A Review Of Hereditary Colorectal Cancers

Miguel Medina Pabón; Hani Babiker

A Review Of Hereditary Colorectal Cancers

Introduction

Colorectal cancer (CRC) is the fourth leading cause of death in the world. It has links with inappropriate food habits such as low consumption of fruits, vegetables, fiber, fish, vitamin C, dairy products, vitamin D and with high consumption of foods containing heme-iron (red and processed meat). Moreover, poor lifestyles such as high alcohol consumption, obesity and lack of exercise are other factors that increase its incidence. The inherited CRC syndromes are a series of diseases that have specific mutations that predispose to CRC, so these are more aggressive and have a worse prognosis since they correlate with other tumors and some do not respond to chemotherapy. Early diagnosis is a challenge for physicians due to the absence of pathognomonic clinical findings. The evidence shows that 50% of the patients are asymptomatic and usually present with symptoms (such as rectal bleeding, weight loss, and intestinal obstruction) when the disease is already advanced. Familial adenomatous polyposis (FAP) and syndromes not associated with polyposis, such as Lynch syndrome, are the most common cause of the onset of hereditary syndromes. When considered together, they represent 6 to 10% of all cases of CRC.[1] Estimates are that tumors found in young adults are related to hereditary CRC syndromes. This article will review the most common genetic syndromes in the development in CRC and the medical-surgical treatment approach according to current evidence.

Etiology

Hereditary colorectal cancer (HCRC) is not a single disease; it is a group of diseases or syndromes, which have a mutational genetic component; these generate a clinically differentiated phenotype. It subdivides into two large HNPCC groups and the HPCC:

1. Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant cancer syndrome; the incidence of this syndrome is 1.7 to 4.2% among all CRCs patients, (represents 3 to 8 cases per million inhabitants in the world, according to Globocan 2018).[2][3]

Lynch syndrome (LS) is the commonest of hereditary cancers and correlates with an increased risk of colorectal, endometrium, ovary, stomach, and small bowel cancer. LS has associations with mutations of DNA mismatch repair (MMR)as MLH1(76%), MSH2(40%), MSH6, PMS2, and EPCAM.[4] LS is incidence represents 3 to 5 cases per million inhabitants, according to Globocan 2018).[5]
Sporadic colorectal carcinomas, MLH1-/PMS2-deficient.[6]
Muir-Torre syndrome:( The genes most commonly mutated MLH1, MSH2, MSH6, and PMS2). It is incidence represents 2 cases per ten million inhabitants, according to Globocan 2018).[7]
Turcot syndrome type I: The frequency is approximately 20% to 25% among all TS. It is related to mutations of the MMR gene.[8]

2. Hereditary polyposis colorectal cancer (HPCC) accounts for approximately 3 to 5 % of all CRC cases.[9][10] (represents 5 to 9 cases per million inhabitants in the world, according to Globocan 2018).

Familial adenomatous polyposis (FAP) is related to the germline mutations of the APC gene. FAP is incidence represents 2 to 3 cases per million inhabitants, according to the data from the Danish Polyposis Registry 2017.[11]
Adenomatous polyposis syndromes (APC and MUTYH).[12]
Juvenile polyposis coli: (BMPR1A and SMAD4).[13] It is estimated the incidence of 1 per one million inhabitants.[14][15]
Peutz-Jeghers syndrome: (STK11/LKB1), is incidence represents 1.2 per one million inhabitants.[16][17]
PTEN hamartoma tumor syndrome: (PHTS; PTEN).[18]
Cowden syndrome:(affecting the PTEN-gene).[19] It is incidence represents 6 cases per ten million inhabitants.[20][21][22]
Turcot syndrome type II: The frequency is approximately 75% to 80% among all TSs. It is related to the APC gene mutation.[23]
Gardner syndrome: (involved APC gene).[24] It is incidence represents 1 per one million people within the United States.[24]

