Genome-Based Multi-targeting of Cancer: Hype or Hope?

Edwin Smith Papyrus (3000 BC)

Described a breast cancer-like disease

Eberus Papyrus (1500 BC)

Described soft tissue tumors and used cautery, knives, salts, and arsenic paste to treat this

Hippocrates (Greek physician, 460–375 BC)

Used the terms carcinos and carcinoma to describe non-ulcer-forming and ulcer-forming tumors

Aulus Celsus (Roman physician, 28 BC–50 AD)

Translated the Greek term into cancer, the Latin word for crab

Gaius Plinius Secundus (Roman, 23–79 AD)

Recommended herbal remedies for advanced cancer

Aretaeus of Cappadocia (Egyptian physician, 81–138 AD)

Described symptoms, signs, and treatment of uterine cancer; classified cancer into ulcerated and non-ulcerated

Claudius Galen (Greek physician, 130–200 AD)

Used the word oncos (Greek for swelling) to describe tumors

Oribasius (Greek physician, 325–403 AD)

Identified necrosis in cancer

Lanfranc of Milan (1252–1315 AD)

Differentiated benign tumors of the breast from cancer

Guy de Chauliac (French surgeon, 1300–1368 AD)

Distinguished hot and cold (cancer) lesions

Antonio Benivieni (Florentine physician, 1507 AD)

Published first case report of gastric cancer

Paracelsus (Swiss-German physician, 1493–1541)

Therapeutic use of chemicals, described industrial lung cancer

Ambroise Pare (French Army Surgeon, 1575)

Treated breast cancer with mercury-covered sheet of lead

Felix Platter (Basel physician, 1526–1614)

First described brain tumor

Thomas Venner (London, 1620)

Warned about tobacco dangers in his Via Recta

William Harvey (1628)

Described the systemic blood circulation through the heart and body

Zacutus Lusitani and Nicolaes Tulp (1649)

Created the “Contagion Theory”

George Stahl and Friedrich Hoffmann (1660–1742)

Tumors grow from lymph constantly thrown out by the blood

Bernardino Ramazzini (Italian doctor, 1713)

Absence of cervical cancer in nuns linked to high breast cancer

Giovanni Battista Morgagni (Padua, 1761)

Did autopsies to connect pathologic findings with cancer

John Hill (London surgeon, 1761)

Recognized tobacco as a carcinogen

Percival Pott (London, 1775)

Linked soot in the skin folds of the scrotum to cancer

John Hunter (Scottish surgeon, 1728–1793)

Suggested that some cancers might be cured by surgery

Jean Louis Petit (French surgeon, eighteenth century)

Linked lymphatic glands with breast tumor

Joseph Lister (British surgeon, 1827–1912)

Was the first to perform an adequate axillary dissection

Julius Vogel (Germany, 1845)

Introduced an Atlas of cancer pathology

Henry Bence Jones (English physician, 1848)

Discovered Bence Jones protein

John Birkett (English surgeon, 1850)

Introduced the term lobular carcinoma

James Paget (English surgeon, 1853)

Described the Paget disease of the breast

Alfred Velpeau (French surgeon, 1854)

Described and illustrated bilateral breast cancer

Karl Thiersch (German surgeon, 1860)

Cancers metastasize through the spread of malignant cells

Moritz Kaposi (Hungarian dermatologist, 1872)

Reported Kaposi sarcoma

Richard Von Volkmann (German surgeon, 1873)

Advocated the routine complete removal of the breast

Rudolph Virchow (1821–1902)

All cells, including cancer cells, are derived from other cells

Gaillard Thomas (New York, 1876)

Recommended the use of intraoperative frozen section

Thomas Beatson (Edinburgh, 1878)

Hormonal communication between breasts and ovary in rabbits

William Stewart Halsted (American surgeon, 1889)

Developed radical surgery of breast cancer

Charles Huggins (University of Chicago, 1901–1997)

Regression of metastatic prostate cancer

William Conrad Roentgen (German, 1896)

Discovered “X-Ray,” used to treat cancer

George T. Beatson (Glasgow surgeon, 1896)

Introduced oophorectomy for inoperable breast carcinomas

Pierre Curie and Marie Curie (1898)

Discovered radium which was later used for cancer treatment

David P. von Hansemann (German pathologist, 1902)

