The Genetics of Hereditary Colon and ...
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www.lacolon.com Norman N. Hoffman M.D., Inc. Gary H. Hoffman M.D. Eiman Firoozmand M.D. Liza M. Capiendo M.D. With a myriad of vexing abbreviations and obscure terminology, the genetics controlling the formation of colonic polyps and malignancies may be diffi- cult to appreciate. A review of these colonic disorders will aid in an under- standing of the underlying genetics. SPORADIC, FAMILIAL AND INHERITED DISEASE Eighty to ninety percent of cases of colon cancer occur sporadically. Ten to fifteen percent of patients have familial col- orectal cancer, meaning that there are two or more colorectal malignancies found in a given family and that a specific causative gene has not been identified. Five percent of patients have an inherited or hered- itary form of colon cancer and a genetic abnormality has been found to be associated with the malignancy. To further subdivide this group, the colonic malignancy may be associated with one of several polyposis syndromes in which there are a variable number of adeno- matous or hamartomatous colonic polyps lining the mucosa, or with nonpolyposis syn- dromes in which there are few or no colonic polyps associated with the colon cancer. POLYPOSIS SYNDROMES Adenomatous Polyposis Syndromes Perhaps the best-known disease in this group is Familial Adenomatous Polyposis (FAP). The mutation responsible for this syndrome is found in the adenomatosis polyposis coli (APC) gene. The gene is located on the long (q) arm of chromosome 5. The APC gene normally is responsible for the expression of a protein that prevents uncontrolled cellular growth and division. Six hundred mutations have been discovered in this gene and any of these mutations may give rise to an aberrant protein that is abnormally short, nonfunctional and unable to suppress the cellular overgrowth that leads to colonic polyp and cancer formation. Inherited in an autosomal dominant manner, only one parent is required to have a copy of the defec- tive gene and this gene must be transmitted to the child for the FAP pheno- type to be expressed. At least fifty percent of offspring will receive this aberrant gene and develop FAP. Surgical treatment does not lessen this risk. As one third of newly diag- nosed patients with FAP do not have an affected parent, the disease in these patients may represent a new mutation in the APC gene which may be passed down the family tree. The Genetics of Hereditary Colon and Rectal Cancer: Understanding is the First Step Toward Treatment PART I, THE BASICS Beverly Hills: (310) 273-2310 • Culver City: (310) 836-0013 continued on back... Alert to the genetics and findings in patients with hereditary colorectal cancer syndromes, physicians may be better able to diagnose and recommend treatment for the colonic manifesta- tions of each disease.
Transcript of The Genetics of Hereditary Colon and ...
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Norman N. Hoffman M.D., Inc. Gary H. Hoffman M.D. Eiman Firoozmand M.D. Liza M. Capiendo M.D.
With a myriad of vexing abbreviationsand obscure terminology, the geneticscontrolling the formation of colonicpolyps and malignancies may be diffi-cult to appreciate. A review of thesecolonic disorders will aid in an under-standing of the underlying genetics.
SPORADIC, FAMILIALAND INHERITED DISEASEEighty to ninety percent of cases of coloncancer occur sporadically.
Ten to fifteen percent ofpatients have familial col-orectal cancer, meaningthat there are two or morecolorectal malignanciesfound in a given familyand that a specificcausative gene has notbeen identified.
Five percent of patientshave an inherited or hered-itary form of colon cancerand a genetic abnormalityhas been found to be associated with themalignancy. To further subdivide this group,the colonic malignancy may be associatedwith one of several polyposis syndromes inwhich there are a variable number of adeno-matous or hamartomatous colonic polypslining the mucosa, or with nonpolyposis syn-dromes in which there are few or no colonicpolyps associated with the colon cancer.
POLYPOSIS SYNDROMESAdenomatous Polyposis SyndromesPerhaps the best-known disease in this groupis Familial Adenomatous Polyposis (FAP).The mutation responsible for this syndrome isfound in the adenomatosis polyposis coli(APC) gene. The gene is located on the long(q) arm of chromosome 5. The APC genenormally is responsible for the expression of aprotein that prevents uncontrolled cellulargrowth and division. Six hundred mutationshave been discovered in this gene and any of
these mutations may giverise to an aberrant proteinthat is abnormally short,nonfunctional and unableto suppress the cellularovergrowth that leads tocolonic polyp and cancerformation.
Inherited in an autosomaldominant manner, onlyone parent is required tohave a copy of the defec-tive gene and this genemust be transmitted to thechild for the FAP pheno-
type to be expressed. At least fifty percent ofoffs pring will receive this aberrant gene anddevelop FAP. Surgical treatment does notlessen this risk. As one third of newly diag-nosed patients with FAP do not have anaffected parent, the disease in these patientsmay represent a new mutation in the APCgene which may be passed down the familytree.
The Genetics of HereditaryColon and Rectal Cancer:Understanding is the First Step Toward TreatmentPART I , THE BASICS
Beverly Hills: (310) 273-2310 • Culver City: (310) 836-0013
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Alert to the genetics andfindings in patients withhereditary colorectal cancersyndromes, physicians maybe better able to diagnoseand recommend treatmentfor the colonic manifesta-tions of each disease.
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Beverly Hills: (310) 273-2310 • Culver City: (310) 836-0013
testinal tract, bones, central nervous system, eyes, and genitourinary tract,is associated with a ten percent lifetime risk of developing colon cancer.Juvenile Polyposis, immature hamartomatous polyps associated with gas-trointestinal bleeding, is also associated with a ten percent lifetime risk ofdeveloping colon cancer, but only in those affected patients harboringgreater than five polyps. Patients with single polyps have very little risk ofdeveloping colon cancer.