Epidemiology

Colorectal cancer (CRC) is the third cause of all cancers and the fourth cause of death in the world. Estimated age-standardized incidence and mortality rates in 2018, worldwide, both sexes, all ages is 19.7 per 100000 inhabitants, and the mortality rate is 8.9 per 100000 patients, according to Globocan. The incidence increases significantly by six times when it is related to obesity.[25] The hereditary CRC occur in those individuals with a family history of colorectal cancer who do have characteristics of familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer, the most common being Lynch syndrome.[4] These are detected in 6 to 10% of all CRC, diagnosed before age 50,[26] that is, its incidence would be 2 per 100000 inhabitants in the world population.[1] The risk of advanced neoplasia after a small tubular adenoma in the initial colonoscopy is four times higher when the patient is positive in a fecal immunochemical test.[27] Additionally, the relative risk of colorectal cancer is higher when patients have a history of colon cancer as opposed to rectal cancer.[28]

Pathophysiology

The mutational mechanisms associated with CCR are:

Genomic instability:
- Instability Chromosome: is the most common type found in 85% of the CRC.[29] This mutation causes the loss of heterozygosity in tumor suppressor genes and mutations in proto-oncogenes.[30] Mutations affect the following genes: APC, TP53 and K-ras, allelic loss of 18q and aneuploidy. For example, FAP develops cancer from this route (CRC risk 90% without colectomy and risk of extracolonic cancers 10 to 99 adenomas).[31] There are many mutations in the APC gene (this is a large “housekeeping” gene), include micro-deletions and frameshift mutations, and more than 60% of the mutations are present at the 5′ end of the exon, on the 5q21 chromosome.[32]
- Microsatellite instability: It is present in 15% of CRC.[29] It is caused by errors in the repair system due to DNA damage (MMR), mainly due to failure in base complementarity, which generates the expansion of short sequences in tandem and an increase in the number of mutations. The MMR system is made up of seven genes: hMLH1, hMLH3, hMSH2, hMSH3, hMSH6, hPMS1, and hPMS2; Currently, more than 500 different mutations have been described.[33] For example, LS progresses to cancer from the aforementioned (Lifetime risk of CRC 70%).[31] Cumulative incidence at 75 years for colorectal cancer were 46%, 43% and 15% in path MLH1, MSH2, and MSH6 carriers, respectively.[34]
Epigenetic (DNA methylation) Methylation of CpG islands occurs in sporadic CRC 15%,[35] and also it affects the expression of DNA repair genes or Mismatch genes.[36]

History and Physical

We will focus on the two most frequent pathologies of hereditary colorectal cancer according to the polyposis classification:

1. (HNPCC) -Lynch syndrome (LS): Characteristically presents with flat polyps, located in the right colon, which generate CRC and other cancers (endometrium, stomach, ovary, pancreas, ureter and renal pelvis, cerebral glioblastoma, biliary tract, cancer of the small intestine, sebaceous carcinomas and keratoacanthomas). Endometrial cancer occurs in relatively young women.[37] The diagnosis is a challenge for the doctor due to the absence of pathognomonic clinical signs, and a genetic study is required to establish the definitive diagnosis, so it is recommended to make a previous selection of these patients with the criteria of Bethesda and Amsterdam.[38]

2. (HPCC) -Familial adenomatous polyposis (FAP): It is characterized by hundreds or thousands of precancerous adenomatous polyps, which generates CRC and other cancers, Also, may occur extracolonic manifestations (desmoid tumor, osteomas, epidermoid cysts, papillary thyroid carcinoma, pancreatic carcinoma, gastric cancer, duodenal cancer, hepatobiliary and CNS tumors), this is due to mutations in the gene (APC), which controls cell proliferation and the regulation of a new long non-coding RNA (lncRNA).[39] It is classified clinically in two ways:

Classic FAP: Consists of the involvement of the entire colon with the appearance of 100 to 1000 adenomatous polyps, the age of onset of polyps comprises between 10 and 20 years of age; estimates are that the diagnosis of CRC corresponds to 30 to 40 years of age,[40] It correlates with the majority of cancers described above, which increases comorbidity.[41]
Attenuated FAP: Frequently affects the right colon, with an appearance of 10 to 100 adenomatous polyps, the age of onset of polyps between 20 to 30 years of age, estimates are that the diagnosis of CRC corresponds to 40 to 50 years of age. It commonly carries associations with gastric, duodenal, and thyroid cancer.[42][43]

Evaluation

The diagnostic basis of hereditary CRC is from clinical findings, family history, genetic tests, and diagnostic images.

