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Familial Colorectal Cancer

Familial colorectal cancer (FCC) is a general term that may refer to colorectal cancer arising within the scope of Lynch syndrome, polyposis syndromes, or other, as-of-yet undefined genetic conditions. Mutations in genes encoding for mismatch repair proteins give rise to Lynch syndrome, the best defined and most common variant of FCC, but there are many combinations of low-penetrance genes that may result in an increased familial incidence of malignancies in the colon or rectum. In these cases, the only evidence of a genetic predisposition is often found in the family history.


Presentation

Patients developing FCC tend to remain asymptomatic for prolonged periods of time, and in almost half of all cases, the disease does not clinically manifest until metastases have formed [1]. Possible symptoms of FCC comprise non-specific gastrointestinal complaints such as abdominal pain, a feeling of intestinal pressure that is not relieved by bowel movements, diarrhea or constipation, hematochezia, and rectal bleeding. In advanced stages of the disease, patients may report fatigue and weakness, possibly exaggerated by anemia, as well as unintended weight loss.

Additional symptoms may result from comorbidities, which are especially frequent in patients with syndromic FCC [2].

Fatigue
  • […] about Colorectal Cancer prevention For more information see Puerto Rico Central Cancer Registry Colorectal cancer symptoms Change in bowel habits (diarrhea or constipation) Blood on the stool Thin stool Nausea and vomiting Abdominal pain Weight loss and fatigue[purificar.rcm.upr.edu]
  • In advanced stages of the disease, patients may report fatigue and weakness, possibly exaggerated by anemia, as well as unintended weight loss.[symptoma.com]
  • Healthy Lifestyles Physical Activity Nutrition and Weight Management Supplement Use Immunizations and Infections Late Effects/Long-Term Psychosocial and Physical Problems Anthracycline-Induced Cardiac Toxicity Anxiety and Depression Cognitive Function Fatigue[nccn.org]
  • […] intestinal bleeding (hematochezia, melena), changes in bowel habit (constipation and/or diarrhea), constitutional syndrome (weight loss, anorexia and/or asthenia), anorectal symptoms (pain, tenesmus), abdominal-related (pain, mass), unspecific symptoms (fatigue[journals.plos.org]
  • Patients should be asked about symptoms of hemodynamic compromise, including dyspnea, chest pain, lightheadedness, and fatigue. [7] Physical findings [ edit ] Orthostatic hypotension implies at least a 15% loss of blood volume and suggests a more severe[en.wikipedia.org]
Accelerated Growth
  • Patients known to be at risk for FCC should be examined by colonoscopy every 1–2 years, so tumors can be identified and monitored for accelerated growth and a possible malignant degeneration.[symptoma.com]
Abdominal Pain
  • View an educational video about Colorectal Cancer prevention For more information see Puerto Rico Central Cancer Registry Colorectal cancer symptoms Change in bowel habits (diarrhea or constipation) Blood on the stool Thin stool Nausea and vomiting Abdominal[purificar.rcm.upr.edu]
  • Possible symptoms of FCC comprise non-specific gastrointestinal complaints such as abdominal pain, a feeling of intestinal pressure that is not relieved by bowel movements, diarrhea or constipation, hematochezia, and rectal bleeding.[symptoma.com]
  • Results : The patients were predominantly male, mainly presenting with rectal bleeding intestinal obstruction or abdominal pain. Three patients had ulcerative colitis.[tishreen.edu.sy]
  • Abdominal pain, weight loss and blood in the stool can be the presenting symptoms regardless of the location of the cancer. Abdominal pain is usually due to either obstruction of the bowel or peritoneal spread.[lecturio.com]
  • pain especially with recent travel history suggests infectious colitis; pain with defecation occurs with hemorrhoids and anal fissure; change in stool caliber and weight loss is concerning for colon cancer ; abdominal pain can be associated with inflammatory[en.wikipedia.org]
Suggestibility
  • The purpose of this study was to identify factors that might suggest an inherited component in the transmission of CRC. METHOD: The study monitored 880 consecutive patients between 1980 and 2005 treated for CRC.[ncbi.nlm.nih.gov]
  • However, a few studies in large series of CRC patients suggest that in a small percentage of CRC cases, bi-allelic MUTYH germline mutations can be found in the absence of the MUTYH-associated polyposis phenotype.[ncbi.nlm.nih.gov]
  • Fine mapping on a total of 184 DNAs from 83 kindreds was done in regions suggesting linkage. Linkage analysis was accomplished with Merlin analysis package.[ncbi.nlm.nih.gov]
  • Ashkenazi individuals (n 472 155 males, 317 females) were genotyped for the GREM1 duplication, 194 with CRC, 131 had other cancer types (endometrial, pancreatic and ovarian) that show a syndromic association with CRC, and 147 were cancer-free with a suggestive[ncbi.nlm.nih.gov]
  • Histopathologic differences highly suggestive of LS CRCs do not appear to be shared by FCCTX.[ncbi.nlm.nih.gov]