Introduced histologic grading of carcinoma

Hugh H. Young (American surgeon, 1904)

Carried out a radical operation for prostate cancer

Paul Ehrlich (German biochemist, 1909)

Introduced the word “chemotherapy”

Peyton Rous (Pathologist, 1910)

Transmitted sarcoma in hens by cell-free filtrate

Peyton Rous (New York, 1911)

Induced cancer in chickens by Rous sarcoma virus

Alexis Carrel and Montrose T. Burrows (1914)

First to grow human cancer tissue in culture

Katsusaburo Yamagiwa and Koichi Ichikawa (1915)

Induced cancer by tar in animals

Edward B. Krumbhaar (US Army pathologist, 1919)

Noticed that mustard gas causes leukopenia

James Ewing (Hematopathologist, 1921)

Reported a deadly bone cancer known as Ewing’s sarcoma

George Papanicolaou (1923)

Developed Pap smear test for cervical cancer diagnosis

Antoine M. Lacassagne (French physician, 1932)

Breast cancer can be induced by estrogen injections in mice

Harvey W. Cushing (American neurosurgeon, 1932)

Reported Cushing’s disease

Yellapragada Subbarao (1947)

Discovered methotrexate as anticancer agent

Sidney Farber (1948)

Showed remission of childhood leukemia with aminopterin

Sauberlich and Baumann (1948)

Discovered leucovorin from Leuconostoc citrovorum

James Watson and Francis Crick (1953)

Discovered the chemical structure of DNA

Charles Heidelberger (1957)

Discovered 5-fluorouracil as an anticancer drug

Renato Dulbecco (1975)

Discovered viruses that can cause cancer

Howard Temin and David Baltimore (1975)

Discovered the enzyme reverse transcriptase

Robert L. Egan (1956)

Used low-energy X-rays to diagnose human breast cancer

Denis P. Burkitt (1958)

Discovered childhood cancer; named it “Burkitt’s lymphoma”

Stanley Cohen (1962)

Isolated first growth factor, epithelial growth factor

Ozegowski and Krebs (1963)

Discovered bendamustine, an alkylating agent,

Di Marco A (1965)

Discovered daunorubicin from a bacterium

Hamao Umezawa (1966)

Discovered bleomycin

Monroe Wall and Mansukh Wani (1967)

Discovered paclitaxol as an anticancer drug

von Wartburg and Hartmann F. Stähelin (1967)

Discovered podophyllotoxin that lead to etoposide

John Montgomery and Kathleen Hewson (1968)

Discovered fludarabine as an anticancer drug

G. Steve Martin (1970)

Discovered first oncogene that can cause cancer

Yoshinori Kidan (1976)

Discovered anticancer drug oxaliplatin

Larry Hertel (1986)

Discovered gemcitabine, an antiviral drug to kill leukemia cells

Sun HD (1992)

Discovered arsenic trioxide, effective in acute promyelocytic leukemia

Brian Druker and Nick Lydon (1996)

Discovered imatinib, a BCR-ABL inhibitor for chronic myeloid leukemia

Based on Hajdu (2011a, b, 2012a, b), Hajdu and Darvishian (2013), Hajdu and Vadmal (2013) and Harvey (1974)

2.3 Cancer Is a Disease of Old Age

The incidence of cancer increases as we get older; only 2 % of all cancers are diagnosed in children, the remaining 98 % are diagnosed in adults. In the United States, the average age at diagnosis of cancer in both males and females is 45–50 years (http://www.cancer.org/index). Interestingly, however, after age 70 years, the incidence of most cancers declines (Anand et al. 2008a), perhaps in part due to the aging of the cancer cells. Naked mole rats, however, challenge the theories that link cancer with aging (Kim et al. 2011). This animal shows negligible senescence, no age-related increase in mortality, and high fecundity until death. In addition to experiencing delayed aging, it is resistant to both spontaneous cancer and experimentally induced tumorigenesis.