1. The physical examination: Should include evaluation of adenopathies mainly supraclavicular, cervical and axillary, digital rectal examination, abdominal palpation in search of masses or ascites, hepatomegaly suggesting a hepatic metastatic compromise.

2. Total colonoscopy: It is a gold standard technique since it allows the resection and biopsy of the lesions observed during the procedure.[44] Moreover, endoscopy with a colonic capsule is a promising technique for noninvasive colon screening; however, it is a risk to detect polyps and not be able to biopsy them.[45]

3. Family history: with more than one criteria raises suspicion of LS.

Modified Bethesda criteria, which are[46]:
- Patients with CRC who belong to families that meet the criteria of Amsterdam.
- Patients with two neoplasms associated with HNPCC, including synchronous or metachronous CRC and extracolonic cancer (endometrium, ovary, gastric, hepatobiliary, small intestine, ureter or renal pelvis)
- Patients with CRC and a first degree relative with CRC, extracolonic neoplasm associated with HNPCC or colorectal adenoma; one of the cancers diagnosed before 50 years of age and the adenoma before of 40 years of age.
- Patients with CRC or endometrial cancer diagnosed before 50 years of age.
- Patients with CRC located in the right colon and histologically undifferentiated, diagnosed before 50 years of age.
- Patients with CCR-type cells in the signet ring (composed of more than 50% of signet ring cells) diagnosed before 50 years of age.
- Patients with colorectal adenoma diagnosed before 40 years of age.

Amsterdam criteria II, which are[47]:
- Three or more relatives affected by a neoplasm associated with HNPCC (CRC, cancer of the endometrium, small intestine, ureter or renal pelvis), one of them being a first-degree relative of the other two, and;
- Two or more successive generations affected, and;
- One or more relatives affected by CRC diagnosed before 50 years of age, and;
- Exclusion of FAP in cases of CCR.

4. Molecular and genetic testing: LS Diagnosis is made by tumor testing with MMR immunohistochemistry and PCR for MSI (microsatellite instability), a genetic phenotype that characterizes these tumors. Therefore, having a positive genetic test (MSI), a positive Bethesda or Amsterdam item and the tumor located on the right side of the colon, are highly suspicious findings of Lynch syndrome.[48] When colonic polyposis presents in a single person with a negative family history, consideration should be to test for a de novo APC mutation; if negative follow with MUTYH genetic testing when colonic polyposis is present only in siblings, consider recessive inheritance and test for MUTYH first.[39]

5. Diagnostic Imaging: It is suggested to perform computed tomography with contrast of chest, abdomen, and pelvis to estimate the stage of the disease to all patients with colorectal cancer. Additional, It is suggested to perform computed tomography or magnetic resonance imaging of the pelvis to assess the status of the mesorectal margin in selected cases.

Differential Diagnosis

Gardner syndrome: is a variant of FAP, is an autosomal dominant inherited disease characterized by multiple intestinal polyps together with extra-intestinal manifestations including multiple osteomas, connective tissue tumors, thyroid carcinomas, hypertrophied pigmented epithelium of the retina, and also frequent retained supernumerary teeth and odontomas.[24] This condition carries a high risk of developing colon cancer.[64]

Muir-Torre syndrome: MTS is a rare subtype of LS characterized by the presence of sebaceous neoplasms of the skin and visceral malignancies with colonic carcinoma being the most common.[65]

