CXC family of chemokines as prognostic or predictive biomarkers and possible drug targets in colorectal cancer

Colorectal cancer(CRC) is the third most common cancer in men and the second most common cancer in women,worldwide. In the early stages of the disease, biomarkers predicting early relapse would improve survival rates.In metastatic patients, the use of predictive biomarkers could potentially result in more personalized treatments and better outcomes. The CXC family of chemokines(CXCL1 to 17) are small(8 to 10 kDa) secreted proteins that attract neutrophils and lymphocytes. These chemokines signal through chemokine receptors(CXCR) 1 to 8.Several studies have reported that these chemokines and receptors have a role in either the promotion or inhibition of cancer, depending on their capacity to suppress or stimulate the action of the immune system, respectively.In general terms, activation of the CXCR1/CXCR2 pathway or the CXCR4/CXCR7 pathway is associated with tumor aggressiveness and poor prognosis; therefore,the specific inhibition of these receptors is a possible therapeutic strategy. On the other hand, the lesser known CXCR3 and CXCR5 axes are generally considered to be tumor suppressor signaling pathways, and their stimulation has been suggested as a way to fight cancer.These pathways have been studied in tumor tissues(using immunohistochemistry or measuring mRNA levels)or serum [using enzyme-linked immuno sorbent assay(ELISA) or multiplexing techniques], among other sample types. Common variants in genes encoding for the CXC chemokines have also been investigated as possible biomarkers of the disease. This review summarizes themost recent findings on the role of CXC chemokines and their receptors in CRC and discusses their possible value as prognostic or predictive biomarkers as well as the possibility of targeting them as a therapeutic strategy.

Advances in immunotherapy for treatment of lung cancer

Different approaches for treating lung cancer have been developed over time, including chemotherapy, radiotherapy and targeted therapies against activating mutations. Lately, better understanding of the role of the immunological system in tumor control has opened multiple doors to implement different strategies to enhance immune response against cancer cells. It is known that tumor cells elude immune response by several mechanisms. The development of monoclonal antibodies against the checkpoint inhibitor programmed cell death protein 1(PD-1) and its ligand(PD-L1), on T cells, has led to high activity in cancer patients with long lasting responses. Nivolumab, an anti PD-1 inhibitor, has been recently approved for the treatment of squamous cell lung cancer patients, given the survival advantage demonstrated in a phase III trial. Pembrolizumab, another anti PD-1 antibody, has received FDA breakthrough therapy designation for treatment of non-small cell lung cancer(NSCLC), supported by data from a phase I trial. Clinical trials with anti PD-1/PD-L1 antibodies in NSCLC have demonstrated very good tolerability and activity, with response rates around 20% and a median duration of response of 18 months.

A prospective analysis of factors that influence weight loss in patients undergoing radiotherapy

Malnutrition occurs frequently in patients with cancer.Indeed,a variety of nutritional and tumorrelated factors must be taken into account in these patients.Recognizing this relationship,we aimed to prospectively evaluate the risk factors that influence weight loss in patients undergoing radiotherapy with oral nutritional supplementation and dietetic counseling.Weight loss of 74 patients during radiotherapy and 1 month after treatment was analyzed.Parameters such as age,gender,tumor location,tumor stage,Eastern Cooperative Oncology Group performance status(ECOG PS)score,and the use of chemotherapy were analyzed to evaluate their influence on weight loss.All patients underwent oral nutritional supplementation and dietetic counseling.Forty-six(65.7%)patients lost weight,with a mean weight loss of(4.73±3.91)kg,during radiotherapy.At 1 month after treatment,45(66.2%)patients lost weight,presenting a mean weight loss of(4.96±4.04)kg,corresponding to a(6.84±5.24)%net reduction from their baseline weight.Head and neck cancer patients had a mean weight loss of(3.25±5.30)kg,whereas the remaining patients had a mean weight loss of(0.64±2.39)kg(P=0.028)during radiotherapy.In the multivariate analysis,the head and neck tumor location(P=0.005),use of chemotherapy(P=0.011),and ECOG PS score of 2-3(P=0.026)were considered independent risk factors.Nutritional status and parameters,such as tumor location(especially the head and neck),the use of chemotherapy,and the ECOG PS score,should be evaluated before radiotherapy because these factors can influence weight loss during radiotherapy and 1 month after treatment.

