GENETICS OF COLORECTAL CARCINOMA

Dr. Debabrata Sahana PGT Unit II

Gene mutations causing colon Cancer

MUTATION TYPE Germ line Somatic GENES INVOLVED APC MMR Oncogenes : myc ras src erbB2 Tumor suppressor genes: TP53 APC DCC MMR genes : bMSH2 bPMS2 bMLH1 bMSH6 bPMS1 bMSH3 TYPE OF DISEASE CAUSED Familial adenomatous polyposis HNPCC ( Lynch syndrome) Sporadic disease

Genetic polymorphism APC

Familial colon cancer in Ashkenazi Jews

TUMOR SUPPRESSOR GENES

APC gene Chromosome 5q Participates in cell cycle control - regulates intracytoplasmic -catenin pool - regulates Wnt expression

TUMOR SUPPRESSOR GENES contd

Earliest mutations
Germline APC truncation mutation- AD FAP syndrome Mutational cluster region Attenuated FAP mutation close to 5 end

TUMOR SUPPRESSOR GENES contd

Classic FAP mutations in codon 1250 - 1464

30% denovo germline mutations

Truncation mutations-- 85% sporadic cases

I1307 point mutation colorectal cancers in Ashkenazi

Jews

TUMOR SUPPRESSOR GENES contd

p53 Most frequently mutated (75% colorectal CA) Chromosome 17p

Induces apoptosis in response to cellular damage Guardian of genome

Chromosome 18q mutations - SMAD2, SMAD4, DCC, DPC4

MYH Mutations
Base excision repair Mutations caused by oxidative DNA damage Multiple MYH mutations may coexist Seen in northern Europeans, Indians, Pakistanis

Phenotype similar to FAP

MYH Mutations contd

More than one germ line mutations in a single patient greater no. of polyps & duodenal adenomas Bi-allelic mutations- increased risk Distinguish from FAP Siblings at more risk

Mismatch repair genes

Correct DNA replication errors Mutations result in HNPCC Produce Microsatellite Instability, errors in S phase

MSI seen in 10-15% sporadic cases & 95% HNPCC

Oncogenes
Protooncogenes- regulated proliferation of cells Oncogenes- uncontrolled proliferation of cells Products growth factors

- growth factor receptors

- signal transducers - nuclear protooncogenes and transcription factors 50% have ras mutations (Chr 12)

ADENOMA CARCINOMA SEQUENCE

GENETICS OF HEREDITARY CANCER SYNDROMES

Colon cancer syndrome HNPCC Gene involved AD MLH1, Chr 3p MSH2, Chr 2p MSH6/GTMP , Chr 2p PMS1, Chr 2q PMS2, Chr 7q AD APC, Chr 5q AD APC, Chr 5q MLH1 , PMS2 AD p10, Chr 10q

FAP/Gardners syndrome Turcots syndrome Cowdens Disease

GENETICS OF HEREDITARY CANCER SYNDROMES contd...

Colon cancer syndrome
Familial Juvenile polyposis

Genes involved
AD SMAD4 DRC4 , Chr 10q

Peutz Jeghers Syndrome

Ruvalcaba-Myhre-Smith Syndrome (Bannayan-Zonana Syndrome)

AD
AD

STK11, Chr 19q

p10, Chr 10q

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