Turcot syndrome: TS is the association of primary brain tumors. It divides into two subtypes: TS type I (Intestinal polyps are large, fewer in number than 100, and are apt to undergo a malignant change. Associated brain tumor is usually a glioblastoma or an astrocytoma.) and TS type II (Familial adenomatous polyposis-associated type. There is a predisposition to development of medulloblastoma.)[66] Tumors can also arise from the spinal cord, manifesting with symptoms of spinal cord compression.[67]

Juvenile polyposis coli: JPC is a rare disease characterized by the presence of juvenile hamartomatous polyps in the gastrointestinal tract. The lifetime risk of CRC is 20%.[68] JPC is diagnosed with the presence of more than five juvenile polyps in the colon and/or rectum; the presence of juvenile polyps along the digestive tract, including the stomach; the presence of any number of juvenile polyps in association with a family history of JIP.[69] Clinical signs include isolated rectal bleeding, anemia, abdominal pain, intestinal invaginations, diarrhea, rectal prolapse, and spontaneous anal elimination of polyps in juvenile polyposis coli and generalized juvenile polyposis. Other associated signs may include growth retardation and edema.[70]

Peutz-Jeghers Syndrome: PJS is characterized by pigmentation of mucocutaneous melanin and multiple gastrointestinal polyposis. The clinical manifestations mainly included black spots, abdominal pain, and anemia.[71] These polyps have a higher risk of developing GI cancers of the colorectal, pancreatic and gastric organs, in addition to a wide variety of non-GI epithelial malignancies, such as cancers of the breast, uterus, cervix, ovary, testicular and lung. The lifetime risk of CRC is 39%.[72] Patients with PJS present a high risk of intussusception and should receive regular follow-up due to the high risk of cancer and the possibility of relapse.[73]

Hamartoma tumor syndrome: This is called PTEN (PHTS).[74] PTEN correlates with multiple benign diseases (macrocephaly, Hashimoto's thyroiditis, mucocutaneous hamartomas, colon polyps, and vascular malformations) and malignant tumors (breast, thyroid, renal, endometrial and colon cancer),[74] as well as neurodevelopmental disorders such as autism.[75] PHTS patients may also demonstrate an increased risk of immunological dysregulation, including autoimmunity and immune deficiencies.[18]

Cowden syndrome: CS classically is characterized by multiple hamartomas that can occur in any organ, macrocephaly, mucocutaneous lesions, and an increased risk of breast and thyroid cancers, ovarian, colon cancer. The lifetime risk of CRC 13%.[21][76]

Bannayan-Riley-Ruvalcaba syndrome: BRRS is a congenital disorder that is frequently characterized by hamartomatous intestinal polyps, lipomas, macrocephaly, and genital lentiginosis. BRRS patients with a PTEN mutation share the same risk of developing cancer as patients with CS.[77]

Proteus syndromes: PS is a disorder characterized by progressive excessive growth at the level of the skeleton, skin, fat and central nervous system, with few hamartomatous polyps. Complications include hemimegaencephaly, bullous lung disease, pulmonary embolism, and deep vein thrombosis. The tumors are usually benign, although there are reports of rare cases of malignant tumors.[78]

Solamen syndrome: The term 'SOLAMEN syndrome' "Segmental Overgrowth, Lipomatosis, Arteriovenous Malformation, and Epidermal Nevus." These patients are carriers of germline mutations in the phosphatase and PTEN homologs.[79]

Prognosis

In their study, Lee and his colleagues indicated that those with sporadic colorectal cancer (CRC) and a family history of CRC had better overall survival but a cancer recurrence similar to those who did not have CRC family history.[80]
CRC survivors (5 to 10 years post-diagnosis) reported overall good health-related quality of life but significantly poorer social functioning and more problems with dyspnea, constipation, diarrhea, and finances than controls; mainly among younger subjects.[81]

