Let’s know About Lynch Syndrome

A friend of mine recently had surgery for colon cancer, and further examinations after the surgery revealed that he was a colorectal cancer patient with Lynch syndrome. During his treatment, we had a lot of discussions, and he also urged me to learn more about Lynch syndrome, which I would like to share with you here. Lynch syndrome is an autosomal dominant genetic disease caused by mutations in the mismatch repair gene (MMR) .

This syndrome carries a higher risk of colorectal cancer and endometrial cancer . The incidence rates of colorectal cancer and endometrial cancer in positive carriers are 80% and 60%, respectively. The incidence of other tumors is also higher than that of the general population.

Colorectal cancer patients

Lynch syndrome colorectal cancer patients account for 2% to 3% of all colorectal cancers. In other words, about 2.8 out of every 100 colorectal cancer patients have LS. This is an epidemiological report from the United States.

I remember when I was in school, whenever I heard the teacher talk about the epidemiology of a certain disease , I felt that he was nitpicking and a bit bluffing to show off his academic knowledge. After staying in the clinic for a long time, I found that this is an issue that everyone is very concerned about, because once you find out that you have a disease, you will feel like you have fallen into the abyss or have fallen into the abyss, and you urgently need to have a self-assessment. Doctors often bring out these data at this time, so let’s take a look:

Colorectal cancer is one of the most common gastrointestinal malignancies , and ranks among the top 4 in both incidence and mortality worldwide. In China, the number of cases of colorectal cancer in men accounts for 8.59% of new cancer patients, ranking fifth, while in women it accounts for 9.08%, ranking third; the mortality rate of colorectal cancer patients in China ranks fifth.

In fact, there is no need to pursue these figures. There is a saying that goes, where there is a will, there is a way. Hard work pays off. In any matter, some people succeed while most people fail. Similarly, even if you are diagnosed with a disease, it does not mean that you will be killed in one blow. There is hope of survival under any circumstances. The above statistics just illustrate this point. It depends on your sincerity and strength to work hard to change.

Genetic disease

Let’s get back to the topic. Lynch syndrome is a genetic disease, and it is inherited in an autosomal dominant manner. So we should pay attention to the mismatch repair gene (MMR) mutation.

In a nutshell, at the genetic level, at least one of the MMR coding genes, such as MLH1, MSH2, MSH6, PMS2, or EPCAM, is missing, resulting in loss of MMR function, making it difficult to correct mismatches during DNA replication, and ultimately causing DNA microsatellite instability (MSI). MSI in key regions has a significant impact on normal signal transduction, gene translation, and

It affects transcription and protein modification expression, ultimately leading to the formation of tumor cells and causing tumor occurrence.

One or two soldiers in the headquarters’ guard company caused mischief, and the entire guard company was paralyze. There was no one to deliver newspapers and water to the headquarters, and the protection of the leaders became lax, leading to major problems in the headquarters.

My friend has a twin sister. After he was diagnose with the disease, he was first worried about whether his sister would also have the problem, and immediately made an appointment for her to have a comprehensive examination. So, are the siblings and children of people with Lynch syndrome at a high risk of developing the disease? Are the parents at a high risk of developing the disease?

To answer this question, for a family, the best way to rule out LS is to test all suspected patients or each family member at the MMR gene level.

Autosomal

Lynch syndrome is an autosomal genetic disease , not a sex chromosome-linked genetic disease, so theoretically, the incidence rate of males and females is equal. Clinically, the lifetime risk of malignant tumors in male and female Lynch syndrome gene carriers is 91% and 69%, respectively. From another perspective, if Lynch syndrome is first discover in children, then the risk of parents’ illness should be pay close attention and screening should be carry out as soon as possible.

The word syndrome is a bit confusing. In addition to colorectal cancer, can the same person also have tumors in other parts of the body or organs?

Lynch syndrome was originally call hereditary non-polyposis colorectal cancer (HNPCC). Carriers of the gene mutation for this disease have a lifetime risk of colorectal cancer of 60% to 85%. It is name because carriers of abnormal genes in the family often develop colorectal cancer at an early age (all at the age of 44). The same person may also develop multiple primary cancers simultaneously and successively, and the most common ones are endometrial cancer, ovarian cancer, gastric cancer and other malignant tumors in other parts of the body, and the incidence rate is significantly higher than that of the normal population. Therefore, it is call the most common hereditary colorectal cancer syndrome.

