COLON CANCER

JIFFY.K.JOHNY IV yr GENETIC ENGINEERING SRM UNIVERSITY

 Cancer

occurs when cells become abnormal and divide without control. This extra mass of tissue can be malignant or benign tumors.
tumors are rarely a threat to life, malignant tumors are a threat to life.

Benign

Cancer

cells break away from malignant tumor and enter into blood stream or lymphatic system, this spread of cancer is called metastatis .

 Part

of the bodys digestive system. The colon starts on the lower right side of the abdomen.
first six feet of the large intestine are called colon or large bowel and last 6 inches form rectum. It absorbs water , salt and fat soluble vitamins. site in which flora-aided (largely bacterial) fermentation of unabsorbed material occurs.

The

The

 Chinese

used herbs to treat the disease nearly 6,000 years ago. Ancient Greeks relied on olive oil to cleanse their colons, while traditional Indian ayurvedic medicine recommended mustard. In 1913, American pathologist Aldred Scott Warthin first identified the hereditary links of colon cancer later named as Lynch Syndrome I and II. Dukes in 1932 described the stages of colon cancer.

Pope John Paul II(died of influenza)

Tony Snow, US White House secretary under Bush(died because of colon cancer spread to liver) Ronald Reagan ,US President(died of pneumonia) Corazon Aquino, former president of Philippines(died of cardiorespiratory arrest after complications of colon cancer) Lillian Board, British athlete(died because of colon cancer spread to stomach)

 Globally

third leading cancer in males and fourth in females.

in Western world, rare in Asia and

Common

Africa.
Lowest

in India and Indians in Singapore among South Asian countries ( Globocan 2002)

Increases your likelihood of developing cancer.

Various risk factors are: IBD(inflammatory bowel disease) Age Diet Being overweight Polyps Personal medical history Family history Smoking Physical inactivity alcohol

Local colon cancer symptoms Affect colon itself Symptoms: Change in bowel habits Constipation Diarrhea Red blood in your stools Abdominal discomfort

Systemic colon cancer symptoms Have symptoms that affect your whole body Symptoms: Loss of appetite Vomiting Jaundice Anemia Weight loss Fatigue

Non- genetical Diets high in fat are believed to predispose humans to colon cancer. It is believed that break down product of fat metabolism leads to formation of carcinogens.
Vegetables

and high fiber food reduce the risk of cancer.

Genetical Polyp is benign growth on the lining or inside of mucous membrane ,but if left untreated-cancer.

On basis of shape- pedunculated and sessile. Pedunculated is mushroom like tissue growth with stalk. sessile has no stalk sit right on the membrane .

Types inflammatory Adenomatous Hyperplastic Villous Lymphoid(benign) juvenille

 Most

of colon cancers develop due to colon polyps. polyps develop when chromosome damage occurs in cells of the inner lining of the colon. polyps are initially Benign, later acquire additional chromosome damage to become cancerous.

Colon

Colon

 Even

though family history of colon cancer is an important risk factor, majority (80%) of colon cancers occur sporadically in patients with no family history of colon cancer. Approximately 20% of cancers are associated with a family history of colon cancer. And 5 % of colon cancers are due to hereditary colon cancer syndrome. of reasons are TP53, APC, CTNNB1(beta catenin)AX1N1,AX1N2(analogous to APC) gene mutations and the most affected is Wnt Signaling pathway.

Some

FAP(Familial Adenomatous Polyposis)

Autosomal dominant disorder that affects 1/13,000 births. Most compelling feature is onset and progression of 100 -1000 small adenomatous polyps throughout the colon. Though it starts by 20,noted to occur until age of 40. Deletion of human chromosome 5q21. Gene responsible for FAP is Adenomatous Polyposis coli(APC) gene, have 15 exons. APC is involved in chromosomal segregation, involved in transcription independent mediated apoptosis, Wnt signaling pathway. APC mutation leads to aneuploidy and enhancement of loss of heterozygosity observed sporadic colon
cancers.

Wnts comprise a highly conserved multimember ligand family, which play important roles in a variety of developmental processes, including patterning and cell fate determination Recent evidence indicates that in certain adult tissues, Wnts play important roles in stem/progenitor cell proliferation and differentiation Wnt binds to two coreceptors, the seven-transmembrane Frizzled and single-membranespanning LRP5/6. Coreceptor activation leads to recruitment of axin and disheveled proteins to the cell membrane and to inhibition of the serine threonine kinase GSK-3.

GSK-3 normally phosphorylates -catenin as part of a multiprotein complex involving GSK-3, APC, and Axin
Phosphorylation targets -catenin degradation through the ubiquitination pathway. Wnt-induced inhibition of GSK3 results in the inhibition of -catenin degradation and its accumulation in the cytoplasm in an uncomplexed form. The latter is then translocated to the nucleus and through interaction with the TCF/LEF transcription factors activates transcription Target genes of the -catenin-TCF/LEF complex include the proto-oncogene c-myc and cyclin D1.

