1-3% of all CRC
Autosomal dominant genetic disorder
80% pentrence
Due to germline mutations in a single DNA mismatch repair (MMR) genes (micro-setalite instability).
MMR genes: MLH1,MSH2,MSH6,PMS2
Gastrointestinal cancer risk associated with Lynch syndrome is variously reported as around 80% for colorectal cancer and 13 to 20% for gastric cancer.
Evidence indicates that the colorectal cancer risk for males is higher than that for females.
Between 0.3% and 2.4% of all patients with colorectal cancer have a family history criteria of Lynch syndrome.
The proportion of colorectal cancer cases due to mutations in DNA MMR genes is 2 to 3%,
Synchronous tumour: two or more tumours present at the same time
Metachronous tumour:first tuomour is followed by a second one at a later date
both are common
Increase risk of endomerial cancer, ovarian, urinary tract and skin cancer.
Diagnosis:
Difficult as no specific phenotype.
Two main diagnostic guideline in the West to identify patients:
Families with Lynch syndrome should be referred to the regional clinical genetics service or other specialist service to facilitate risk assessment, genetic testing and screening of family members.
(Recommendation grade: C)
Management:
-Large bowel surveillance for Lynch syndrome family members and gene carriers
-Total colonic surveillance (at least biennial) should commence at age 25 years
full colonoscopy or barium enema remains the best options available.
Patients who have developed a colorectal malignancy and who come from a Lynch syndrome family, or carry a mutation in an MMR gene, should be counselled and offered a surgical procedure(colon resection) that serves both as cancer control element and prophylaxis to prevent future cancer risk.
(Recommendation grade: C)
(Recommendation grade: C)
Autosomal dominant genetic disorder
80% pentrence
Due to germline mutations in a single DNA mismatch repair (MMR) genes (micro-setalite instability).
MMR genes: MLH1,MSH2,MSH6,PMS2
Gastrointestinal cancer risk associated with Lynch syndrome is variously reported as around 80% for colorectal cancer and 13 to 20% for gastric cancer.
Evidence indicates that the colorectal cancer risk for males is higher than that for females.
Between 0.3% and 2.4% of all patients with colorectal cancer have a family history criteria of Lynch syndrome.
The proportion of colorectal cancer cases due to mutations in DNA MMR genes is 2 to 3%,
Synchronous tumour: two or more tumours present at the same time
Metachronous tumour:first tuomour is followed by a second one at a later date
both are common
Increase risk of endomerial cancer, ovarian, urinary tract and skin cancer.
Diagnosis:
Difficult as no specific phenotype.
Two main diagnostic guideline in the West to identify patients:
Families with Lynch syndrome should be referred to the regional clinical genetics service or other specialist service to facilitate risk assessment, genetic testing and screening of family members.
(Recommendation grade: C)
Management:
-Large bowel surveillance for Lynch syndrome family members and gene carriers
-Total colonic surveillance (at least biennial) should commence at age 25 years
-Surveillance should continue to age 70 to 75 years or
until co-morbidity makes it clinically inappropriate.
full colonoscopy or barium enema remains the best options available.
Patients who have developed a colorectal malignancy and who come from a Lynch syndrome family, or carry a mutation in an MMR gene, should be counselled and offered a surgical procedure(colon resection) that serves both as cancer control element and prophylaxis to prevent future cancer risk.
(Recommendation grade: C)
-Upper
gastrointestinal surveillance for Lynch syndrome family members and/or MMR gene carriers:
In families manifesting gastric cancer as part of the
phenotype, biennial upper gastrointestinal endoscopy should be considered.
Surveillance should continue to age 75 or until the
causative mutation in that family has been excluded.(Recommendation grade: C)
A 45-year-old presents with rectal bleeding. Colonoscopy reveals a cecal cancer and no other polyps. There is no family history of polyps or cancer. What is the most likely diagnosis?
ReplyDeleteA. Familial adenomatous polyposis
B. Attenuated familial adenomatous polyposis
C. MYH-associated polyposis
D. Lynch syndrome
answer D.
Lynch syndrome tends to present with isolated early-onset colorectal cancers without a preponderance of polyps. The other choices are all known causes of multiple colorectal adenomas.
