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Fundamentals of Rectal Cancer SurgeryFundamentals of Rectal Cancer Surgery

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Rectal Cancer Biology and Hereditary Cancer Syndromes

Rectal Cancer Biology and Hereditary Cancer Syndromes is a topic covered in the Fundamentals of Rectal Cancer Surgery.

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ASCRS U Education Portal is the one-stop place for all things related to colorectal surgery. Provided by the American Society of Colon & Rectal Surgeons. Powered by Unbound Medicine. Explore these free sample topics:

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Rectal Cancer Biology

Pathogenesis of Colorectal Cancer

Our understanding of the genetic and molecular changes leading to the development of colorectal cancer (CRC) continues to evolve. A complex system of checks and balances maintains normal colorectal mucosa homeostasis and integrity during cell division and replication. Alterations in these mechanisms can lead to malignant change (Figure 2.1). In general, colorectal cancer results from a multistep process that entails the accumulation of genetic and epigenetic changes over time. Mutations in oncogenes may result in over-expression of a gene or pathway, leading to constitutive cellular signaling or proliferation. Conversely, mutations or loss of tumor suppressor genes may remove an inhibitory signal that produces uncontrolled cell growth. Furthermore, mutations in caretaker genes may lead to oncogenesis by losing the ability to induce apoptosis or repair damaged DNA. The underlying genetic and epigenetic changes leading to colorectal cancer influence the disease course including clinical phenotype, prognosis, and response to therapy. Clinical management and research must be executed with the knowledge that colorectal cancer is not a single entity but rather a heterogeneous disease, different in each person.[1]

Figure 2.1
Descriptive text is not available for this image

At least three major molecular pathways have been described for the development of colorectal cancer: 1) chromosomal instability; 2) microsatellite instability, and; 3) methylator phenotype. Each pathway has unique characteristics, but there is some overlap between the pathways and two or more pathways may co-exist in the same patient.[1]

Chromosomal instability is the most common form of genomic instability in colorectal cancer, accounting for about 75% of all colorectal cancers.[2] Chromosomal instability refers to an alteration in the chromosome copy number or structure. Physical loss of a chromosome segment may delete entire genes and produce loss of heterozygosity for those genes. That is, when one allele is lost, only one functional copy of the gene exists and there is no longer redundancy for that gene. Loss of the second allele then results in complete loss of that gene function (Figure 2.2). Adenomatous polyposis coli (APC) and p53 are examples of tumor suppressor genes, whose loss via this mechanism results in chromosomal unstable colorectal cancer. The traditional adenoma-to-carcinoma sequence as described by Vogelstein and Fearon is characterized by the accumulation of genetic changes over time and the prototypical chromosomal instability colorectal cancer.[3] Clinically, colorectal cancers arising via chromosomal instability tend to arise in the left colon, have male predominance, and develop later in life. Genetically, key genes mutated in this pathway include adenomatous polyposis coli (APC), KRAS, and p53.[2]

Figure 2.2
Descriptive text is not available for this image

The APC gene, a tumor suppressor, has been called the gatekeeper gene because it is the key initiating step to malignant transformation for many colorectal adenocarcinomas. The APC protein regulates the WNT signaling pathway via intracellular binding of β-catenin.[2] Mutations in the APC gene lead to transcription of no protein or a protein without normal function. Decreased quantity or function of APC protein allows for intracellular accumulation of β-catenin and thus its increased translocation into the nucleus where it serves as a transcription factor responsible for proteins involved in cell signaling, proliferation, and cell-to-cell adhesion.

KRAS is an oncogene involved in the mitogen-activated protein kinase (MAPK) pathway whose upstream signaling receptor is the epidermal growth factor receptor (EGFR).[2] This pathway drives nuclear transcription of cellular proliferation. Oncogenic mutations turn on the KRAS signal and drive uncontrolled cell growth, regardless of upstream signaling. Mutant KRAS proteins provide constitutive MAPK signaling, and upstream blockage of EGFR is ineffective in blocking MAPK. KRAS mutations are present in nearly 40% of colorectal cancer.[4] In practical terms, the tumor should be tested for the KRAS mutation if the patient is being considered for anti-EGFR therapy.

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Rectal Cancer Biology

Pathogenesis of Colorectal Cancer

Our understanding of the genetic and molecular changes leading to the development of colorectal cancer (CRC) continues to evolve. A complex system of checks and balances maintains normal colorectal mucosa homeostasis and integrity during cell division and replication. Alterations in these mechanisms can lead to malignant change (Figure 2.1). In general, colorectal cancer results from a multistep process that entails the accumulation of genetic and epigenetic changes over time. Mutations in oncogenes may result in over-expression of a gene or pathway, leading to constitutive cellular signaling or proliferation. Conversely, mutations or loss of tumor suppressor genes may remove an inhibitory signal that produces uncontrolled cell growth. Furthermore, mutations in caretaker genes may lead to oncogenesis by losing the ability to induce apoptosis or repair damaged DNA. The underlying genetic and epigenetic changes leading to colorectal cancer influence the disease course including clinical phenotype, prognosis, and response to therapy. Clinical management and research must be executed with the knowledge that colorectal cancer is not a single entity but rather a heterogeneous disease, different in each person.[1]

Figure 2.1
Descriptive text is not available for this image

At least three major molecular pathways have been described for the development of colorectal cancer: 1) chromosomal instability; 2) microsatellite instability, and; 3) methylator phenotype. Each pathway has unique characteristics, but there is some overlap between the pathways and two or more pathways may co-exist in the same patient.[1]