Understanding the function and dysfunction of the immune system in lung cancer: the role of immune checkpoints

Survival rates for metastatic lung cancer, including non-small cell lung cancer(NSCLC) and small cell lung cancer(SCLC), are poor with 5-year survivals of less than 5%. The immune system has an intricate and complex relationship with tumorigenesis; a groundswell of research on the immune system is leading to greater understanding of how cancer progresses and presenting new ways to halt disease progress. Due to the extraordinary power of the immune system—with its capacity for memory, exquisite specificity and central and universal role in human biology—immunotherapy has the potential to achieve complete, long-lasting remissions and cures, with few side effects for any cancer patient, regardless of cancer type. As a result, a range of cancer therapies are under development that work by turning our own immune cells against tumors. However deeper understanding of the complexity of immunomodulation by tumors is key to the development of effective immunotherapies, especially in lung cancer.

What is the purpose of launching World Journal of Respirology?

Congratulations to the publisher,members of the editorial board of the journal,and all the authors and readers for launching the World Journal of Respirology(WJR).The WJR is a peer-reviewed journal that will report novel theories,methods and techniques for the prevention,diagnosis,treatment,rehabilitation and nursing of patients with respiratory disease.Some of the topics that will be covered in the journal include diagnostic imaging,respiratory physiology,respiratory endoscopy,respiratory system tumors,chronic obstructive pulmonary disease,bronchial asthma,respiratory infections,critical respiratory illness,sleep-related respiratory disorders,interstitial lung disease,pulmonary vascular diseases,pulmonary embolism,traditional medicine,integrated Chinese and Western medicine,evidencebased medicine,epidemiology and nursing.Importantly,the WJR is an online,open-access journal,which will enable it to reach both experts and the general public without the need for registration or payment.If you want to share your work and findings,you will find the WJR an excellent journal for your publications!

Lack of evidence for germline WWP1 pathogenic variants in gastrointestinal polyposis and other phenotypes suggestive of PTEN-hamartoma-tumor syndrome

Germline activating variants in WWP1,which encodes an E3 ubiquitin ligase that antagonizes PTEN tumor suppressive function,have been proposed as an alternative mechanism of PTEN inactivation in PTEN-hamartoma-tumor syndrome(PHTS)-like patients with wildtype PTEN.1 More specifically,heterozygous,potentially activating wwP1 variants were first identified by Lee et al in patients affected with gastrointestinal oligopolyposis,including adenomatous,hyperplastic/serrated,and hamartomatous polyps,and occasionally with colorectal cancer(Table 1).Subsequently,based on the PHTS phenotypic features,wWP1 mutational screening was performed in patients with thyroid nodules,2 or normocephalic autism spectrum disorder(ASD),3 where germline WWP1 variants were also identified(Table S1).

Ductal prostate cancer:Clinical features and outcomes from a multicenter retrospective analysis and overview of the current literature

Objective:The aim of the study is to evaluate clinical features and outcomes after different therapeutic strategies for ductal prostate adenocarcinoma(DPC),a rare but aggressive subtype of invasive prostate cancer(PCa)accounting for,in the pure and mixed form,1%or less and 5%or less,respectively,of all the newly diagnosed PCa.Materials and methods:Patients with a proven diagnosis of DPC undergoing surgery,radiotherapy,and androgen deprivation therapy,alone or in combination,were considered for this multicenter,retrospective study.The study assessed overall survival(OS),disease-free survival(DFS),and age-related disease-specific survival.Results:Eighty-one patients met the study inclusion criteria.Pure DPC was found in 29 patients(36%)and mixed ductal-acinar-PCa in 52 patients(64%).After a median follow-up of 63 months(range,3-206 months),3-and 5-year OS rates were 84%and 67%,respectively,and 3-and 5-year DFS rates were 54%and 34%,respectively.There were no significant differences in OS or DFS between the pure and mixed DPC groups.Pure DPC was associated with a higher rate of metastatic disease at onset.Patients 74 years or younger had better disease-specific survival(p=0.0019).A subgroup analysis favored radiotherapy as the primary treatment for nonmetastatic,organ-confined DPC(3-and 5-year DFS of 80%and 50%,respectively,compared with 5-year DFS of 35%for surgical patients;p=0.023).Conclusions:Our study found DPC to be rarer,more aggressive,more likely to metastasize,and have a worse prognosis than the common acinar variant,especially in its pure form.Multicenter series are encouraged to obtain large data sets,or propensity score matching analyses with patients with conventional PCa are desirable to understand the best therapeutic approach and improve outcomes.