A 49-year-old patient is found to have colon cancer. Based on the patient’s age at diagnosis, microsatellite instability analysis and immunohistochemistry for mismatch repair proteins MLH1, MSH2, MSH6, and PMS2 is performed. These tests show a high level of microsatellite instability and absent staining of the MLH1 and PMS2 proteins. BRAF mutation analysis confirms the presence of a V600E mutation. The family history is negative for any cancer diagnoses. Which one of the following statements is true?
ReplyDeleteA. This tumor results are diagnostic of Lynch syndrome.
B. Genetic testing is unlikely to reveal a mutation in either the MLH1 or the PMS2 gene.
C. The patient’s siblings should undergo annual colonoscopy based on the tumor testing results.
D. The patient should consider prophylactic hysterectomy at the time of colon surgery.
answer B
Explanation
Evidence of MSI and abnormal IHC of mismatch repair gene proteins are found in 15% of all colorectal cancers, and are not necessarily due to Lynch Syndrome. The results above are most likely to be due to somatic (not inherited) hypermethylation of the MLH1 gene promoter, which leads to loss of MLH1 and PMS2 proteins. The next step in the patient’s evaluation is to perform genetic testing to look for mutations in the MLH1 and PMS2 genes. If a pathogenic mutation is found, then the patient would be diagnosed as having Lynch syndrome.
Positive IHC or MSI test results indicate that you have malfunctions in the genes that are connected to Lynch syndrome. But results can't tell you whether you have Lynch syndrome because some people develop these gene mutations only in their cancer cells. People with Lynch syndrome have these gene mutations in all of their cells. A small portion of all colon cancers have a positive MSI result, but most aren't caused by Lynch syndrome. Newer tests can help determine if a tumor is Lynch syndrome related or not.
DeleteA 35-year-old woman diagnosed with endometrial cancer was found to carry an MSH2 mutation. She has been referred to gastroenterology for colon cancer screening based on the finding of a MSH2 mutation. Which of the following statements is true?
ReplyDeleteA. Colonoscopy should be recommended every 3 years.
B. Her children should begin colonoscopy surveillance at age 20-25 if also found to carry the familial MSH2 mutation.
C. She reports that her maternal uncle was recently diagnosed with pancreatic cancer and asks if this could be related to the MSH2 mutation, but you reassure her that this would not be related to the MSH2 mutation in the family.
D. Her mother, who is 68-years-old, also carries the mutation and has had normal colonoscopies for the past 15 years. Based on this, her mother can increase her screening interval to every 5 years.
answer B
Explanation
Individuals with Lynch syndrome are recommended to undergo colonoscopy screening every 1-2 years based on high cancer risk, accelerated polyp progression, and demonstrated benefit for diagnosing colon cancer at an early stage and reducing mortality. Pancreatic cancer has been more recently recognized as part of the tumor spectrum associated with Lynch syndrome. While data are still insufficient to prove a benefit to screening for pancreatic cancer, individuals with hereditary risk for pancreatic cancer should be referred to a high-risk center to consider screening under care of multidisciplinary team.
Lynch-associated tumors include those affecting the endometrium, ovaries, stomach, small intestine, kidney, brain or liver.
DeleteWhich of the following statements about genetic testing for Lynch Syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]) is true?
ReplyDeleteA. If no mutation can be found in any family member, the family does not have Lynch Syndrome.
B. Within a family with an identified pathogenic mismatch repair gene mutation, an individual who tests negative has the same risk of developing colon cancer as the general population.
C. Colorectal cancers that develop in Lynch Syndrome are generally microsatellite stable.
D. Prophylactic colectomy should be recommended to family members who are found to carry a Lynch Syndrome gene mutation.
answer B
Explanation
The inability to identify a mutation does not rule out Lynch Syndrome, since in a subset of families with a classic family history, no mutation can be identified in the known mismatch repair genes with currently available techniques. However, once a pathogenic mutation is identified in an affected individual, it can be used to screen other at-risk relatives. Those individuals who are negative for that mutation would not be at an increased risk for developing colon cancer (i.e., they would have the same risk for colon cancer as the general population). Colon cancers in HNPCC are found to be microsatellite unstable (i.e., to have microsatellite instability [MSI]). The majority of mutation carriers can be managed without undergoing prophylactic colectomy; the recommended surveillance is colonoscopy every 1-2 years starting at age 20-25.