Chromosomal instability is the most common form of genomic instability in colorectal cancer, accounting for about 75% of all colorectal cancers.[2] Chromosomal instability refers to an alteration in the chromosome copy number or structure. Physical loss of a chromosome segment may delete entire genes and produce loss of heterozygosity for those genes. That is, when one allele is lost, only one functional copy of the gene exists and there is no longer redundancy for that gene. Loss of the second allele then results in complete loss of that gene function (Figure 2.2). Adenomatous polyposis coli (APC) and p53 are examples of tumor suppressor genes, whose loss via this mechanism results in chromosomal unstable colorectal cancer. The traditional adenoma-to-carcinoma sequence as described by Vogelstein and Fearon is characterized by the accumulation of genetic changes over time and the prototypical chromosomal instability colorectal cancer.[3] Clinically, colorectal cancers arising via chromosomal instability tend to arise in the left colon, have male predominance, and develop later in life. Genetically, key genes mutated in this pathway include adenomatous polyposis coli (APC), KRAS, and p53.[2]

Figure 2.2
Descriptive text is not available for this image

The APC gene, a tumor suppressor, has been called the gatekeeper gene because it is the key initiating step to malignant transformation for many colorectal adenocarcinomas. The APC protein regulates the WNT signaling pathway via intracellular binding of β-catenin.[2] Mutations in the APC gene lead to transcription of no protein or a protein without normal function. Decreased quantity or function of APC protein allows for intracellular accumulation of β-catenin and thus its increased translocation into the nucleus where it serves as a transcription factor responsible for proteins involved in cell signaling, proliferation, and cell-to-cell adhesion.

KRAS is an oncogene involved in the mitogen-activated protein kinase (MAPK) pathway whose upstream signaling receptor is the epidermal growth factor receptor (EGFR).[2] This pathway drives nuclear transcription of cellular proliferation. Oncogenic mutations turn on the KRAS signal and drive uncontrolled cell growth, regardless of upstream signaling. Mutant KRAS proteins provide constitutive MAPK signaling, and upstream blockage of EGFR is ineffective in blocking MAPK. KRAS mutations are present in nearly 40% of colorectal cancer.[4] In practical terms, the tumor should be tested for the KRAS mutation if the patient is being considered for anti-EGFR therapy.

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Last updated: November 22, 2021

Citation

"Rectal Cancer Biology and Hereditary Cancer Syndromes." Fundamentals of Rectal Cancer Surgery, 2021. ASCRS U, www.ascrsu.com/ascrs/view/Fundamentals-of-Rectal-Cancer-Surgery/2831002/all/Rectal Cancer Biology and Hereditary Cancer Syndromes.
Rectal Cancer Biology and Hereditary Cancer Syndromes. Fundamentals of Rectal Cancer Surgery. 2021. https://www.ascrsu.com/ascrs/view/Fundamentals-of-Rectal-Cancer-Surgery/2831002/all/Rectal Cancer Biology and Hereditary Cancer Syndromes. Accessed March 21, 2023.
Rectal Cancer Biology and Hereditary Cancer Syndromes. (2021). In Fundamentals of Rectal Cancer Surgery https://www.ascrsu.com/ascrs/view/Fundamentals-of-Rectal-Cancer-Surgery/2831002/all/Rectal Cancer Biology and Hereditary Cancer Syndromes
Rectal Cancer Biology and Hereditary Cancer Syndromes [Internet]. In: Fundamentals of Rectal Cancer Surgery. ; 2021. [cited 2023 March 21]. Available from: https://www.ascrsu.com/ascrs/view/Fundamentals-of-Rectal-Cancer-Surgery/2831002/all/Rectal Cancer Biology and Hereditary Cancer Syndromes.
* Article titles in AMA citation format should be in sentence-case
TY - ELEC T1 - Rectal Cancer Biology and Hereditary Cancer Syndromes ID - 2831002 Y1 - 2021/11/22/ BT - Fundamentals of Rectal Cancer Surgery UR - https://www.ascrsu.com/ascrs/view/Fundamentals-of-Rectal-Cancer-Surgery/2831002/all/Rectal Cancer Biology and Hereditary Cancer Syndromes DB - ASCRS U DP - Unbound Medicine ER -
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Grapherence® [↑21]
    • Fundamentals of Rectal Cancer Surgery
    • Background
    • Rectal Anatomy
    • Rectal Cancer Biology and Hereditary Cancer Syndromes
    • Rationale for Multi-Modality Therapy
    • Preoperative Issues
    • Preoperative Staging
    • Role of Tumor Board
    • Indications for Preoperative Neoadjuvant Therapy
    • Local Excision
    • Indications for LAR Versus Intersphincteric Resection Versus APR
    • Indications for Extended Resection
    • Preoperative Preparation
    • Interoperative
    • Patient Positioning and Equipment for Rectal Cancer Surgery
    • Inferior Mesenteric Artery
    • Inferior Mesenteric Vein (IMV)
    • Splenic Flexure Mobilization
    • Surgical Techniques for Length
    • Technique of Total Mesorectal Excision (TME)
    • Tailored Mesorectal Excision (TME)
    • Bowel Transection and Anastomosis
    • Indications for Fecal Diversion
    • Abdominoperineal Resection
    • Standardized Operative Report
    • Management of Intraoperative Vascular and Urinary Complications
    • Postoperative Issues
    • Rectal Cancer Pathology Assessment
    • Adjuvant Therapy for Rectal Adenocarcinoma
    • Surveillance After Rectal Cancer Treatment
    • Management of Local Recurrences
    • Short-Term Complications - Anastomotic
    • Short-Term Complications - Urinary
    • Ostomy Complications and Management
    • Long-Term Complications – Bowel Dysfunction
    • Long-Term Complications - Sexual Dysfunction and Its Management
    • Parastomal and Perineal Hernias
    • Impact of Postoperative Complications On Oncologic Outcomes
    • Course Complete
    • Final Assessment
Grapherence® [↑21]
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