2.4 Cancer Is More Common in Western/Developed Countries

According to the WHO, the global cancer burden jumped to 14.1 million new cases and accounted for 8.2 million deaths in 2012 (http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx). Epidemiological data suggest that both cancer incidence and cancer mortality are much more prevalent in developed countries than in developing countries (Table 2.2). In the United States, for instance, with a population of 320 million, two in every three people are diagnosed with cancer today. In 2014, 1,665,540 new cases of cancer will be diagnosed and 585,720 patients will die of this disease in the United States (http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2014/). When adjusted for age, 459 of 100,000 people will be diagnosed as having cancer. In the United States today, there are 14.5 million cancer survivors; by 2024, the number of cancer survivors is estimated to increase to almost 19 million. In comparison, in India, a developing country with a population of 1.3 billion, cancer was diagnosed in 1,000,000 people in 2013 and 700,000 people died of this disease (http://timesofindia.indiatimes.com/india/7-lakh-Indians-died-of-cancer-last-year-WHO/articleshow/27317742.cms). One in 10 Indians is at risk of developing cancer before 75 years of age, whereas 7 in 100 are at risk of dying from cancer before age 75 (Goss et al. 2014).

Table 2.2

Cancer incidence and mortality in the top 50 most populated countries

Country	Population	New cases	Deaths	Incidence/100,000	Deaths/100,000
China	1,343,239,923	3,065,400	2,205,900	174	122
India	1,205,073,612	1,014,900	682,000	94	65
United States	313,847,465	1,603,600	617,200	318	106
Indonesia	248,645,008	299,700	194,500	134	89
Brazil	193,946,886	437,600	224,700	206	104
Pakistan	190,291,129	148,000	101,000	112	80
Nigeria	170,123,740	102,100	71,600	100	72
Bangladesh	161,083,804	122,700	91,300	104	81
Russia	142,517,670	458,400	295,400	204	123
Japan	127,368,088	703,900	378,000	217	94
Mexico	114,975,406	148,000	78,000	132	67
Philippines	103,775,002	98,200	59,000	140	91
Vietnam	91,519,289	125,000	94,700	140	109
Ethiopia	91,195,675	61,000	45,000	108	85
Egypt	83,688,164	108,600	152,000	72	103
Germany	81,305,856	493,800	217,600	284	101
Turkey	79,749,461	148,000	91,800	205	129
Iran	78,868,711	84,800	53,400	128	82
Congo	73,599,190	37,400	30,800	108	93
Thailand	67,091,089	108,600	152,000	72	103
France	65,630,692	371,700	154,600	325	108
United Kingdom	63,047,162	327,800	157,800	273	110
Italy	61,261,254	354,500	170,000	279	102
Burma	54,584,650	63,600	49,200	141	113
South Korea	48,860,500	55,400	38,900	181	126
South Africa	48,810,427	77,400	47,400	187	118
Spain	47,042,984	215,500	102,800	249	98
Tanzania	46,912,768	33,900	23,600	124	92
Colombia	45,239,079	71,400	37,900	161	85
Ukraine	44,854,065	141,000	87,300	193	114
Kenya	43,013,341	41,000	28,500	182	135
Argentina	42,192,494	115,200	66,400	217	115
Poland	38,415,284	152,200	24,100	246	99
Algeria	37,367,226	37,900	21,700	124	75
Canada	34,300,083	182,200	74,100	296	103
Sudan	34,206,710	8,700	6,600	133	106
Uganda	33,640,833	29,400	21,500	170	134
Morocco	32,309,239	35,000	22,800	118	78
Iraq	31,129,225 30,419,928	25,700	17,500	135	97
Afghanistan	31,129,225 30,419,928	20,000	15,400	115	98
Nepal	29,890,686	18,800	14,300	85	68
Peru	29,549,517	42,800	26,200	155	92
Malaysia	29,179,952	37,400	21,700	144	86
Uzbekistan	28,394,180	22,600	14,900	100	70
Venezuela	28,047,938	41,800	23,500	140	86
Saudi Arabia	26,534,504	17,500	9,100	91	54
Yemen	24,771,809	11,400	8,400	80	64
Ghana	24,652,402	15,800	10,700	92	64
North Korea	24,589,122	219,500	81,500	308	100
Mozambique	23,515,934	22,000	17,000	137	115

Data derived from GLOBOCAN 2012 (http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx)

Among the most populated countries in the world, China, with a population of 1.4 billion, had 2.6 million patients who were diagnosed as having cancer in 2010, and 1.8 million died of the disease (http://english.peopledaily.com.cn/90001/90776/90882/7122372.html). In comparison, in 2013, 3.5 million new cancer cases were identified and 2.5 million cancer deaths were reported (http://www.china.org.cn/2013-04/16/content_28556502.htm). These numbers are more comparable with those of the United States than with those of India.