表观遗传学如何诠释人肿瘤转移microRNA的新作用

转移过程的特征是肿瘤细胞可通过血液系统播散到远端组织，然后这些变异的细胞在那里增殖，并形成继发性肿瘤，这也是肿瘤患者死亡最主要的原因。近年来，一系列重要的肿瘤相关基因陆续被报道，如钙粘素、层粘连蛋白、乙酰肝素硫酸盐、蛋白水解酶、血管生成抑制剂等。但是，这些基因在肿瘤转移中发生改变的机制尚不明了，因为尽管它们的表达普遍下调，

IHC、FISH和RT-PCR检测对EML4-ALK重排的一致性

棘皮动物微管结合蛋白-间变性淋巴瘤激酶（echinoderm microtubule-associated prote i n-l ike4-anaplastic lymphoma kinase,EML4-ALK）在肺癌中已成为第二个最重要的驱动致癌基因,在4%-6%的肺腺癌中EML4-ALK已经成为第一个可以靶向治疗的融合基因位点。伴随着ALK分离探针荧光原位杂交（fluorescent in situ hybridization,FISH）试剂盒的上市,克唑替尼已经被批准治疗ALK阳性的进展期非小细胞肺癌（non-small cell lung cancer,NSCLC）。然而,一种靶向药物的成功主要取决于一种敏感且特异的筛选实验方法来检测分子药物作用的靶点。以作者的经验看,用RTPCR来检测EML4-ALK,比用FISH和免疫组化（immunohistochemistry,IHC）方法更敏感,结果更可靠。尽管通过FISH检测ALK已经经过大量的临床实验验证,然而该方法在技术层面仍存在许多具有挑战性的问题,而通过IHC和RT-PCR方法检测ALK仍需要临床进一步的探索。

Colorectal cancer: From prevention to personalized medicine

Colorectal cancer(CRC)is a very heterogeneous disease that is caused by the interaction of genetic and environmental factors.CRC develops through a gradual accumulation of genetic and epigenetic changes,leading to the transformation of normal colonic mucosa into invasive cancer.CRC is one of the most prevalent and incident cancers worldwide,as well as one of the most deadly.Approximately 1235108 people are diagnosed annually with CRC,and 609051 die from CRC annually.The World Health Organization estimates an increase of77%in the number of newly diagnosed cases of CRCand an increase of 80%in deaths from CRC by 2030.The incidence of CRC can benefit from different strategies depending on its stage:health promotion through health education campaigns(when the disease is not yet present),the implementation of screening programs(for detection of the disease in its early stages),and the development of nearly personalized treatments according to both patient characteristics(age,sex)and the cancer itself(gene expression).Although there are different strategies for screening and although the number of such strategies is increasing due to the potential of emerging technologies in molecular marker application,not all strategies meet the criteria required for screening tests in population programs;the three most accepted tests are the fecal occult blood test(FOBT),colonoscopy and sigmoidoscopy.FOBT is the most used method for CRC screening worldwide and is also the primary choice in most population-based screening programs in Europe.Due to its non-invasive nature and low cost,it is one of the most accepted techniques by population.CRC is a very heterogeneous disease,and with a few exceptions(APC,p53,KRAS),most of the genes involved in CRC are observed in a small percentage of cases.The design of genetic and epigenetic marker panels that are able to provide maximum coverage in the diagnosis of colorectal neoplasia seems a reasonable strategy.In recent years,the use of DNA,RNA and protein markers in different biological samples has been explored as strategies for CRC diagnosis.Although there is not yet sufficient evidence to recommend the analysis of biomarkers such as DNA,RNA or proteins in the blood or stool,it is likely that given the quick progression of technology tools in molecular biology,increasingly sensitive and less expensive,these tools will gradually be employed in clinical practice and will likely be developed in mass.

