About 100 years ago, Aldred Scott Warthin, an American pathologist, noticed that the seamstress in his family was sullen and asked her why she was unhappy. The seamstress said that many members of her family had tumors of the intestines or female reproductive organs, and that she feared that the specter of cancer would not leave her alone and that she would sooner or later get cancer too. As it turned out, the seamstress really did get endometrial cancer and died as a result. Aldred Scott Warthin then called the family a cancer-prone family. I recently had a patient with a family history of colon cancer. The patient was a 33-year-old man who presented to the emergency surgery department with a sudden onset of stomach pain and was found to have an incomplete bowel obstruction due to intussusception, which resolved after conservative treatment. Following my instructions, he later went to the gastroenterology department for colonoscopy and was diagnosed with colon cancer, which was located in the transverse colon near the hepatic flexure. I performed a radical right hemicolectomy on him not long ago, and the operation went well, and he was discharged from the hospital after the operation. The patient’s father, who is also my patient, suffered from rectal cancer and is receiving preoperative radiotherapy in the outpatient clinic because of the large and fixed tumor. One ancient and one modern, one seamstress and one young man, both of their families are frequently attacked by the specter of cancer, and it seems that they cannot avoid the fate of cancer. So, why is this? Who is this abominable ghost? Actually, its name is “Lynch Junction” – Lynch syndrome, also known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC). So, what is Lynch syndrome? It also starts with genes. When it comes to genes, many people feel that this field is mysterious. So what exactly are genes? Each of us carries 23 pairs of chromosomes, each of which originates from the paternal and maternal sides, respectively. These 23 pairs of chromosomes are the carriers of all the genetic material in the human body, and the traits we inherit from our parents (such as height, eye size, etc.) are transmitted by the genetic material carried on the chromosomes. The genetic material on chromosomes that determines traits (height, eye size, skin color, etc.) is what we call “genes”. We can easily find similarities between children and their parents in our lives, and these similarities are passed on through genes, so that the offspring acquire the characteristics of their parents, which we call heredity. The offspring can inherit the genes of their parents, and genes, as the main material basis of inheritance, determine inherited traits, such as: skin color, height, single or double eyelids. Genes not only determine the inheritance of physical appearance, but some diseases are also inherited from parents to children through genes, such as: hemophilia, sickle cell anemia and other single gene inherited diseases; in some cancers there are also genes that cause the disease, such as breast cancer, colorectal cancer and so on. Among the many genetic phenomena of colorectal cancer, there is one type of hereditary colorectal cancer that has been studied more clearly, which can accurately screen for genetic defects and accurately predict the probability of colorectal cancer in patients’ offspring or relatives, and can guide patients and their family members to carry out prevention in a targeted manner. This is the special type of colorectal cancer that I would like to introduce to you – Lynch syndrome. It is an autosomal dominant disease, accounting for only 5%-15% of all colorectal cancers. Lynch syndrome occurs not only with colorectal malignancies, but also with extraintestinal malignancies such as endometrial cancer, gastric cancer, ovarian cancer, small intestine cancer, ureteral and renal pelvis cancer, brain cancer, bile duct cancer, and skin cancer. Compared with sporadic colorectal cancer, it has the clinical characteristics of early age of onset, high incidence of simultaneous or heterozygous multiple primary colorectal cancers (i.e., cancers occurring simultaneously or sequentially in different parts of the large intestine), and high incidence of malignant tumors inside and outside the intestine in family members. Genetic factors are decisive factors in the occurrence of Lynch syndrome. Timely diagnosis of Lynch syndrome and family lineage investigation are of great significance to reduce the incidence and mortality of Lynch syndrome-related tumors such as colorectal cancer and endometrial cancer in patients and their families. If someone in your family has colorectal cancer, please don’t panic and don’t be easily labeled as “Lynch syndrome”, in fact, more than 80% of colorectal cancers are sporadic and only a few are caused by “Lynch-kun”. So, how to know whether it is Lynch syndrome or not? Regarding the diagnosis of Lynch syndrome, scholars have made a lot of exploration and have put forward several diagnostic criteria. At present, the internationally accepted one is Amsterdam Criteria-II, also known as “3-2-1-0” criteria, namely: 1. At least 3 family members have Lynch syndrome-related tumors (colorectal, endometrial, small intestine, ureteral or renal pelvis cancer), and one of them should be the first degree relative of the other 2; 2. 2. at least 2 consecutive generations were involved; 3. at least 1 person was younger than 50 years old at the time of diagnosis; 4. familial adenomatous polyposis should be excluded. Of course, the diagnosis of Lynch syndrome also requires molecular genetic testing (i.e., genetic testing) to detect pathogenic germline mutations. With the gradual research on Lynch syndrome, scholars have realized that there are four genetic defects caused by Lynch syndrome, which are MLH1, MSH2, MSH6, and PMS2, and they are known as mismatch repair genes (MMR) in medical science. So what’s the deal with mismatch repair genes? It turns out that human cells are constantly dividing, proliferating, and differentiating, and the genetic material in the cells, DNA, is constantly being copied and passed on to daughter cells. But God always likes to play a joke with human beings, in the process of DNA replication can also make mistakes, so that the daughter cells get