The types of cancer that occur in various countries vary a great deal. In the United States, the top five cancers in men are lung, colon, bladder, melanoma, and prostate; in US women, the top cancers are breast, lung, colon, and melanoma. In India, however, the top five cancers in men are lip/oral cavity, lung, stomach, colorectum, and pharynx, whereas among women they are breast, cervix, colorectum, ovary, and lip/oral cavity.

In comparing the incidence of age-standardized prostate cancer in the United States and India, the US incidence was found to be 12.8 per 100,000 but was 4.4 per 100,000 in India, suggesting that cancer is a disease of lifestyle. As further evidence, one-third of all cancers in the United States have been linked to cigarette smoking, whereas half of all cancers in Indian men have been linked to smoking and chewing tobacco. Overall, another third of all cancers have been linked to diet, 14–20 % to obesity, 18 % to infections, and 7 % to environmental pollution and radiation (Anand et al. 2008a). Heredity plays a role in causing cancer, but in only 5 % of cases. Further evidence that cancer is a disease of lifestyle has been seen in immigrants such as women from Japan, who after immigrating to the United States had an increased incidence of breast cancer, from about 10 per 100,000 to more than 80 per 100,000 over the course of three generations (Kolonel et al. 2004).

Sadly, the incidence of global cancer appears to be increasing, with new cases expected to reach 16 million in 2020 and 20 million in 2030; the numbers of cancer deaths are expected to increase as well to 10 million and 14 million, respectively.

Although the incidence of cancer is increasing throughout the world, the incidence of infectious diseases is decreasing worldwide. Although certain cancers are caused by infections, the question has been raised about whether other cancers might be prevented by infections, perhaps through activation of the immune system. Investigation of the reciprocal relationship between infection and cancer goes back through the centuries (Aggarwal 2003) and led to the discovery of Coley’s toxin, used even today (McCarthy 2006). In fact, Bacillus Calmette-Guerin (BCG) treatment used for bladder cancer is based on these discoveries (Kamat et al. 2009). Intravesical instillation of BCG was first used for bladder cancer therapy in 1974 (Morales et al. 2002); to date, it is the most successful adjuvant agent for treating noninvasive bladder cancer (Herr et al. 2011).

Chronic infections, obesity, alcohol, tobacco, irradiation, environmental pollutants, and high-calorie diet have been recognized as major risk factors for the most common types of cancer (Ahn et al. 2007). All these risk factors are linked to cancer through inflammation. Linkage between cancer and inflammation is indicated by transcription factors, nuclear factor-kappa B (NF-κB), and signal transducers and activators of transcription 3 (STAT3), two major pathways for inflammation that are activated by most cancer risk factors (Aggarwal et al. 2009b; Aggarwal 2005). NF-κB itself and proteins regulated by it have been linked to cellular transformation, proliferation, apoptosis suppression, invasion, angiogenesis, and metastasis of cancer (Aggarwal 2004, 2009). However, controlled activation of NF-κB is needed for the function of the immune system, and its constitutive activation can cause inflammation and tumorigenesis (Aggarwal and Sung 2011). Thus, it exhibits a double-edged sword and behaves like friend or foe depending on the activation (Shishodia and Aggarwal 2004). Chemotherapeutic agents and gamma irradiation activate NF-κB and lead to chemoresistance and radioresistance (Ahn et al. 2008). Thus, suppression of these proinflammatory pathways may provide opportunities for both prevention and treatment of cancer (Aggarwal 2006, 2008a; Ralhan et al. 2009).

