Hereditary nonpolyposis colon carcinoma (HNPCC) (Lynch Syndrome)

Also known as the Lynch Syndrome and defined as the presence of colorectal cancer in three or more family members of whom two are first degree relatives, family members in at least two generations and one family member diagnosed before the age of 50 years.

Autosomal dominant with 70-80% lifetime risk of colorectal cancer.

Nearly 1 million individuals in the US have the Lynch syndrome, but most are unaware of the diagnosis.

Accounts for up to 5% of CRC.

Around 10 to 15% of early onset call rectal cancers can be attributed to the Lynch syndrome

Most of the estimated 1.2 million Americans (1 in 279) who have Lynch syndrome are undiagnosed.

 Prevalence in the general population is approximately 0.3%

It is recommend universal testing for Lynch syndrome in patients with CRC or endometrial cancer.

It is caused by germline mutations in the DNA mismatch repair open (MMR) genes which correct errors that spontaneously occur during DNA replication.

Microsatellites instability occurs when tumors accumulate numerous insertions or deletions at sites of repetitive DNA units called microsatellites.

MMR deficiency increases the likelihood of acquiring somatic genetic mutations, particularly in short repetitive sequences, leading to varying lengths of these regions called microsatellite instability.

While the disease is inherited in the classic Mendelian dominant way, tumors act in the recessive disease-like process, a somatic mutation is needed to inactivate the uninvolved allele.

Related to a 1 mutated copy on genes associated with DNA damage mismatch repair (MMR).

MMR deficiencies lead to changes in the length of nucleotide repeat sequences known as microsatellite instability (MSI).

Patients with the Lynch syndrome are phenotypically normal at birth, but carry a silent germline mutation which at some point undergoes a second hit which initiates the progression towards neoplasia.

Colorectal cancer develops through the adenoma carcinoma sequence but at an accelerated rate and at a younger age than sporadic colorectal cancer.

Tumors associated with Lynch syndrome characterized by high microsatellite instability, the result of functional MMR deficiency caused by bIallelic MMR gene inactivation through a somatic alteration as a second mutation event.

Linked to alteration in a variety of MMR genes, leading to deficient mismatch repair also termed microsatellite instability-high.

Caused by germline alterations in DNA mimatch repair genes MLH1, MLH2, MSH6, or PMS2 or EPCAM and confers a 40-80% lifetime risk of colorectal cancer.

Prevalence in the general US population is 1 in 300.

Higher prevalence of  HNPCC  among African-Americans

Accounts for 5-8% of hereditary forms of colorectal cancer.

Responsible for 1-3% of the total colorectal cancer burden.

Accounts for approximately 2.3% of all endometrial cancers.

Colon and endometrial cancers are the most common malignancies in Lynch syndrome and occur at about equal frequency, the range 40-60%.

Carriers have a lifetime risk of developing colorectal cancer of about 50%, however these carriers do not show an increase frequency of adenomatous polyps.

Inactivation of the MMR system may accelerate a progression from adenoma to carcinoma in patients with the Lynch syndrome mutation.

Amsterdam criteria for diagnosis: at least three relatives with colon cancer and one affected person is a first degree relative of the other 2 affected persons, two successive generations affected, at least one case of colon cancer diagnosed before the age of 50 years and exclusion of FAP.

Mismatch repair genes MLH1, MSH2, MSH6, PMS2, and PMS1 have been identified in HNPCC families as are deletions in the EPCAM gene.

EPCAM gene deletions, a gene located immediately upstream of MSH2, is an alternative mechanism for MSH2 silencing in Lynch syndrome.

Lynch syndrome characteristically demonstrates an MMR deficiency, defined as microsatellite instability or loss of the MMR protein expression, which is the hallmark of this process.

Inactivation of MMR genes leads to loss of MMR protein expression in tumor cells, and this can be detected by immunohistochemistry tests.

Immunohistochemical assessment of an MMR proteins is inexpensive and sensitive way to screen for this process.