Assays for predicting and monitoring responses to lung cancer immunotherapy

Immunotherapy has become a key strategy for cancer treatment, and two immune checkpoints, namely, programmed cell death 1(PD-1) and its ligand(PD-L1), have recently emerged as important targets. The interaction blockade of PD-1 and PD-L1 demonstrated promising activity and antitumor efficacy in early phase clinical trials for advanced solid tumors such as non-small cell lung cancer(NSCLC). Many cell types in multiple tissues express PD-L1 as well as several tumor types, thereby suggesting that the ligand may play important roles in inhibiting immune responses throughout the body. Therefore, PD-L1 is a critical immunomodulating component within the lung microenvironment, but the correlation between PD-L1 expression and prognosis is controversial. More evidence is required to support the use of PD-L1 as a potential predictive biomarker. Clinical trials have measured PD-L1 in tumor tissues by immunohistochemistry(IHC) with different antibodies, but the assessment of PD-L1 is not yet standardized. Some commercial antibodies lack specificity and their reproducibility has not been fully evaluated. Further studies are required to clarify the optimal IHC assay as well as to predict and monitor the immune responses of the PD-1/PD-L1 pathway.

Radiation and concomitant chemotherapy for patients with glioblastoma multiforme

Postoperative external beam radiotherapy was considered the standard adjuvant treatment for patients with glioblastoma multiforme until the advent of using the drug temozolomide(TMZ) in addition to radiotherapy. High-dose volume should be focal, minimizing whole brain irradiation. Modern imaging, using several magnetic resonance sequences, has improved the planning target volume definition. The total dose delivered should be in the range of 60 Gy in fraction sizes of 1.8-2.0 Gy. Currently, TMZ concomitant and adjuvant to radiotherapy has become the standard of care for glioblastoma multiforme patients. Radiotherapy dose-intensification and radiosensitizer approaches have not improved the outcome. In spite of the lack of high quality evidence, stereotactic radiotherapy can be considered for a selected group of patients. For elderly patients, data suggest that the same survival benefit can be achieved with similar morbidity using a shorter course of radiotherapy(hypofractionation). Elderly patients with tumors that exhibit methylation of the O-6-methylguanine-DNA methyltransferase promoter can benefit from TMZ alone.

Genetic predisposition to colorectal cancer:Where we stand and future perspectives

The development of colorectal cancer(CRC)can be influenced by genetic factors in both familial cases and sporadic cases.Familial CRC has been associated with genetic changes in high-,moderate-and low-penetrance susceptibility genes.However,despite the availability of current gene-identification techniques,the genetic causes of a considerable proportion of hereditary cases remain unknown.Genome-wide association studies of CRC have identified a number of common lowpenetrance alleles associated with a slightly increased or decreased risk of CRC.The accumulation of low-risk variants may partly explain the familial risk of CRC,and some of these variants may modify the risk of cancer in patients with mutations in high-penetrance genes.Understanding the predisposition to develop CRC will require investigators to address the following challenges:the identification of genes that cause uncharacterized hereditary cases of CRC such as familial CRC type X and serrated polyposis;the classification of variants of unknown significance in known CRC-predisposing genes;and the identification of additional cancer risk modifiers that can be used to perform risk assessments for individual mutation carriers.We performed a comprehensive review of the genetically characterized and uncharacterized hereditary CRC syndromes and of lowand moderate-penetrance loci and variants identified through genome-wide association studies and candidate-gene approaches.Current challenges and future perspectives in the field of CRC predisposition are also discussed.

PD-L1 expression associated with better response to EGFR tyrosine kinase inhibitors

Cancer evades host immune surveillance by using immune checkpoints,w hich are inhibitor y pathways cr ucial for maintaining self-tolerance1.Tumor cells express multiple inhibitory ligands,and tumor-infiltrating lymphocytes(TIL)express a variety of inhibitory receptors.Inhibitory receptors cytotoxic T-lymphocyte-associated protein 4(CTLA-4)and programmed

Human endogenous retroviruses and cancer

Human endogenous retroviruses(HERVs) are retroviruses that infected human genome millions of years ago and have persisted throughout human evolution. About 8% of our genome is composed of HERVs, most of which are nonfunctional because of epigenetic control or deactivating mutations. However, a correlation between HERVs and human cancer has been described and many tumors, such as melanoma, breast cancer, germ cell tumors, renal cancer or ovarian cancer, express HERV proteins, mainly HERV-K(HML6) and HERV-K(HML2). Although the causative role of HERVs in cancer is controversial, data from animal models demonstrated that endogenous retroviruses are potentially oncogenic. HERV protein expression in human cells generates an immune response by activating innate and adaptive immunities. Some HERV-derived peptides have antigenic properties. For example, HERV-K(HML-6) encodes the HER-K MEL peptide recognized by CD8+ lymphocytes. In addition, HERVs are twoedged immunomodulators. HERVs show immunosuppressive activity. The presence of genomic retroviral elements in host-cell cytosol may activate an interferon type I response. Therefore, targeting HERVs through cellular vaccines or immunomodulatory drugs combined with checkpoint inhibitors is attracting interest because they could be active in human tumors.