2.5 Cancer Is a Multigenic Disease

Extensive research in the last half of the twentieth century revealed that cancer is caused by dysregulation of not a single gene but multiple genes. Since cancer is a hyperproliferative disorder, most of these genes are linked to the proliferation of tumor cells. Investigation of the genomic landscape of the most common cancers has recently revealed that a limited number of genetic alterations are responsible for most cancer subtypes. Approximately 140 of the 23,000 human genes appear to drive almost all cancers (Vogelstein et al. 2013). How many genes have undergone mutations and what are those genes has also been identified for most cancers (Table 2.3). Interestingly, although 163 mutations were identified in small-cell lung cancer, as few as 8 mutations were linked with acute amyloid leukemia. Although some of these genes and their roles in cancer are well recognized, the functions of quite a few cancer-linked genes are not fully understood. For instance, NOTCH-1, p53, Wnt, EGFR, Ras, Raf, PI3K, HER2, BCR-ABL, ER, PR, PSA, and JAK2 genes have been studied extensively, and their roles in cancer are well recognized. In contrast, the roles of other genes in cancer, including ATRX, DAXX, CD20, and CD25, are still not fully understood.

Table 2.3

Identification of various somatic mutations and predictive tumor biomarkers in human cancers

Cancers	No. of mutations	Predictive tumor biomarkers
Pediatric cancers
Glioblastoma	14	H3F3A/ATRX, DAXX, TP53
Neuroblastoma	12
Acute lymphocytic leukemia	11	NOTCH-1
Medulloblastoma	8	HH, Wnt, MLL2, MLL3
Rhabdoid cancer	4
Adult cancers
Lung cancer (small cell)	163	EGFR, EML4-ALK, KRAS, MEK, SOX2
Lung cancer (non-small cell)	147	EGFR, SIK2 kinases, ARID1A, RBM10
Melanoma	135	BRAF
Esophageal squamous cell cancer	79
Non-Hodgkin’s lymphoma	74	CD25
Colorectal cancer	66	BRAF, CEA, EGFR, KRAS, PI3CA, UGT1A1, MSI/MMR
Head and neck cancer	65	TP53, CDKN2A, PI3K3CA, HRAS, FBXW7, NOTCH-1, TP63, IRF6, PTEN, HRAS
Esophageal adenocarcinoma	57
Gastric cancer	53	CA19-9, HER2, ARID1A
Endometrial cancer	49
Pancreatic cancer	45	CA 19–9, HER2
Ovarian cancer	42	CA-125, HE4, OVA1, PI3KCA, ARID1A, PPP2R1A, KRAS
Prostate cancer	41	AR, PSA, ETS2, MLL2; FOXA1, MLL2, UTX, ASXL1
Hepatocellular cancer	39	ARID1A
Glioblastoma	35	1p/19q, IDH1, IDH2
Breast cancer	33	CYP2D6, ER, HER2, PI3KCA, PR
Chronic lymphocytic leukemia	12	CD20
Chronic myeloid leukemia		BCR-ABL
Acute myeloid leukemia	8	CEBPA, FLT3, Kit, NPM1, IDH-1, IDH-2, JAK2, TET2, DNMT3A
Diffuse large B-cell lymphoma	30	MLL2
Liver		AFP
Kidney		Non-LDT
Bladder		NMP22

This data was based on Vogelstein et al. (2013), Fojo and Parkinson (2010)

1p/19q codeletion of chromosomal arms 1p and 19q, ALL acute lymphocytic leukemia, AFP a-fetoprotein (AFP), AML acute myeloid leukemia, APL acute promyelocytic leukemia, AR androgen receptor or nuclear receptor subfamily 3, group C, member 4 (AR); B-CLL B-cell chronic lymphocytic leukemia, BRAF v-raf murine sarcoma viral oncogene homologue B1 or proto-oncogene B-Raf (BRAF), BCR-ABL breakpoint cluster region and Abelson murine leukemia viral oncogene homologue 1 gene fusion, CML chronic myeloid leukemia, CA-125 cancer antigen 125 or mucin 16 (MUC16), CA 19–9 cancer antigen 19–9, CEA carcinoembryonic antigen or glycosyl phosphatidyl inositol (GPI) cell surface-anchored glycoprotein (CEACAM), CEBPA (CCAAT/enhancer binding protein a C/EBPa), CML chronic myeloid leukemia, CYP2D6 cytochrome P450 2D6 (CYP2D6), DPYD dihydropyrimidine dehydrogenase (DPYD), EGFR epidermal growth factor receptor (EGFR), EML4-ALK echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase fusion (EML4-ALK), ER estrogen receptor alpha (ESR1), FLT3 fms-related tyrosine kinase 3(FLT3), GIST gastrointestinal stromal tumor, HE4 human epididymis protein 4 or WAP four-disulfide core domain (WFDC2), HER2 human epidermal growth factor receptor 2 or receptor tyrosine-protein kinase erbB-2 (ERBB2), IDH1 isocitrate dehydrogenase 1 (IDH1), JAK2 Janus kinase 2 (JAK2), Kit c-Kit (Kit, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homologue), KRAS Kirsten rat sarcoma viral oncogene homologue, LDT lab-developed Abelson murine leukemia viral oncogene homologue 1 gene fusion, MPD myelodysplastic disorder, MSI/MMR microsatellite instability/mismatch repair proteins, NHL non-Hodgkin’s lymphoma, NMP22 nuclear matrix protein 22, NPM1 nucleophosmin 1 (NPM1), NRAS neuroblastoma RAS viral oncogene homologue (NRAS), NSCLC non-small cell lung cancer; Oncotype Dx Breast breast biomarker panel, Oncotype Dx Colon colon biomarker panel, Oncotype Dx Prostate prostate biomarker panel, OVA1 ovarian biomarker panel, PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit a or PI3K p110a (PIK3CA), PML-RARa promyelocytic leukemia and retinoic acid receptor alpha fusion (RARa), PR progesterone receptor (PGR), PSA prostate-specific antigen, gamma-seminoprotein, kallikrein-3 (KLK3), SCCHN squamous cell carcinoma of the head and neck, UGT1A1 UDP glucuronosyltransferase 1A1 (UGT1A1)