NONPOLYPOSIS SYNDROMESHereditary Nonpolyposis Colorectal Cancer is also known asHNPCC or Lynch Syndrome. HNPCC is an autosomal dominantdisease and is the most common hereditary colon cancer syndrome,accounting for two to four percent of all colon cancers. The syndromeoccurs as a result of mutations in the mismatch repair genes MSH2located on chromosome 2, MSH6, also located on chromosome 2,MLH1 located on chromosome 3, or PMS2, located on chromosome 7.These genes normally produce enzymes responsible for removing mis-paired nucleotides which may have mispaired during faulty DNA repli-cation. With these mutations, mismatch repair cannot be accomplishedand cellular growth is altered or deranged leading to neoplastic growth.HNPCC is seen against the background of a normal colon, or in a colonwith only a few small polyps. The disease is divided into Lynch I andLynch II.
In Lynch I, colorectal cancer is the most common pathologic finding.The lifetime risk of developing a colorectal cancer in an individual withLynch I syndrome is eighty percent. Most of the neoplasms are locatedproximal to the splenic flexure, produce mucin, and demonstrate signetring cells and tumor-infiltrating lymphocytes on pathologic examina-tion. Synchronous and metachronous lesions are not uncommon, sig-naling a mismatch repair defect. The average age of diagnosis is fortyfour years old, compared to age sixty four in the sporadic form of coloncancer.
Lynch II describes the association of colorectal cancer with other malig-nancies. In women with Lynch II, there is a thirty to fifty percent lifetimerisk of developing endometrial cancer, with the average age of diagnosisbeing forty six. Gastric cancer, transitional cell carcinoma of the ureterand renal pelvis, small bowel cancers occurring most commonly in theduodenum and jejunum, and central nervous system tumors, most oftenglioblastomas, are part of the Lynch II syndrome.
Familial Colorectal Cancer Type X is a rare disease in which thoseinvolved meet the criteria of the nonpolyposis syndrome but have none ofthe positive genetic test results found in the nonpolyposis syndromes. Morespecifically, patients with familial colorectal cancer type X do not have ademonstrable mismatch repair defect. The risk of developing colorectalcancer is lower than in those patients with HNPCC, and the age of diagnosis of colon cancer is higher. Unlike patients with the Lynch IIsyndrome, these individuals do not seem to develop malignancies inother organ systems.
Alert to the genetics and findings in patients with hereditary colorectalcancer syndromes, physicians may be better able to diagnose and recom-mend treatment for the colonic manifestations of each disease.
In the teenage years, the number of colonic polyps observed in patientswith FAP begins to increase. The average age of development of coloncancer is thirty nine years. Although associated with only one percent ofcolorectal cancers, without surgical treatment, there is an almost onehundred percent risk of developing of colon cancer.
In FAP, there is also a lifetime risk of developing desmoid tumors (15%),duodenal cancer (4%), thyroid cancer (2%), brain cancer (2%),ampullary cancer (1.7%), pancreatic cancer (1.7%), hepatoblastoma(1.6%) or gastric cancer (0.6%).
Attenuated Familial Adenomatous Polyposis (AFAP) is associated withfewer colonic adenomas, a tendency towards smaller and more proximaladenomas and a later age of onset of malignant transformation. The APCgene is also responsible for AFAP.
MYH-associated polyposis (MAP) is a form of polyposis caused by amutation in the MUTYH gene, a base excision repair gene located on theshort (p) arm of chromosome 1. MAP is inherited in an autosomal reces-sive fashion, meaning that each parent must have one copy of the gene andboth copies of the gene must be present in the child for the phenotype tobe expressed. MUTYH glycosylase, an enzyme expressed by the MUTYHgene, repairs nucleotide mismatches prior to DNA replication. A defectivegene expresses faulty MUTYH glycosylase and thus allows for the uncon-trolled cellular growth and division leading to the formation of colonicpolyps with the possibility of subsequent malignant transformation. Polypsassociated with a mutant MUTYH gene do not appear until adulthood andare less numerous than those found in patients with APC gene mutations.
Several other syndromes involving a defective APC gene have beendescribed and now are thought to be variants of FAP. Gardner’s Syndrome,multiple colon polyps or cancers with various extra colonic neoplasms inthe oral cavity or retina, and Turcot Syndrome, multiple colon polyps orcancers with central nervous system malignancies are examples of thesesyndromes. APC I1307K, also an FAP variant, describes the location ofan alteration in the APC allele. An allele is a normal but alternate formof a gene. A defective allele at APC I1307K leads to an increase in colorectal adenomas and carcinomas at a younger age than in patientswith sporadic carcinoma. Found in Ashkenazy Jews, APC I1307K isthought to be carried by 360,000 Americans and gives rise to colorectalcancer in three to seven percent of this affected kindred. It is autosomaldominant in transmission.
Hamartomatous Polyposis SyndromesA hamartoma is a benign overgrowth of tissue containing all of the fea-tures of the normal underlying tissue but in a disordered randomfashion. Hamartomas in and of themselves are not premalignant.However, the risk exists that the hamartomatous tissue may develop adenomatous areas which may undergo malignant transformation. Thisrisk is lower than in FAP.
Peutz-Jeghers Syndrome, benign hamartomatous polyps in the gastroin-testinal tract and hyperpigmented macules on the lips and oral mucosa, isassociated with a thirty percent lifetime risk of developing colon cancer.Cowden’s disease, hamartomatous neoplasms of the skin and gastroin-
