sporadic EGFR mutation andgermline T790M EGFR mutation EGFR isconsidered to beamajor cancer predisposition gene, associated anestimatedwith 31% 6

Review ecancer 2020, 14:1008; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1008 was amother of four affected daughters andoneunaffected son.In thisfamily, individualsin whom YAP1 mutation was detected (smokers an external cohortof 1,135participants cancerwithout and1,312patients with lungadenocarcinoma [66]. The proband of theoriginalfamily in thetransactivationR331W) domain was identifiedby of NGS samplesfrom afamily lungadenocarcinomawith clustering and validated in YES-associated protein 1isatranscriptionalcoactivator thatinfluences tissuegrowth andorgan size. In 2015,agermline mutation (YAP YAP1 further studiesare needed[66]. mutation, V659E, inone patient. These data,however, are notdefinitive for theattribution of carcinogenic potential to thesemutations, and exon 17ofofin samples HER2 315sporadic NSCLCs, 253of which were adenocarcinomas, andidentified anovel non-synonymous somatic lung adenocarcinomas. With thehypothesis that mutations inthetransmembrane domainof actasdrivers, HER2 the researchers sequenced years who was treated lobectomy,with subsequently but recurred. At thetimeof thestudy, she was 53 years oldandhadmultiplebilateral high rate ofcancer. lung The proband was a woman who was alight smoker with ahistory of multiplelung adenocarcinomas at theage of 44 susceptibility to lungcancer [65]. The germline variant G660D was identified through whole-exome sequencingina Japanese family with a A Japanese studyin 2013 published wasfirst the to germline describe mutations HER2 inthetransmembrane domainasconferring potential nonsmokers, adenocarcinomas, patients of Asian ethnicity andfemales [65]andare associated with poor treatment response [64]. however, somaticmutation of israre. HER2 Suchmutations are found of in1.6%–2.5% NSCLC cases[64]. They are more frequent among is an oncogeneHER2 EGFR inthe family. Itis overexpressed inpatients with breast cancer ata frequency of 15%–20%[63].In lungcancer, Human epidermalgrowth factor 2(HER2) ment of possibletherapeutic approaches. pendentof sex andage. Theseare findings importantnot only to guidetheapplication preventive measures alsofor but thefuture develop- cancer (OR= 4.5,95%CI2.15–9.38), cancer (OR= 4.02,95%CI1.14–14.15)andlaryngeal cancer (OR =3.4,95%CI1.12–10.39),inde- for frequenciesof other cancers were higherin hereditarysubjects among thaninnon-hereditary branches of thefamilies of patients eligible BRCA mutations have always beenassociated more frequently with breast andovarian , a2017study but showed that the BRCA found were Genome Atlas,14 pathogenic mutations in five genes were identified. Among patients with TP53mutations, themostcommon variants patients,non-smokers)] most amongpatients the syndromewith [60].In ananalysis of 555lungadenocarcinoma casesfrom The Cancer In 2017,preliminary datafrom randomisedthe LIFESCREEN trialrevealedclinical agreater frequency of lungadenocarcinoma [22%(five an adrenocortical carcinoma or choroid plexus carcinoma, irrespective of family history [58]. breastmultiple cancers), two of which are tumours of LFS spectrum, with thefirst occurring at age <46 years; ORaproband diagnosed with cancer ifproband the hasbreastcancer) onsetwith at age <56 years or tumours;a proband OR with multiple tumours (exceptwith multiple cancer) diagnosed at age <46 years andat leastonefirst-degree or second-degree relative with atumour of LFS (except spectrum breast a single tumour of LFS(sarcoma, spectrum premenopausalbreast cancer, brain tumour, adrenocortical, leukaemia or lung[bronchoalveolar] extended version of theChompret criteria was published, included lungcancerwhich intheLFS tumour asfollows: spectrum, aproband with cancer diagnosedatage <45 years, andfirst-or second-degree relative with cancer onset atage <45 years or sarcoma at any age). In 2009,an [59]. Lung cancer isnotLFSin theclassic included criteria (proband diagnosed with sarcoma at <45 years of age, first-degree relative with carcinoma.cal Lung cancer occursof in2.3%–6.8% patients LFSwith [58],mostfrequently men, amedianagewith at diagnosisof 48 years Tumours classically associated syndromethis with breastinclude cancer, soft-tissue sarcoma, osteosarcoma, brain tumours andadrenocorti- promoter of theEGFR In somereports, EGFR BRCA testing, especially inthelung,kidney, liver andlarynx [62]. Members of hereditary family branches hadgreater probabilities of lung TP53 R267Q gene andmake thegene more susceptible to theoccurrence of mutations [61]. mutations have beendetected inpatients with LFS who develop lungcancer; thelossof p53functionmay free the , TP53 P152L and TP53 R158L, allpreviously linked to LFS [33]. 7