A number of lessons have been learned from these genomic studies. For instance, it was calculated that in colorectal tumorigenesis, approximately 17 years are needed for a large benign tumor to evolve into advanced cancer, and less than 2 years are needed for cells within that cancer to acquire the ability to metastasize (Jones et al. 2008). Furthermore, it was found that few selective events are required to transform a highly invasive cancer cell into one with the capacity to metastasize. Another study showed that half or more of the somatic mutations in cancers of self-renewing tissues originate before tumor initiation (Tomasetti et al. 2013). Welch et al. found that most of the mutations in acute myeloid leukemia (AML) genomes are actually random events that occurred in hematopoietic stem/progenitor cells before they acquired the initiating mutation (Welch et al. 2012). In many cases, only one or two additional cooperating mutations are needed to generate a malignant founding clone.

Cancer is a genomic disease associated with gene mutations, resulting in a loss of control over vital cellular functions. Of all mutated genes, driver genes have been causally linked to oncogenesis, whereas passenger genes are believed to be irrelevant for tumorigenesis. Driver genes can be classified into 12 signaling pathways that regulate three core cellular processes: cell survival, cell fate, and genome maintenance (Table 2.4). Basic cancer research is needed to understand these pathways (Vogelstein et al. 2013).

Table 2.4

List of driver genes linked to cell survival, cell fate, and genome maintenance

Cell survival	MAP3K1	ARID1B	NOTCH-2
ABL1 (PTK)	MED12	ARID2	PAX5
ACVR1B (ALK4)	MET	ASXL1	PBRM1
AKT1	MPL	ATRX	PHF6
ALK	MYD88	AXIN1	PRDM1
B2M	NF1	BCOR	PTCH1
BCL2	NFE2L2	CDH1	RNF43
BRAF	NPM1	CREBBP	RUNX1
CARD11	NRAS	CTNNB1	SETD2
CASP8	PDGFRA	DAXX	SETBP1
CBL	PIK3CA	DNMT1	SF3B1
CDC73	PIK3R1	DNMT3A	SMARCA4
CDKN2A	PPP2R1A	EZH2	SMARCB1
CEBPA	PTEN	FAM123B	SMO
CIC	PTPN11	FBXW7	SPOP
CRLF2	RB1	FOXL2	SRSF2
CSF1R	RET	GATA1	TET2
CYLD	SMAD2	GATA2	U2AF1
EGFR	SMAD4	GATA3	WT1
ERBB2	SOCS1	H3F3A
FGFR2	SOX9	HIST1H3B	Genome maintenance
FLT3	STK11	HNF1A	ATM
FUBP1	TNFAIP3 (A20)	IDH1	BAP1
GNA11	TRAF7	IDH2	BRCA1
GNAQ	TP53	KDM5C	BRCA2
GNAS	TSC1	KDM6A	MLH1
HRAS	TSHR	KLF4	MSH2
JAK1	VHL	MEN1	MSH6
JAK2		MLL2	STAG2
JAK3	Cell fate	MLL3
Kit	APC	NCOR1
KRAS	AR	NF2
MAP2K1	ARID1A	NOTCH-1

