1. What is the proportion of hereditary tumors? What is the inheritance pattern? Generally speaking, for most common tumors, hereditary tumors account for a relatively small proportion, for example, hereditary breast cancer and colorectal cancer account for less than 10% of the total number of tumors; however, for rare tumors, the hereditary component is increased, for example, pheochromocytoma, adrenal cortical malignancy, and optoblastoma, about 40-60% are related to heredity. What is the inheritance pattern of hereditary tumors? The most common mode of inheritance is autosomal dominant inheritance with mutations in oncogenes/oncogenes, although the ectopic rate of this inheritance is usually not 100%; in addition, a chromosomal variant mode of inheritance also exists, but is less common and mostly associated with childhood tumors. What are the characteristics of tumors that are inherited in an autosomal dominant manner? (1) Multiple generations of disease in a family; (2) Early age of onset; (3) A single patient may carry multiple primary foci/bilateral tumors. 2.What is hereditary colorectal cancer about? You may have heard that some intestinal diseases are associated with the incidence of colorectal cancer. Specifically, the lifetime probability of colorectal cancer in the general population is 6%, 15-40% in patients with inflammatory bowel disease, 70-80% in Lynch syndrome (also known as hereditary non-adenomatous colorectal cancer (HNPCC)), and up to 95% or more in patients with familial adenomatous polyposis (FAP). As can be seen, hereditary colorectal cancer is divided into two major groups: non-polyp Lynch syndrome and hereditary polyp syndrome, while the latter can be further divided into adenomatous polyps (mainly FAP) and misshapen polyps (including Peutz Jegher syndrome, juvenile multiple polyp syndrome, and Cowden syndrome, which are described in the hereditary breast cancer (introduced in the section on hereditary breast cancer). 3.What are the characteristics of Lynch syndrome (HNPCC)? How to screen for it? Among the hereditary colorectal cancers mentioned above, the most common one is Lynch syndrome, what are the characteristics of colorectal cancer associated with Lynch syndrome? (1) The tumors are younger, with an average age of 45 years; (2) 2/3 are right-sided colon cancers; (3) The prognosis is better than that of colorectal cancers of the same stage; (4) In addition to colorectal cancer, patients with Lynch syndrome have a 25-60% chance of developing endometrial cancer during their lifetime, which is the second most common tumor, in addition to ovarian cancer, gastric cancer, urological tumors with a 10% chance, pancreatic cancer with a <5 Lynch syndrome is an autosomal dominant genetic mutation disease in which the germ cell line has a base mismatch (MMR) gene and the tumor is microsatellite instable (MSI). The reason why we say that Lynch syndrome-associated colorectal cancer is more important is that, in addition to being a relatively common genetic colorectal cancer, its therapeutic use is different from that of ordinary colorectal cancer. How do we screen for patients who need genetic screening for Lynch syndrome in clinical practice? There is an "Amsterdam criterion", which is easy to remember (the "3-2-1 rule"): 3 or more relatives with tumors related to Lynch syndrome (colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, urological tumors, hepatobiliary tumors, neurological tumors, and neurological tumors). However, the sensitivity and specificity of the Amsterdam criteria are not high (around 50%). Another simpler screening method is to perform MSI genetic screening (gene level) or MMR protein immunohistochemistry (protein level) in all younger colorectal cancer patients, and the results: 80% of Lynch syndrome colorectal cancers are highly - microsatellite unstable (MSI-H), while the proportion of MSI-H in disseminated colorectal cancer patients is only 15%, and this portion of disseminated patients are similar to those with Lynch syndrome and have a better prognosis. However, it should be noted that the screening results for MSI-H are not very specific: still 50% of MSI-H patients are not Lynch syndrome. Therefore, for MSI-H tumors, further germline genetic testing is needed to definitively diagnose Lynch syndrome. What can be done to prevent it? Patients with definite diagnosis of Lynch syndrome need to be screened for colorectal cancer by colonoscopy every 1-2 years from age 20, and prophylactic hysterectomy or endometrial biopsy from age 30 onwards is recommended for women who have completed childbirth. 