Workup

The diagnosis of FCC is based on the identification of colorectal cancer in patients with a) one first-degree relative who has been diagnosed with colorectal cancer under the age of 50 years, b) two first-degree relatives who have been diagnosed with this disease at any age, or c) three first or second-degree relatives who have developed colorectal cancer. Patients with such a family history should be included in surveillance programs before the development of malignant neoplasms [1].

The identification of colorectal cancer in FCC patients is not different from sporadic cases and is based on the visualization of the primary tumor, which is generally done endoscopically, the performance of biopsies and the subsequent analysis of suspicious lesions, and tumor staging with diagnostic imaging [3].

The confirmation of FCC should prompt genetic testing for hereditary cancer syndromes and any non-syndromic predisposition to the disease. In this regard, the patient's medical and familial history may be of great help to shorten the list of likely differential diagnoses. Histological features and the precise location of colorectal malignancies, the occurrence of other types of cancer, and the respective patient's age at the time of diagnosis provide valuable hints as to the underlying condition. Lynch syndrome, for instance, is usually related to poorly differentiated malignancies arising in the proximal part of the colon, to endometrial cancer, and young age of onset [4]. Due to the relatively high prevalence of Lynch syndrome, some authors recommend all patients with FCC to be tested for this disease [1] [5] [6].

In a further step, the diagnostic workup may be specified according to the genetic background of the disease, and medical care may be provided in compliance with the respective guidelines.

Lymphocytic Infiltrate
  • Colorectal tumors that are microsatellite instability (MSI)-positive have distinctive features, including a tendency to arise in the proximal colon, lymphocytic infiltrated, and a poorly differentiated, mucinous or signet ring appearance. [1] Investigators[emedicine.medscape.com]

Treatment

Patients known to be at risk for FCC should be examined by colonoscopy every 1–2 years, so tumors can be identified and monitored for accelerated growth and a possible malignant degeneration. Colectomy is the technique of choice to deal with unmanageable polyps. In this context, segmental resection or subtotal colectomy with ileorectal anastomosis may be performed and should be followed by annual surveillance. The additional diagnosis of numerous rectal lesions, however, indicates the need for total proctocolectomy and ileal-anal pouch surgery.

The incidental detection of early-stage FCC is infrequent but essentially managed as described above. FCC patients who are not included in surveillance programs are rarely diagnosed before the development of metastases, which may change the therapeutic approach. Palliative chemotherapy may be considered to prolong progression-free and overall survival. The administration of chemotherapeutic agents is also known to improve the patient's quality of life. For that same purpose, patients may receive radiation therapy. Both chemotherapy and radiotherapy may be applied in a neoadjuvant or adjuvant manner, or outside the setting of surgery [7].

Molecular targeted therapies against FCC have received considerable attention, and a number of monoclonal antibody therapies has already been approved for the treatment of this type of malignancies. The respective compounds are bevacizumab (an inhibitor of angiogenesis) as well as cetuximab and panitumumab (both of which are inhibitors of the epidermal growth factor receptor) [7].

Prognosis

Patients who fulfill the aforementioned criteria for the inclusion in surveillance programs have a lifetime risk for colorectal cancer of 10-25%, depending on the number of relatives with such malignancies and their age at the time of diagnosis [1].

The outcome largely depends on the tumor stage at the time of diagnosis: The detection of preneoplastic lesions or early-stage colorectal cancer significantly improves the outcome, while the likelihood of survival is low when metastatic FCC has been detected. In sum, the five-year survival rates of patients diagnosed with localized colorectal cancer, regional spread, and metastatic disease are 90, 69, and 12%, respectively. Survivors of FCC are at increased risks of developing second
primary cancers of the colon and rectum, though [7].