MSI, microsatellite instability testing can also be used for screening.

The overall estimated germ line mutations is 7.1%.

The majority of cases are undetected.

Intense colorectal cancer screening by colonoscopy and prophylactic gynecological surgery reduce the incidence and mortality of tumors.

The most common associated cancers are premenopausal breast cancer, osteosarcoma, soft tissue sarcomas, brain tumors, leukemia, adrenal cortical carcinoma, ovarian cancers endometrial carcinoma, stomach cancer. small bowel cancer, pancreatic cancer, urinary tract and cutaneous sebaceous gland tumors.

Approximately 5% of urinary tumors (UTs) are thought to be caused by inherited genetic syndromes, whereas 25% of ovarian cancers are estimated to be due to an inherited syndrome.

Patients with these component cancers and associated personal and family histories should undergo genetic testing to identify mutation carriers to reduce risk of associated cancers with prophylactic surgeries, frequent colonoscopies and chemoprevention.

hMSH2 and hMLH1 account for more than 90% of the germline mutations found on DNA analysis.

Approximately 10% mismatches located in MSH6 and PMS2.

Characteristic phenotype of Lynch syndrome tumors is microsatellite instability (MSI)a sign of defective MMR.

Carriers of mismatch repair (MMR) gene mutations are at high risk of early onset colorectal and endometrial cancers.

The above abnormal functioning genes leading to errors during DNA replication, especially in repetitive sequences , micro satellites.

Somatic inactivation of the remaining normal allele by genetic or epigenetic events lead to microsatellite instability in colon and endometrial tumors at a young age.

Carriers have an increased risk of developing colorectal adenomas at a younger range then non carriers.

Carriers of the above germline mutation have a risk of colorectal cancer 22-69% higher than the general population which is 2.1-2.5%.

Patients have a 16-30% chance of developing a second primary colorectal cancer in the 10 years after their first colon cancer diagnosis.

First-degree relatives of patients with colorectal cancer with Lynch syndromehave a 50% risk of inheriting the Lynch syndrome.

Repair genes mutations probably accelerate tumor progression.

Excess body weight increases the risk of colorectal adenomas in patients with Lynch syndrome, and this is seen only in men.

The key epigenetic modification is the methylation of cytosines that precede a guanosine in the DNA sequence and hypermethylation of gene promoters associated with transcriptional silencing.

Women with hereditary nonpolyposis colorectal cancer are at risk for endometrial carcinoma, ovarian carcinoma, stomach, small intestine, hepatobiliary system, kidney, sebaceous glands and ureter.

Lifetime risk of endometrial carcinoma in women from hereditary nonpolyposis colorectal carcinoma families as high as 60%, and may be a greater lifetime risk than clon cancer.

Endometrial cancer may be the sentinel cancer among women with Lynch syndrome (LU KH et l).

Lifetime risk of ovarian carcinoma in women from hereditary nonpolyposis colorectal carcinoma families is 10-12%.

Lifetime risk of ovarian cancer in patients with the Lynch syndrome is 8% compared with 1.4% in the general population.

Early onset of colorectal cancer among patients with this syndrome with an average age of 45 years.

Predilection of colorectal cancer is the proximal colon.

Colonoscopy initiated at age 25 and is repeated annually.

Cumulative risk of prostate cancer in patients with Lynch syndrome is 2 fold higher than the general population.

Microsatellite instability occurs in more than 90% of patients and is the hallmark of the syndrome.

Multiple polyposis with more than 100 polyps is not part of the syndrome but patients usually have a few polyps which may be more likely to become malignant because of accelerated tumorigenesis.

Associated with excess early onset right sided colorectal cancers which are metachronous.

Excess malignancies including stomach, biliary, small intestine, transitional cell cancers also reported with this syndrome.

Aspirin reduces the risk for colorectal cancer by more than half and 5 years (Colorectal Adenoma/Carcinoma Prevention Programme-2 trial).

Leave a Reply

Your email address will not be published. Required fields are marked *