If I have undergone surgery for colorectal cancer, does that mean that Lynch syndrome has been cure? Will it recur or metastasize in the colorectum?

Most Lynch syndrome patients undergo surgery based on the stage of colon and endometrial lesions after diagnosis. Some patients undergo chemotherapy after surgery, but they still need regular checkups to be alert to recurrence and other malignant tumors. Although the age of onset of Lynch syndrome is significantly younger than that of sporadic cases, the prognosis is relatively good.

What treatments are currently available for Lynch syndrome?

It mainly includes surgical resection of lesions , chemotherapy, and immunotherapy.

Studies have found that the 10-year recurrence rate of colorectal cancer in patients with Lynch syndrome who underwent local resection was about 16%, which was significantly higher than the 0-3.4% of patients who underwent total colectomy. Therefore, some doctors have propose that total or subtotal colectomy should be use for colorectal cancer treatment, rather than local resection for traditional colorectal cancer treatment .

Tumor in rectum

For patients whose tumor is located in the rectum, the recurrence rate after total proctocolectomy + ileal pouch-anal anastomosis is significantly lower than that after anterior rectal resection. Therefore, IPAA surgical treatment is recommended for such patients.

The proportion of LS patients with MSI-H phenotype is very high. Although these patients have good early therapeutic effects and are not prone to relapse, they are insensitive to 5-fluorouracil chemotherapy after recurrence and metastasis . PD-1 immunotherapy can be consider for such patients with advanced colorectal cancer.

The surprise is that last year, U.S. researchers developed a new vaccine that destroys mutated cells in mice containing Lynch syndrome DNA , which may one day prevent people with the genetic disease Lynch syndrome from developing colorectal cancer . Steven Lipkin, MD, Ph.D., of Weill Cornell Medicine, reported the results of the cancer prevention vaccine test at the 2019 American Association for Cancer Research Annual Meeting.

Please read the following links carefully for the current global clinical trial projects related to Lynch syndrome, including those that have already ended. If you have any questions, please leave a message and we will answer you as soon as possible.

https://clinicaltrials.gov/ct2/results?cond=%22hereditary+nonpolyposis+colorectal +cancer%22+OR+%22colorectal+neoplasms%2C+hereditary+nonpolyposis%22

For everyone, what are the tips or warnings, or what do you need to pay attention to?

Lynch syndrome cases

The number of cases of Lynch syndrome found is just the tip of the iceberg compared to developed countries. This may be related to the lack of public awareness and insufficient attention in clinical work. It is recommend that the following situations can be consider as high-risk groups and should be included in the screening of hereditary colorectal cancer :

(1) patients with new colorectal cancer; (2) the same patient has more than two colorectal cancers (in different time periods); (3) patients with colorectal cancer suffer from tumors in other parts of the body at the same time or at different times (gastric cancer, small intestine cancer, female reproductive system cancer, urinary system cancer, hepatobiliary system cancer); (4) more than two cases of colorectal cancer or ovarian cancer in the family. In addition, patients with colorectal cancer lack MMR protein immunohistochemistry , and further gene sequencing is recommend to clarify the mutation site and guide family census.

Current studies have confirmed that the mismatch repair genes associated with Lynch syndrome are mainly MLH1, MSH2 (accounting for 85%~90%), MSH6 and PMS2 (accounting for 10%~15%).

NCCN edition

The 2017 edition of the National Comprehensive Cancer Network (NCCN) and the 2017 edition of the European Society for Medical Oncology (ESMO) have not updated the monitoring guidelines for LS compared with the previous versions.

The monitoring guidelines point out that LS patients should be monitor every 1 to 2 years, with colonoscopy being the main means of monitoring .

① LS patients and their first-degree relatives such as parents, children, and siblings should undergo colonoscopy every 1-2 years starting from the age of 20-25 years or 2-5 years before the youngest age at which colorectal cancer was diagnose in the family (<25 years old); ② For patients with MLH1 or MSH2 mutations, the monitoring method in ① can be adopted; ③ For patients with MSH6 or PMS2 mutations, they should undergo colonoscopy every 1-2 years starting from the age of 30-35 years, and every 2-3 years after the age of 40-50 years.