Etiology

FCC may arise in the setting of well defined inherited syndromes or be diagnosed in patients with a family history consistent with a genetic predisposition. Those well defined inherited syndromes include Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, and certain hamartomatous polyposis conditions. The former are related to mutations in genes encoding for mismatch repair proteins, tumor suppressor APC, and MUTYH, which is involved in DNA damage repair, among others. The pathogenic variants of these genes are highly penetrant: The lifetime risk for colorectal cancer ranges between 50-80% for Lynch syndrome, 70-100% for familial adenomatous polyposis, and 80% for MUTYH-associated polyposis. Hamartomatous polyposis conditions like Peutz–Jeghers syndrome and juvenile polyposis syndrome result from mutations in tumor suppressors STK11 and SMAD4 or BMPR1A, respectively, and they are associated with a lifetime risk for colorectal cancer of 39% [4].

As implied above, FCC may develop outside the setting of these syndromes. There is high-risk, non-syndromic FCC, which is caused by single high-penetrance genes, and there is common FCC as defined by the family history. Several hundred low-penetrance susceptibility loci and specific polymorphisms have been related to the latter and have been shown to have additive effects on the individual risk for colorectal cancer [4] [6] [8].

FCC type X shall be described exemplarily to demonstrate the heterogeneity of non-syndromic FCC. FCC type X may be considered the poorly defined counterpart of Lynch syndrome and is diagnosed when patients fulfill the criteria for Lynch syndrome but do not have a mutation in a mismatch repair gene. It may be provoked by single genes of high penetrance, which probably confer autosomal dominant inheritance, or multiple genetic anomalies of low penetrance. FCC type X tumor cells are characterized by chromosomal instability with several duplications and deletions, long telomeres, abnormal DNA methylation patterns, and an upregulation of genes involved in G protein-coupled pathways. Individual triggers of tumorigenesis have not yet been defined, but have been speculated to be located on the long arm of chromosome 20 [6].

Epidemiology

Colorectal cancer is a rather frequent disease. It is the second most common type of cancer in women and the third most common one in men, with approximately 600,000 people dying each year from colorectal malignancies. Besides advanced age, male sex, and lifestyle decisions, a positive family history is among the most important risk factors for colorectal cancer [3]. The total share of hereditary cancer syndromes among colorectal malignancies is around 10% and may exceed 15% in patients diagnosed under the age of 50 [5]. What's more, carcinogenic genes of lower penetrance are suspected to play key roles in up to one-third of malignant colorectal neoplasms, even though the criteria for hereditary cancer may not be fulfilled [4]. Lynch syndrome has been estimated to account for 4% of all cases of colorectal cancer, rendering this syndrome the most common cause of FCC [5].

Incidence rates of colorectal cancer vary largely. They are highest in Oceania (44.8 and 32.2 per 100,000 in men and women, respectively) and other parts of the developed world. The lowest rates are reported in Africa, where <10 per 100,000 men and women are diagnosed each year. About one-third of all these cases may be assumed to occur in genetically predisposed families, but the geographical distribution of certain types of FCC is likely to differ from that of other variants of FCC and sporadic colorectal cancer.

Sex distribution
Age distribution

Pathophysiology

In line with the heterogeneity of FCC, there are distinct pathways to cancer development. Lynch syndrome, for instance, is related to microsatellite instability. The dysfunction of DNA mismatch repair proteins predisposes to the accumulation of (potentially cancerogenic) mutations and thus explains the high incidence of neoplasms in these patients. By contrast, familial adenomatous polyposis is provoked by the inactivation of tumor suppressor gene APC and the subsequent dysregulation of the Wnt signaling pathway. This same pathway seems to be affected in FCC due to mutations in the CTNNB1 gene, which encodes for catenin β1. Of note, an aberrant location of catenin β1 may also be observed in tumors with defective mismatch repair. These examples illustrate the complex pathophysiology of FCC, where certain events may favor or exclude other pathogenic developments [Zetner].