Complications

Severe complications during colonoscopy represent the most important adverse effect of colorectal cancer screening programs. The immediate complication occurred in 3.3%, as perforation and hemorrhagic events. However, the following factors increase the risk of early and late complications, including a history of colon disease, a history of anticoagulation, a history of pelvic surgery or abdominal radiotherapy, and a history of perforation.[82]
After a total colectomy, systemic complications can occur in 22%, mainly in those older than 65 years due to significant comorbidities, while the incidence of surgical complications was 8%, such as anastomotic leakage, major infections in the wound, and postoperative hemorrhage.[83]

Deterrence and Patient Education

There is a need for educational efforts to raise awareness about CRC, particular in the young. There is also a need to improve adherence to screening in young patients eligible for screening, and to emphasize early evaluation of symptoms. These are essential steps to decreasing the burden of CRC in younger patients.[84]
Good lifestyle and dietary habits are recommended, to reduce the most critical factor in colorectal carcinogenesis starting in the early stages of life.[85]

Enhancing Healthcare Team Outcomes

An interprofessional approach includes a gastroenterologist, oncologist, colorectal surgeon, primary care provider, nurse practitioner, and a geneticist.
Consider offering genetic testing to people with suspected hereditary colorectal cancer and their family members, after genetic counseling.[86]
Suggestions are that in individuals with a family history in the first degree of classical FAP, the screening strategy is annual colonoscopy from 12 to 15 years, up to 30 to 35 years of age and then it is suggested to continue screening every five years.[87][88]
In the population with suspicion or family history of HNPCC, suggestions are that the screening strategy is colonoscopy every two years, from 20 to 25 years, or five to ten years before the age of the youngest case diagnosed in the family.[89][90]
Studies consistently report that registration and screening result in a reduction of CRC incidence and mortality in patients with FAP and LS.[91][Level II]
The MSI test is an effective screening test for Lynch syndrome. However, it must correlate with the panel of markers used or the thresholds used to denote a positive test.[92][Level II]
The studies indicate that in adenomatous polyposis coli patients with APC promoter, hypermethylation is an early event in carcinogenesis of CRC and could be a valuable diagnostic marker for early-stage CRC.[93][94][Level II]
Currently, the evidence of chemoprevention is for NSAIDs, sulindac, and aspirin in low doses that reduce the progression of polyps and reduce the long-term incidence of colorectal cancers, in patients with FAP and HNPCC, respectively.[95] [Level II]
Strict vigilance is necessary for the syndromes associated with CCR and extracolonic manifestations, especially LS with endometrial cancer, as well as those mentioned in the differential diagnosis section.[96]
The risk factors that increase mortality are advanced age, male sex, African-American race, elevated CEA and not undergoing curative surgery. Likewise, patients with CRC have an association with an increased risk of cardiovascular death, especially during the first year after diagnosis.[97][Level II]
Overall, FOLFOX was the most effective first-line treatment [Level I], and FOLFIRI plus cetuximab (KRAS/NRAS wild) was the most effective treatment in terms of long-term survival, Wang and colleagues, in their analysis of 75 RCTs published after 1997. This treatment is preferable for patients with CRC in clinical practice.[98][Level I]
The use of bevacizumab represents hope for increased survival and a chance of metastasectomy for patients with metastatic CRC. However, there are serious adverse events associated with its use, especially severe hypertension and gastrointestinal perforation, that merit consideration.[99][Level I]
The treating physician should recommend a diet rich in dietary fiber because it decreases CRC risk and post-operative relapses.[100][101][102] Currently, there is inadequate data to support the benefits of exercise in the field of colorectal surgery.[103][104][Level III]

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Main sites of metastases for common cancer types, Brain, Skin Melanoma, Bone Metastases, Lung Metastases, Breast Cancer, Adrenal gland metastases, Pancreas cancer, Colorectal cancer, Ovarian cancer
Contributed by Wikimedia Commons,"Medical gallery of Mikael Häggström 2014" (Public Domain)

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Colorectal Carcinoma Screening Gu
Colorectal Carcinoma Screening Gu

Article Details

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