Review mutations, their mutations shouldnot beconsidered to bepredictive of prognosis [71]. appeared to behypermutated relative to theothers. As the overall survival of thesepatients was not altered by thepresence of germline p.A559T). A(rs17129219, a potential therapeutic target for EGFR-dependent adenocarcinomas [68]. A study in published 2017 demonstrated that YAP acts as an ground-glass opacities. This was associated with a5.9-fold increased risk of lungcancer development [67]. and never-smokers, aged 50–89 years) hadbeendiagnosed lung adenocarcinomawith or were beingmonitored dueto thedetection of p.V284M), likely pathogenic germline mutations among young patients was 78.3%. The maingermline mutations identified were BPIFB1(rs6141383, line variants from36 initialpatients the adenocarcinoma and28additionallung cases were analysed; thefrequency of pathogenic and tumour per mutations somatic 4,344–60,259 identified age of years ≤45 at diagnosed In astudyin 2018, published whole-genomeofsequencing samplesfrom 36never-smoking Chinesepatients lungadenocarcinomawith authors alsofound germline mutations inmany genes of non-coding RNA. frequencies in samples from subjects with thefamilial lungcancer or in lung cancer tissue compared with samples from healthy subjects. The potentially associated with lungcancer development. Some mutations in the tion and DNAtion they sequencing, identified five genes (ARHGEF5 five healthy relatives) using whole-genomesequencing. Amongthe 12mosthighly mutated genes, as validated by apolymerase chainreac ecancer 2020, 14:1008; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1008 tobacco burden is falling rapidly in many countries. Muchremains to thispathology, belearnedabout which has proven to be very different Lung cancer innever-smokers istheseventhlethal most cancer worldwide, anditsincidence will increase intheupcoming years, asthe Conclusions Kanwal Other genes to establishthepathogenic role of thisCHEK2mutation . inhuman familialcancer as nostructural described, change was observed intheother mutated genes. However, further needto studies beperformed disrupting thesaltbridge betweenmaking itunstable. and p.E394, p.R474 This effect appeared to have acausative relationship with the homozygous mutations in quently developed breastcancer, patientmale andthe had ahistory of prostate andcolon cancers. Exome analysis revealed non-synonymous Kukita CHEK2 cancer,as germline such lung cancer variants, andnoguidelinehasbeenestablishedfor thebest way to manage unaffected carriers of variants associated with lung In addition,genetictesting options forcancer lung remain very limited. Most commercial laboratories offer limited or notesting for hereditary of lungcancer innon-smokers, unlesstheproband fulfilscriteriafor aknown hereditary syndrome. Geneticcounselling forcancer lung remainsa challenge. No guidelinefor hasbeenestablishedbasedsolely onafamily history Discussion patients, buttheoptimum frequency of suchevaluation isuncertain. et al etal CHD4 [69] reported ontwo siblings historieswith of primary multiple lungcancers at theage of 60 years. The female patient subse- [70] analysed germline mutations associated the familialwith lungcancer inninesubjects(four patients lungcancerwith and (rs74790047, p.D140E), EGFRT790M, CHEK2, FCGRT missense germlineTP53 missense mutation (rs121912664, p.R205H) was found inoneindividual with atumour that HER2 andYAP1 , INPP5J PARP1 (rs3219145, NUDT1 p.K940R), (rs4866, p.V83M),RAD52 (rs4987207, p.S346*)and MFI2 , MYO18B and mutations. Screening low-dosewith CT may beincorporated into thecare of these EGFR , downstream signalling molecule, modulating lung cell proliferation, and is SFI1. The mutation in , ANKRD20A2 , MUC12 ZNF595, FOXD4L3 [70]. To evaluate genetic predisposition risk,germ- CHEK2 altered the tertiary structure of byCHK2 ZNF812 andMYO18B) with germline mutations and FOXD4L5 genes occurred at greater 8 -

Review

ecancer 2020, 14:1008; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1008 13. 12. 11. 10. References The authors declare noconflicts of interest. Conflicts of interest statement No funding was received for thisarticle. Funding statement More research is warranted to provide evidence-based screening guidelinesfor carriers of germline lungcancer riskalleles. genetic counselling is indicated is needed to provide effective screening methods and detect asymptomatic carriers in predisposed families. to thediseasestage at diagnosis,abetter understanding of thegenetic factors associated with lungcancer innever-smokers andof when predisposition,and several genes have beenassociated an increasedwith riskof lungcancer development. As theprognosis isrelated closely from lungcancer related to smoking,not only epidemiologically butalsoat themolecular level. Many affected patients show clear hereditary

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Review ecancer 2020, 14:1008; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1008 71. 70. 69. LuoW, P,Tian and Wang Y, population Gene Chinese the Madihacancerfrom K,Xiao-Jie lung familial D,in mutations andZhans-Han ofgermline M,et (2017)Characterization al lung cancer with accompanying cancers inother organs Kukita Y, Okami J, and Yoneda-kato N,etal (2016) J Cancer 1431696–1705https://doi.org/10.1002/ijc.31542 PMID: [http://dx.doi.org/10.1016/j.gene.2017.10.020] Characteristics of genomic alterations of lung adenocarcinoma in young never-smokersyoung in adenocarcinoma lung of alterations genomic of et al(2018)Characteristics Homozygous inactivation of CHEK2 is linked to a familial case of multiple primaryof multiple case familial a linkedto is Homozygousof CHEK2 inactivation Cold Spring Harb Mol Case Stud 21–12https://doi.org/10.1101/mcs.a001032 29667179 PMCID: 6175072 13 Int Int

Review