Genes were classified as oncogenes if they had an oncogene score of >20 % and classified as a tumor suppressor gene (TSG) if the TSG score was >20 % (the 20/20 rule). To be classified as an oncogene, there had to be >10 clustered mutations in this database. To be classified as a tumor suppressor gene, there had had to be at least 7 inactivating mutations recorded in this database. Genes with mutations occurring predominantly in tumors with very high rates of mutation, such as in mismatch repair-deficient tumors or melanomas, were excluded (From Vogelstein et al. 2013)

B2M beta 2 microglobulin, CARD11 caspase recruitment domain family, member 11, Cbl (named after Casitas B-lineage lymphoma) is a mammalian gene encoding the protein CBL which is an E3 ubiquitin protein ligase involved in cell signaling and protein ubiquitination, CDC73 cell division cycle 73, Paf1/RNA polymerase II complex component, homologue (S. cerevisiae), also known as CDC73 and parafibromin, CDKN2A cyclin-dependent kinase inhibitor 2A, CEBPA CCAAT/enhancer binding protein (C/EBP), alpha, CIC protein capicua homologue is a protein that in humans is encoded by the CIC gene, CRLF2 gene (protein-coding), cytokine receptor-like factor 2

It is widely accepted that cancer is attributed to the accumulation of genetic aberrations in cells. Hence it is very important to understand the molecular mechanism of cancer progression to identify the genes whose alterations accumulate during cancer progression, as well as the genes that are responsible for the metastatic potential of cancer cells. Various stages of tumor progression have been analyzed, and these studies have revealed that alterations in oncogenes and in tumor suppressor genes accumulate and are responsible for the aggressiveness of cancer (Vogelstein et al. 2013).

Several oncogenes were identified in the early 1980s, which opened the way for the search for genetic alterations in human cancer cells (Wood et al. 2007; Parsons et al. 2008). This search was further aided by the isolation of tumor suppressor genes in the early 1980s and 1990s. In 1986, the first tumor suppressor gene, RB, was isolated from the human genome (Palles et al. 2013). After that, more than 20 tumor suppressor genes have been identified (Nowell 1976). Molecular analyses of these genes have confirmed that more than one tumor suppressor gene is involved in the progression of the tumor cell (Wood et al. 2007; Kinzler and Vogelstein 1997).

These molecular analyses indicated that genetic alterations occur in a stepwise manner during complete tumor progression. In the prospect, several extensive studies were conducted. Tumors from various types of cancers were analyzed to compare the genetic alterations appearing in the early and later stages of tumor development. In most cases, more mutations were found in later-stage tumors than in early stage tumors. These findings have been verified in several genetic models, including colorectal carcinoma models (Kerbel 1990; Bozic et al. 2010; Laurenti and Dick 2012).

In various kinds of human cancers, oncogene alterations have been investigated to determine their association with prognosis in cancer patients. For example, overexpression of the c-erbB-2 oncogene is a marker for aggressiveness in ovarian and breast cancers (Yan et al. 2009; Zhao et al. 2009).

Isolation of high and low metastatic subclones from a primary tumor has made it possible to elucidate and compare the properties of high and low metastatic cells. High and low metastatic cells were found to be different in many aspects. For example, various genes are differentially expressed in these two types of cells; specifically, several genes could induce metastasis whereas others could suppress it. Thus, by analyzing genotype-phenotype correlation with respect to metastatic potential, it should be possible to identify specific genetic alterations responsible for metastasis (Yokota 2000).

In solid tumors such as those derived from the colon, breast, brain, or pancreas, an average of 33–66 genes display subtle somatic mutations that would be expected to alter their protein products. About 95 % of these mutations are single-base substitutions (such as C > G), whereas the remaining are deletions or insertions of one or a few bases (such as CTT > CT). Of the base substitutions, 90.7 % result in missense changes, 7.6 % result in nonsense changes, and 1.7 % result in alterations of splice sites or untranslated regions immediately adjacent to the start and stop codons (Vogelstein et al. 2013).