the wrong genetic information. Everything in nature is always mutually exclusive, and when DNA replicates incorrectly, mismatch repair genes will come forward and express mismatch repair proteins to “correct” the incorrectly replicated DNA. Therefore, the four mismatch repair genes MLH1, MSH2, MSH6 and PMS2 are the “police” of the DNA replication process in the human body. However, God is still playing a joke with human beings, these four genes will also have genetic defects, resulting in the mismatch repair protein can not be expressed or reduced expression, the DNA replication process of error correction “police” will be seriously short of staff, DNA replication process errors will continue to pass to the daughter cells and continue to accumulate, and eventually start the daughter cells of cancer The process will lead to colorectal cancer, endometrial cancer and other Lynch syndrome-related tumors in humans. Since it has been recognized that the essence of Lynch syndrome lies in the genetic defects of four genes, MLH1, MSH2, MSH6 and PMS2, genetic diagnosis has become the “gold standard” for Lynch syndrome. The NCCN (National Comprehensive Cancer Network) and ESMO (The European Society for MedicalOncology), the two leading international cancer diagnostic and treatment authorities, have developed The European Society for Medical Oncology (ESMO) has developed guidelines for the diagnosis of the Lynch syndrome gene. The guidelines emphasize that all newly diagnosed colorectal cancer patients under the age of 70 should be included in Lynch syndrome gene screening, and after immunohistochemistry, microsatellite instability (MSI) primary screening, and then methylation testing, if you still cannot exclude the gene defect, you will enter MLH1, MSH2, MSH6, PMS2 gene screening. If you are screened for a genetic defect, a family screening is performed, meaning that all of your relatives are screened for the appropriate genetic defect. After the young man mentioned above was successfully discharged from the hospital, he was advised by me to take about 10 ml of venous blood at a cost of about$5,000 and underwent advanced genetic testing, which did find a mutation in the mismatch repair gene MLH1 (a shift mutation) and confirmed the diagnosis of Lynch syndrome. If you are tested for a gene defect in one of the four genes MLH1, MSH2, MSH6 and PMS2, you may want to know how likely you are to develop cancer in the future? The NCCN colorectal cancer screening guidelines have published about the likelihood of developing Lynch syndrome-related tumors with the four gene defects: MLH1/MSH2 gene defects have the highest likelihood of developing cancer, 40% to 80% of colon cancer, 25% to 60% of endometrial cancer, and a certain likelihood of stomach, ovarian, and biliary system cancers. Colon cancer and endometrial cancer are the most common cancers that occur from these four genetic defects. If you or your family members (i.e. family screening) are tested for mismatch repair gene defects, and you know that you have a high possibility of cancer, wouldn’t you be in fear of getting cancer? Actually, there is no need to worry. Although God likes to joke with human beings to create genetic defects, but the so-called man is determined to win, human beings have gradually realized the nature of Lynch syndrome in the struggle with colorectal cancer, and have also mastered the prevention and treatment measures of this kind of disease. 1. Frequent colonoscopy: For Lynch syndrome carrying the above-mentioned gene defect, NCCN recommends to start colonoscopy at the age of 20-25 years, or if their family members have Lynch syndrome-related tumors before the age of 20-25 years, they should start colonoscopy 2-5 years before the earliest age of diagnosis of this disease, and the examination should be performed every 1-2 years. Why is the emphasis on 1-2 years for colonoscopy here? Because scholars have found that the process of adenoma to carcinoma in disseminated colorectal cancer generally takes 8-10 years, but the process of Lynch syndrome-related gene variant is only 2-3 years. 1-2 years interval can ensure timely treatment before the adenoma becomes cancerous, i.e. removal of adenoma under colonoscopy to avoid the occurrence of colorectal cancer. 2. Gynecological screening: Meanwhile, for women diagnosed with Lynch syndrome, prophylactic hysterectomy and bilateral ovarian oophorectomy can be considered based on personal wishes and in the absence of reproductive requirements in strict accordance with the recommendations of NCCN guidelines. If patients do not wish to have prophylactic surgery, annual endometrial biopsy, vaginal ultrasound, and CA125 screening are recommended starting at age 25-35 years. 3. Other system screening: Meanwhile, NCCN recommends gastroduodenal endoscopy every 3-5 years starting from age 30-35 to rule out gastric cancer, urinalysis every year starting from age 25-30 to rule out urological tumors, and neurological physical examination every year starting from age 25-30 to rule out central nervous system tumors. If you are not tested for any of these genetic defects, you can just have a general population physical examination. Therefore, even if you are tested for a mismatch repair gene defect, there is no need to get into a panic. It is perfectly possible to avoid the occurrence of Lynch syndrome as long as you perform regular and comprehensive targeted screening and take necessary preventive measures. The significance of genetic screening is to establish an “early warning” for family members with Lynch syndrome, indicating a higher risk of Lynch syndrome-related tumors, so that early prevention, early diagnosis, and early treatment of the disease can be done, and a simple test can keep the whole family away from the terminal disease. When the famous Hollywood actress Angelina Jolie (Angelina Jolie) was tested for breast cancer gene defects, she chose to have her bilateral mastectomies prevented in order to prevent the occurrence of breast cancer, and this brave act was also recognized by the American public. With the progress of molecular biology, the genetic veil of more diseases will be lifted, and genetic testing will gradually fade out of the mystery and become an accessible means of detection, like X-ray and endoscopy, into everyone’s life.