Prevention

The individual risk of developing colorectal cancer can be reduced by opting for a healthy lifestyle - even in patients who are genetically predisposed to the disease [9]. The respective lifestyle decisions include the avoidance of alcohol and tobacco and the maintenance of a balanced diet. The so-called Western diet is rich in fat and calories, but poor in fibers, and has been linked to an increased colorectal cancer risk. If combined with sedentary behavior, it easily leads to overweight or obesity. Conversely, regular physical activity facilitates the maintenance of normal weight and diminishes the risk for colorectal cancer.

Both morbidity and mortality due to FCC can be reduced by population screenings for hereditary cancer. Because of the broad spectrum of gene defects that may predispose to FCC, many of which are poorly defined or remain unknown, such screenings are not typically based on molecular biological studies. Colonoscopy, sigmoidoscopy, and guaiac-based fecal occult blood tests are the usual screening tools, but fecal immunochemical tests, molecular stool and blood tests, virtual colonoscopy, and colon capsule endoscopy may eventually be established as routine instruments for the prevention and early detection of colorectal cancer in the near future [3].

Of course, if a family is known to harbor a determined mutation, family members may directly be tested for this mutation and subsequently be recommended a surveillance plan.

Summary

Colorectal cancer may result from the effects of hereditary or environmental factors. At one end of the scale, there are patients who develop such malignancies due to a very strong genetic predisposition. They are typically diagnosed with hereditary cancer syndromes. At the other end of the spectrum, the implication of hereditary factors cannot be proven, and a diagnosis of sporadic cancer is made. Many cases lie between those extremes, with FCC usually being defined as colorectal cancer in patients with a threefold higher risk for malignant neoplasms of the colon or rectum. Important parameters for the calculation of the individual risk for colorectal cancer include the incidence of such malignancies in first-degree relatives, where one case diagnosed at the age of <50 years or two cases diagnosed at any age should suffice for the inclusion in surveillance programs [1].

Patient Information

Familial colorectal cancer (FCC) refers to malignant tumors arising in the colon or rectum due to a genetic predisposition to the disease. On the one hand, FCC may occur in the setting of hereditary cancer syndromes such as Lynch syndrome and polyposis syndromes, which are associated with lifetime risks of colorectal cancer that exceed 50%. These diseases are usually associated with additional, extra-intestinal manifestations. On the other hand, FCC may be non-syndromic. Within a family, the combination of several genes with low penetrance may result in an increased incidence of colorectal cancer. Due to the involvement of many genes, it is not always feasible to define the underlying genetic condition and to identify other family members at risk. This is more easily done in families affected by Lynch syndrome and similar disorders, since they are caused by single gene defects.

In any case, patients should adhere to their physician's recommendations regarding prophylactic screenings for colorectal cancer. Fecal occult blood tests, sigmoidoscopy, and colonoscopy are most commonly used to this end and allow for the detection of FCC at an early stage: The likelihood of survival is much higher in patients who are diagnosed early.

References

Article

  1. van Erp SJ, Leicher LW, Hennink SD, et al. Identification of familial colorectal cancer and hereditary colorectal cancer syndromes through the Dutch population-screening program: results ofa pilot study. Scand J Gastroenterol. 2016; 51(10):1227-1232.
  2. Lung MS, Trainer AH, Campbell I, Lipton L. Familial colorectal cancer. Intern Med J. 2015; 45(5):482-491.
  3. Kolligs FT. Diagnostics and Epidemiology of Colorectal Cancer. Visc Med. 2016; 32(3):158-164.
  4. Jasperson KW, Tuohy TM, Neklason DW, Burt RW. Hereditary and familial colon cancer. Gastroenterology. 2010; 138(6):2044-2058.
  5. Hampel H. Population Screening for Hereditary Colorectal Cancer. Surg Oncol Clin N Am. 2018; 27(2):319-325.
  6. Zetner DB, Bisgaard ML. Familial Colorectal Cancer Type X. Curr Genomics. 2017; 18(4):341-359.
  7. Siegel R, DeSantis C, Virgo K, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012; 62(4):220-241.
  8. Tenesa A, Dunlop MG. New insights into the aetiology of colorectal cancer from genome-wide association studies. Nat Rev Genet. 2009; 10(6):353-358.
  9. Fardet A, Druesne-Pecollo N, Touvier M, Latino-Martel P. Do alcoholic beverages, obesity and other nutritional factors modify the risk of familial colorectal cancer? A systematic review. Crit Rev Oncol Hematol. 2017; 119:94-112.

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Last updated: 2019-07-11 20:25