Certain types of tumors display many more or fewer mutations than the average. Notable among these outliers are melanomas and lung tumors, which contain ~200 nonsynonymous mutations per tumor. These larger numbers reflect the involvement of potent mutagens (ultraviolet light in melanomas and cigarette smoke in lung tumors) in the pathogenesis of these tumor types. Accordingly, lung cancer specimens obtained from smokers have ten times as many somatic mutations as do those from nonsmokers (Govindan et al. 2012). Tumors with defects in DNA repair form another group of outliers (Gryfe and Gallinger 2001). For example, tumors with mismatch repair defects can harbor thousands of mutations, even more than lung tumors or melanomas. Recent studies have shown that high numbers of mutations are also found in tumors with genetic alterations of the proofreading domain of DNA polymerases POLE or POLD1 (Cancer Genome Atlas Network 2012; http://ecancer.org/news/3237-cancer-genome-atlas-network-maps-colorectal-cancer.php). At the other end of the spectrum, pediatric tumors and leukemia harbor far fewer point mutations: on average, 9.6 per tumor (Vogelstein et al. 2013).

Wide genomic aberration is a hallmark of genomes of all cancer types. Deep sequencing technology recently characterized the geographic and functional spectrum of cancer genomic aberrations and revealed insights into mutational mechanisms (Koboldt et al. 2012; Kidd et al. 2010; Beroukhim et al. 2010). These somatic mutations in cancer genomes may encompass several distinct classes of DNA sequence variations, including point mutations, copy number aberrations (CNA), and genomic rearrangements (Stratton et al. 2009). CNAs are deletions or additions of large segments of a genome and usually include one to tens of genes. Although these somatically acquired changes have been observed in cancer cell genomes, this does not necessarily mean that all abnormal genes are also involved in the development of cancers. Indeed, some genes are likely to make no contribution at all to cancer progression. To distinguish between them, these mutated genes have been coined driver and passenger genes (Stratton et al. 2009; Akavia et al. 2010). A driver gene is causally implicated in the process of oncogenesis, whereas a passenger gene makes no contribution to cancer development itself but is simply a by-product of the genomic instability observed in cancer genomes. Distinguishing driver genes from passenger genes has thus been considered an important goal of cancer genome analysis, especially in the field of personalized medicine and therapy (Santarius et al. 2010; Futreal et al. 2004; Chen et al. 2013).

It was discussed earlier that tumors in all types of cancers evolve through the process of tumor progression by acquiring a series of mutations over time (Nowell 1976; Fearon and Vogelstein 1990). The gatekeeper mutation provides normal epithelial cell, giving a selective growth advantage to outgrow the cells that surround it (Kinzler and Vogelstein 1997). Hence the mutations that confer a selective growth advantage to the tumor cell are called driver mutations (Bozic et al. 2010). The number of mutations in tumors of self-renewing tissues increases with age. It was found that more than half of the somatic mutations identified in such tumors occur during the preneoplastic phase, i.e., during the growth of normal cells. All of these preneoplastic mutations, termed passenger mutations, do not have any effect on the neoplastic process (Tomasetti et al. 2013). These findings explain why advanced-stage brain tumors and pancreatic cancers have fewer mutations than do colorectal tumors: the glial cells of the brain and epithelial cells of the pancreas do not replicate. Genomic sequencing of cancer cells from leukemia patients have shown that mutations occur as random events in normal precursor cells before the cells acquire an initiating mutation (Nowell 1976; Bozic et al. 2010).

So when do the remaining somatic mutations occur during tumorigenesis? A number of mutations in the progressive stages of colorectal and pancreatic cancers have been measured (Jones et al. 2008; Bernards and Weinberg 2002), and researchers concluded that it takes decades for a metastatic cancer to develop into a full-blown tumor. Furthermore, the mutations in metastatic lesions were already present in the cells of the primary tumors. It is possible that just as there are mutations that convert a normal cell to a benign cell or a benign tumor to a malignant tumor, there may be mutations responsible for converting a primary cancer to a metastatic one (Vogelstein et al. 2013). Advanced tumors release millions of cells each day into the circulatory system, but only few of them establish metastatic lesions. These circulating cells lodge in the capillary bed that provides the favorable environment for the growth of the metastatic cell (Yu et al. 2011).

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