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Polyp-Cancer Sequence

by Kevin Pei, MD
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    00:01 Now, let’s talk about the predictable pathway from a polyp to a cancer. This is called appropriately the polyp-cancer sequence. Here’s a slide that demonstrates a mutation from normal epithelium on the left side of the screen to full-on carcinoma. Through this process, there are predictable sides to genetic mutation that allows hyper-proliferation forming a polyp eventually degrading to a carcinoma. Let’s look at some of this in detail. First mutation that occurs is an APC tumor suppressor gene. This allows tumor initiation.

    00:41 Now remember, tumor suppressor genes which we have a lot of, its main job is to suppress overgrowth.

    00:49 Next, K-Ras is a proto-oncogene. K-Ras proto-oncogene mutation alone only causes hyperplastic syndrome.

    00:59 But if it follows APC in this predictable line of mutations, it leads to colon cancer. Scientists are still working on why the K-Ras in this context leads to colon cancer versus the mutation alone that only leads to hyperplastic polyps. This then progress to a deleted in colorectal cancer which is yet another tumor suppressor gene, and finally the p53 which leads to apoptosis.

    01:28 Mutations of p53 then allow a cancer phenotype. Let’s review for a second, another question.

    01:38 What’s the difference between Lynch syndromes 1 and 2? I’ll give you a second to think about this.

    01:46 That’s right. Lynch syndrome 1 again is a familial colon cancer without extracolonic manifestations versus Lynch syndrome 2, it’s associated with other cancers particularly of the GI and reproductive tumors.

    02:02 Amsterdam criteria is an important set of criteria for the diagnosis of Lynch syndrome or hereditary nonpolyposis. This is the classic definition. Three relatives with colon cancer over two generations.

    02:18 At least one of which was diagnosed at a fairly young age. There have been subsequent iterations of this diagnosis. But the bottom line is fairly similar in that we want to see multiple young people diagnosed with colon cancer in a family over multiple generations suggestive of number 1, a genetic mutation, and 2, potentially an autosomal dominance. Here’s Amsterdam criteria II. Amsterdam criteria II liberalized the definitions a little bit. Here, the requirements that there should be at least three relatives with any Lynch syndrome-associated cancer, be it colorectal, cancer of the endometrium, small bowel, ureter, or renal pelvis. One should be a first-degree relative of the other two; at least two successive generations much like the original definition; and at least one should be diagnosed before the age of 50, again very familiar to you. Remember that FAP should be excluded in colorectal cancer cases if any tumors should be verified by pathologic examination. Yet, another criteria, they call the Bethesda criteria is also used for Lynch syndromes. In the Bethesda criteria, colorectal cancer diagnosed in a patient who is less than 50 years of age, there has to be a presence of synchronous or metachronous colorectal, synchronous or metachronous meaning at the same time or at different times, or other nonpolyposis-associated tumors regardless of age. That the colorectal cancer with a gene repair mutation and histology diagnosed in a patient who’s less than 60 years of age. The colorectal cancer diagnosed in a patient with one or more first-degree relatives in a nonpolyposis-related tumor. And lastly, that the colon cancer is diagnosed in a patient with two or more first or second-degree relatives.

    04:14 Basically different spins on the same criteria of multiple relatives, multiple generations, and diagnosis early on. What are some physical findings on colorectal cancer? Unfortunately, the vast majority of patients do not have a classic profile of physical findings that will allow us, clinicians, to detect it early on.

    04:35 That’s why screening is so important. Usually, there’s no pain. Maybe there’s bleeding, maybe a large bowel obstruction. That’s why due to colonoscopy, early detection is the most important thing that we can offer to our patient. By the time you wait for classic physical findings of bleeding and obstruction, it's likely that the colorectal cancer has already progressed into late stages. We now consider colon surgery preventable due to screening and because of the predictable deterioration from a polyp to cancer in the polyp-cancer sequence. Again, no set of routine labs is indicative of colorectal cancer.

    05:18 One may find a drop in the hemoglobin, hematocrit due to a slow bleed. We oftentimes get a CEA or carcinoembryonic antigen both before and after surgery. We don’t use that as a screening tool however.

    05:34 But it is very useful as a follow-up after treatment for detection of recurrences.


    About the Lecture

    The lecture Polyp-Cancer Sequence by Kevin Pei, MD is from the course General Surgery.


    Included Quiz Questions

    1. APC --- K-ras --- TP53
    2. APC --- TP53 --- K-ras
    3. K-ras --- TP53 --- APC
    4. K-ras --- APC --- TP53
    5. TP53 --- APC --- K-ras
    1. APC gene mutation; tumor progression
    2. K-ras mutation alone; colon cancer
    3. K-ras mutation following APC gene mutation; hyperplastic syndrome
    4. DDC gene deletion; tumor suppression
    5. P53 mutation; apoptosis of deleterious cells
    1. A patient has three relatives with colon cancer over two successive generations, one of which was diagnosed at the age of 35.
    2. A patient has two relatives with colon cancer over two successive generations, both of which were diagnosed before the age of 50.
    3. A patient has three relatives with colon cancer over three successive generations, all of which were diagnosed after the age of 65.
    4. A patient has three relatives with colon cancer over three successive generations, all of which were diagnosed before the age of 50.
    5. A patient has 1 relative with colon cancer over two generations, who was diagnosed at the age of 74.
    1. A patient with a family history of mother with endometrial cancer, two cousins with non familial adenomatous polyposis colon cancer who were both diagnosed before the age of 50.
    2. A patient with a family history of grandfather with colorectal cancer and a brother with renal cancer diagnosed at the age of 48.
    3. A patient with a family history of mother, grandmother, and sister all affected by breast cancer before the age of 60.
    4. A patient with a family history of two brothers and a father all with familial adenomatous polyposis colon cancer.
    5. A patient with a family history of a grandfather with colorectal cancer diagnosed at the age of 68, a brother with small bowel cancer diagnosed at the age of 52, and a third cousin with lung cancer diagnosed at the age of 48.
    1. ...prostate cancer.
    2. ...small bowel cancer.
    3. …endometrial cancer.
    4. ...ureter cancer.
    5. ...renal pelvis cancer.
    1. Colorectal carcinoma with high microsatellite instability astrologically diagnosed in a patient less than 50 years old.
    2. Colorectal carcinoma diagnosed in a patient who is less than 50 years old.
    3. The presence of synchronous or metachronous colorectal carcinoma or other Lynch syndrome-associated tumors.
    4. Colorectal carcinoma diagnosed in one or more first-degree relatives with a Lynch syndrome-associated tumor.
    5. Colorectal carcinoma diagnosed in two or more first-degree or second-degree relatives with Lynch syndrome-associated tumors, regardless of age.

    Author of lecture Polyp-Cancer Sequence

     Kevin Pei, MD

    Kevin Pei, MD


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