Which one of the following etiologic gene-cancer associations is correct?
ReplyDeleteA. APC and hereditary pancreatic cancer
B. CDH1 and diffuse gastric cancer
C. MLH1 and attenuated polyposis
D. MYH and uterine cancer
E. BRCA3 and colon cancer
answer B
Explanation
MYH gene mutations are associated with adenomatous polyposis and early onset colorectal cancer; uterine cancer risk is not elevated in mutation carriers. Gynecologic tumors (uterine and ovarian cancers) have a high prevalence in mismatch repair gene (MSH2, MLH1, MSH6, PMS2) mutation carriers. APC is the most common cause of Familial Adenomatous Polyposis, which leads to early onset colorectal cancer if the colon is not prophylactically removed. CDH1 mutations cause diffuse hereditary gastric cancer. BRCA2 mutations have recently been described to be associated with elevated pancreatic cancer risk in certain families, but the colon cancer risk is generally felt not to be elevated. BRCA3 is not a known cancer predisposition gene.
A 50-year-old woman presents for colorectal cancer screening. Her father had colon cancer at age 45 and her sister at age 55. Her colonoscopy reveals a cecal adenocarcinoma. Which of the following statements regarding this syndrome is true?
ReplyDelete1-AD
2-less than 0.1% of CRC
3-increase frequency of female genital cancer
4-maily distal tumour
5-germ line mutuation HMSH2/HMLH1 does not occur
This family meets the Amsterdam criteria for HNPCC. This syndrome is inherited in an autosomal dominant fashion. There is a predominance of proximal tumors. Germline mutations in the hMSH2 or hMLH1 gene are present in 80% of colon cancers. There is an increased frequency of cancers of the female genital tract. This syndrome accounts for approximately 6% of all the colorectal cancers, whereas FAP accounts for less than 1%.
Lynch syndrome runs in families in an autosomal dominant inheritance pattern. This means that if one parent carries a gene mutation for Lynch syndrome, there's a 50 percent chance that mutation will be passed on to each child. The risk of Lynch syndrome is the same whether the gene mutation carrier is the mother or father or the child is a son or daughter.
DeleteWhich of the following statements about the clinical presentations of FAP/Attenuated FAP is true?
ReplyDeleteA. Approximately 50% of patients with classic FAP will develop colorectal cancer, if the disease is left untreated.
B. Patients with FAP have a family history of colon cancer or polyposis in approximately 95% of cases.
C. Patients from families with Attenuated FAP often have a right-sided predominance of polyps.
D. Women with FAP should be screened annually for endometrial cancer.
C Explanation
Due to the large number of colon adenomas, almost all (~100%) patients with FAP will eventually develop colon cancer, in the absence of treatment. Up to 30% of FAP cases represent new mutations. Patients with Attenuated FAP usually have only 10-100 colon adenomas and often they can be scattered in the proximal colon. Hence, full colonoscopy is essential to evaluate the colon. Patients with Lynch Syndrome are at an increased risk for developing endometrial cancer, but not patients with FAP.
Which of the following statements about genetic testing for Lynch Syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]) is true?
ReplyDeleteA. If no mutation can be found in any family member, the family does not have Lynch Syndrome.
B. Within a family with an identified pathogenic mismatch repair gene mutation, an individual who tests negative has the same risk of developing colon cancer as the general population.
C. Colorectal cancers that develop in Lynch Syndrome are generally microsatellite stable.
D. Prophylactic colectomy should be recommended to family members who are found to carry a Lynch Syndrome gene mutation.
B Explanation
The inability to identify a mutation does not rule out Lynch Syndrome, since in a subset of families with a classic family history, no mutation can be identified in the known mismatch repair genes with currently available techniques. However, once a pathogenic mutation is identified in an affected individual, it can be used to screen other at-risk relatives. Those individuals who are negative for that mutation would not be at an increased risk for developing colon cancer (i.e., they would have the same risk for colon cancer as the general population). Colon cancers in HNPCC are found to be microsatellite unstable (i.e., to have microsatellite instability [MSI]). The majority of mutation carriers can be managed without undergoing prophylactic colectomy; the recommended surveillance is colonoscopy every 1-2 years starting at age 20-25.