Liver fat deposition and mitochondrial dysfunction in morbid obesity:An approach combining metabolomics with liver imaging and histology

AIM: To explore the usefulness of magnetic resonance imaging(MRI) and spectroscopy(MRS) for assessment of non-alcoholic fat liver disease(NAFLD) as compared with liver histological and metabolomics findings. METHODS: Patients undergoing bariatric surgery following procedures involved in laparoscopic sleeve gastrectomy were recruited as a model of obesityinduced NAFLD in an observational, prospective, singlesite, cross-sectional study with a pre-set duration of 1 year. Relevant data were obtained prospectively and surrogates for inflammation, oxidative stress and lipid and glucose metabolism were obtained through standard laboratory measurements. To provide reliable data from MRI and MRS, novel procedures were designed to limit sampling variability and other sources of error using a 1.5T Signa HDx scanner and protocols acquired from the 3D or 2D Fat SAT FIESTA prescription manager. We used our previously described 1H NMRbased metabolomics assays. Data were obtained immediately before surgery and after a 12-mo period including histology of the liver and measurement of metabolites. Values from 1H NMR spectra obtained after surgery were omitted due to technical limitations.RESULTS: MRI data showed excellent correlation with the concentration of liver triglycerides, other hepatic lipid components and the histological assessment, w h i c h e xc l u d e d t h e p r e s e n c e o f n o n-a l c o h o l i c steatohepatitis(NASH). MRI was sufficient to follow up NAFLD in obese patients undergoing bariatric surgery and data suggest usefulness in other clinical situations. The information provided by MRS replicated that obtained by MRI using the-CH3 peak(0.9 ppm), the-CH2- peak(1.3 ppm, mostly triglyceride) and the-CH=CH- peak(2.2 ppm). No patient depicted NASH. After surgery all patients significantly decreased their body weight and steatosis was virtually absent even in patients with previous severe disease. Improvement was also observed in the serum concentrations of selected variables. The most relevant findings using metabolomics indicate increased levels of triglyceride and monounsaturated fatty acids in severe steatosis but those results were accompanied by a significant depletion of diglycerides, polyunsaturated fatty acids, glucose-6-phosphate and the ATP/AMP ratio. Combined data indicated the coordinated action on mitochondrial fat oxidation and glucose transport activity and may support the consideration of NAFLD as a likely mitochondrial disease. This concept may helpto explain the dissociation between excess lipid storage in adipose tissue and NAFLD and may direct the search for plasma biomarkers and novel therapeutic strategies. A limitation of our study is that data were obtained in a relatively low number of patients.CONCLUSION: MRI is sufficient to stage NAFLD in obese patients and to assess the improvement after bariatric surgery. Other data were superfluous for this purpose.

关于到 colorectal 癌症的 TGFBR1 和危险性的争论

Recent years have witnessed enormous progress in our understanding of the genetic predisposition to colorectal cancer (CRC). Estimates suggest that all or most genetic susceptibility mechanisms proposed so far, ranging from high-penetrance genes to low-risk alleles, account for about 60% of the population-attributable fraction of CRC predisposition. In this context, there is increasing interest in the gene encoding the transforming growth factor β receptor 1 (TGFBR1 ); first when over a decade ago a common polymorphism in exon 1 (rs11466445, TGFBR1 *6A/9A) was suggested to be a risk allele for CRC, then when linkage studies identified the chromosomal region where the gene is located as susceptibility locus for familial CRC, and more recently when the allele-specific expression (ASE) of the gene was proposed as a risk factor for CRC. Published data on the association of TGFBR1 with CRC, regarding polymorphisms and ASE and including sporadic and familial forms of the disease, are often contradictory. This review gives a general overview of the most relevant studies in order to clarify the role of TGFBR1 in the field of CRC genetic susceptibility.