Evidence indicates that Wnt signaling is constitutively activated in some breast and ovarian tumors by an autocrine mechanism
Genetic alterations of -catenin have been identified in human tumors and cancer cell lines, including colon cancer, melanomas, and hepatocellular carcinomas

The APC tumor suppressor gene product, which is required for -catenin phosphorylation and degradation, also regulates the amount of cytosolic -catenin.
Inactivation of the APC gene leading to increased cytosolic -catenin is found in 80% of colon cancers, and its inactivation occurs at an early stage in tumor progression.

HNPCC(Hereditary NonPolyposis Colorectal cancer) or Lynch Syndrome

Autosominal Patients

dominant mode of inheritance.

have germline mutations in DNA mismatch repair(MMR) genes. HNPCC wild type MMR allele is lost through somatic genetic alteration,as a result, DNA replication errors occur in repeat sequences typically in dinucleotide repeats

In

MAP(Multiple Adenomatous Polyps)

MYH

gene on human chromosome 1p33-34 is a base excision repair gene in which germline mutations are formed ,mostly missense or nonsense.

Autosomal

recessive inheritance, mono allelic carriers do not carry any risk of colorectal cancer. members typically develop 10-100 polyps by age of 40.

Affected

Digital rectal exam(DRE): Useful as initial screening test. Detects tumors large enough to be felt in the distal part of the rectum.

Fecal occult blood test(FOBT): Test for blood in stool

Endoscopy
Sigmoidoscopy : Sigmoidoscope is inserted to rectum and lower colon to check for polyps. Colonoscopy Lighted probe(colonoscope) is inserted into the rectum and the entire colon to look for polyps. Polyps found are removed immediately.

Virtual colonoscopy(CT colonoscopy)

X-rays

are used to make series of pictures of the colon. A computer puts the pictures together to create detailed images that may show polyps and anything else that seems unusual on the inside surface of the colon. This test is also called colonography or CT colonography.

 Carcinoembryonic

antigen(CEA) is a protein found in colorectal tumors which is used to monitor and asses the response of patient for a treatment.

Tissue

Inhibitor of Metalloproteinases 1(TIMP1) is used to monitor and asses colorectal cancer .Increased level of TIMP1 identify patients with very poor prognosis.

 Stage

0 :on innermost of intestine. Stage 1:in inner layers of the colon . Stage 2: spread through the muscle wall of the colon Stage 3: spread to the lymph nodes. Stage 4: spread to other organs

For all stages except IV surgery is the initial treatment Stage 0 Polypectomy: remove the tumor and the surrounding tissue. Anastomosis : to remove the diseased part of the colon and reattach the healthy tissue. Stage 1(Dukes A) Cancer has spread to the second and third layers and inside wall of the colon and has not spread to outer wall of the colon. Surgery is used to remove cancer and small amount of surrounding tissue. 5 year survival rate is 93%.

Stage 2(Dukes B) Chemotherapy or immunotherapy is usually done. 5 year survival rate is 78%. Stage 3(Dukes C) Tumors within the colon wall which involve the lymph node is Dukes stage c1, tumors that have grown through the colon wall and spread to 1-4 lymph node is stage c2 and more than 4 lymph node is stage c3.

Depends on- stage of the cancer, whether the cancer has recurred, patients general health.

Methods 1. Surgery Categorized into Curative: polypectomy and anastomosis is performed. Sometimes artificial orifice(stoma) is created,done when tumor is localized. By pass: when tumor is invaded surgeons prefer to bypass the tumor Fecal diversion : directly connected to rectum

2.

Chemotherapy This is usually given after surgery if cancer has spread to lymph nodes . Can be done for both adjuvant or non-adjuvant Adjuvant(after surgery) -5-flurouracil - leucovorin - oxaliplatin 3. Gene therapy -suicidal gene therapy - gene augmentation therapy Radiation therapy Not routinely used in colon cancer because it is difficult to target.

4.

5. Cancer vaccine TroVax produced by Oxford BioMedica is used in phase 3 trials 6. Asprin Reduces risk of colon cancer by taking asprin over a long period of time.( drug's inhibition of the COX-2 enzyme) 7. Nonsteroidal anti-inflamatory drugs(NSAID) It is a class of pain relief medication include drugs such as ibuprofen helps to reduce risk of polyps and colon cancer. 8. Vitamin B6 intake reduces cancer( American Gastroenterological Association (AGA)

 Stage

of the cancer

Whether

cancer has blocked or created hole in the colon cancer cells left after surgery level before treatment general health

Any CEA

patients

year survival rate for tumors in the ascending colon is 63%, transverse colon is 59% and descending colon is 66%.

Overall

5 year survival for colon cancer in America is 62% and its 43% in Europe. In Australia 5 year survival rate for stage 1 is 93% and stage 3 is 59%.

Artemis Health Institute, Gurgaon Apollo Hospital, Chennai Jaipur Golden Hospital, New Delhi St. Johns Medical College Hospital, Bangalore Bombay Hospital & Medical Research Centre, Mumbai Sir Ganga Ram Hospital, New Delhi Sant Parmanand Hospital, Delhi Kidwai Memorial Institute of Oncology, Bangalore Breach Candy Hospital, Mumbai Rajiv Gandhi Cancer Institute and Research Center, New Delhi

Action taken to lower chance of getting cancer Risk factors and protective factors are considered Ways to prevent cancer Changing lifestyle or eating habits Avoiding things known to cause cancer Taking medicines to treat precancerous condition