Relationship between methylation and colonic inflammation in inflammatory bowel disease

AIM:To investigate the relationship between the methylation status in the SLIT2 and TGFB2 promoters and colonic inflammation in inflammatory bowel disease patients.METHODS:We evaluated the methylation status of 2genes(SLIT2 and TGFB2)in 226 biopsies taken from62 colonoscopies of 38 patients(29 ulcerative colitis and 9 Crohn’s colitis)using methylation-specific melting curve analysis.The relationships between methylation status and clinical,biological,endoscopic and histological activities were evaluated.Twenty-three of the 38patients had a second colonoscopy and were included in a longitudinal analysis.Numerical results were given as the means±SD of the sample and range,except when specified.Student t analysis,U Mann Whitney and ANOVA factor were used to compare the means.Qualitative results were based on theχ2 test.RESULTS:SLIT2 methylation was more frequent in samples with endoscopic activity than with endoscopic remission(55%vs 18%,P<0.001).SLIT2 methylation was also higher in samples with acute inflammation(56.5%)than in samples with chronic(24%)or absent inflammation(15%)(P<0.001).For TGFB2methylation,the correlation was only significant with endoscopic activity.Methylation was higher in the distal colon for both genes(P<0.001 for SLIT2 and P=0.022for TGFB2).In the multivariate analysis,only inflammation status(and not disease duration or extension)was independently associated with SLIT2 methylation[OR=6.6(95%CI:1.65-27.36),P=0.009].In the longitudinal analysis,the maintenance of endoscopic remission was protective for methylation.CONCLUSION:Endoscopic and histological inflammation are predictive for SLIT2 methylation.

Outcome and prognostic factors in 110 consecutive patients with primary uterine leiomyosarcoma:A Rare Cancer Network study

Objective： Primary uterine leiomyosarcomas （ULMS） are rare, and the optimal treatment is controversial. We aimed to assess the outcome and prognostic factors in a multicenter population of women treated for primary ULMS. Methods： We retrospectively collected data of 110 women treated in 19 institutions of the Rare Cancer Network （RCN）. Inclusion criteria consisted of a pathology report confirming the diagnosis of ULMS, aged 18-80 years, complete International Federation of Gynecology and Obstetrics （FIGO） stage information, complete information on treatment, and a minimum follow-up of 6 months. Local control （LC） and locoregional control （LRC）, overall survival （OS） and disease-free survival （DFS） rates were computed using the Kaplan-Meier method. Univariate analysis was implemented using the log rank test, and multivariate analysis using the Cox model. Results： All patients underwent surgery. Seventy-five patients （68%） received adjuvant radiotherapy （RT）, including brachytherapy in 18 （I 6%）. Seventeen patients （15 %） received adjuvant chemotherapy. Median follow-up was 58 （range, 6-240） months. Five-year OS and DFS rates were 50% and 34%, and LC and LRC rates were 88% and 72%, respectively. On multivariate analysis, independent favorable prognostic factors were younger age, FIGO stage I, small tumor size, previous uterine disease, and no vascular invasion for OS and DFS. FIGO stage was the only favorable factor influencing LRC. Adjuvant local or systemic treatments did not improve the outcomes. Eight patients treated with RT presented a grade 3 acute toxicity, and only one patient with grade 3 late toxicity. Conclusions： In this large population of primary ULMS patients, we found good results in terms of LC and LRC. Nevertheless, OS remains poor, mainly due to the occurrence of distant metastases. An early diagnosis seemed to improve the prognosis of the patients. Adjuvant local or systemic treatments, or more aggressive surgical procedures such as the Wertheim procedure, did not seem to impact the outcome.

Systemic treatment in EGFR-ALK NSCLC patients:second line therapy and beyond

Lung cancer is the most frequently diagnosed cancer and a leading cause of cancer mortality worldwide, with adenocarcinoma being the most common histological subtype. Deeper understanding of the pathobiology of non-small cell lung cancer(NSCLC) has led to the development of small molecules that target genetic mutations known to play critical roles in progression to metastatic disease and to influence response to targeted therapies. The principle goal of precision medicine is to define those patient populations most likely to respond to targeted therapies. However, the cancer genome landscape is composed of relatively few "mountains" [representing the most commonly mutated genes like KRAS, epidermal growth factor(EGFR), and anaplastic lymphoma kinase(ALK)] and a vast number of "hills"(representing low frequency but potentially actionable mutations). Low-frequency lesions that affect a druggable gene product allow a relatively small population of cancer patients for targeted therapy to be selected.