4.What are the characteristics of familial adenomatous polyps (FAP)? How can these patients be identified? FAP is an autosomal dominant disease with an APC tumor suppressor gene mutation, multiple adenomatous polyps (100-1000) appearing in adolescence, and early onset of colorectal cancer, usually before the age of 35. It is important to note that 30% of FAP patients have de novo germline mutations, so we cannot easily rule out FAP based on family history alone. hyperplasia. In addition to the "classic FAP" patients mentioned earlier, there is also a category of "delayed FAP" disease that is not very typical. Compared to classical FAP, these patients have a later age of onset (around 50 years old), a smaller number of adenomas (10-100), and a typical adenoma in the right hemithorax, and the cause of this disease is not a problem with the APC gene itself, but with the upstream and downstream DNA of the APC gene. Patients with confirmed FAP need annual colonoscopy from the age of 10 years and prophylactic removal of the entire colon once adenomatous polyps are detected; in addition, patients with FAP need to be alert for thyroid cancer. 5.What is malformation-like hereditary colorectal cancer? We have just talked about the most common non-polypoid Lynch syndrome and the most common type of hereditary polypoid colorectal cancer, FAP, and now we introduce several common types of misshapen colorectal cancer: Peutz Jegher syndrome, juvenile polypoid syndrome and Cowden syndrome. The etiology of PeutzJegher syndrome (PJS) is an autosomal dominant pattern mutation in the STK11 gene; the intestinal manifestation of PJS disease is a misshapen tumor, and patients with PJS have a lifetime risk of developing tumors up to 80%, including a 50% probability of breast cancer, 40% of colorectal cancer, 30% of gastric cancer, 30% of pancreatic cancer, and 13% of small bowel tumors; the more unique manifestations of PJS patients are mucosal hyperpigmentation, including pigmentation of the lips and fingertips, can help us identify them. Juvenile multiple polyp syndrome refers to multiple polyps of the digestive system that appear in adolescence. Patients have a lifetime risk of colon cancer 50% and gastric cancer 20%, in addition to small intestine and pancreatic cancer risk, often complicated with hereditary hemorrhagic capillary dilation. 6.What are the hereditary breast cancers? Similar to colorectal cancer, most breast cancer cases are disseminated, and 15-20% are associated with family factors, which can refer to low prevalence genes, or living environment; in addition, 5-10% of breast cancer patients are hereditary. The main genes/syndromes associated with hereditary breast cancer are the following: BRCA1/BRCA2 gene carriage, Li Fraumeni syndrome (P53-associated), Cowden syndrome (PTEN-associated), PeutzJeghers syndrome (STK11-associated), hereditary pancreatic cancer (PALB2 gene-associated), and diffuse hereditary gastric syndrome (CDH1-associated). 7. What is the story of BRCA1 and BRCA2-associated breast cancer? BRCA1/2 breast cancer is probably the most "well known" of the hereditary breast cancers. These two genes are located on chromosomes 17 and 13, respectively, and they encode proteins that play an important role in genomic stability. In the general population (non-Jewish), breast cancer patients under 35 years of age have a 10% probability of having a BRCA1/2 mutation-associated tumor, while triple-negative breast cancer patients under 50 years of age have a 20% probability of having a causative factor associated with BRCA1/2. BRCA1 mutation carriers have a 50-85% probability of developing breast cancer and a 40% probability of ovarian cancer; BRCA2 mutation carriers have a 40-70% probability of developing breast cancer and a 15% probability of developing ovarian cancer. In addition, BRCA1/2 carriers have an increased probability of developing pancreatic cancer, prostate cancer, and male breast cancer. BRCA1 and BRCA2 carriers have different types of breast cancer: 50-70% of BRCA1 carriers have triple-negative breast cancer, while the majority of BRCA2 carriers have hormone receptor-positive breast cancer. The prognosis of BRCA-carrier-associated ovarian cancer, which is typical of high-grade plasma cell epithelial cancer, is better than that of disseminated cases. What should be done to prevent tumors in BRCA1/2 carriers? In terms of screening means, for breast cancer, it is recommended to have a mammogram every 6-12 months starting from age 20 and annual mammogram as well as MRI starting from age 25 (note: it is "and" not "or", it is recommended to have both tests). For ovarian cancer, annual transvaginal ultrasound and annual CA-125 test are required starting at age 30; in terms of preventive measures, bilateral mastectomy and bilateral ovarian oophorectomy can be performed (not mandatory) (recommended at age 35-40, after the patient has completed childbirth), and endocrine drugs such as tamoxifen can be considered for prevention. 8. Besides BRCA1/2, what other hereditary breast cancer diseases are there? The first is Li-Fraumeni syndrome. Patients with this syndrome have a lifetime probability of developing tumors up to 90%, while men have a slightly lower probability of 70%; the probability of developing tumors before the age of 35 is 50%, among which breast cancer is the most common one, and other tumors include: sarcoma, neurological, adrenal cortical tumors, leukemia and so on. Patients with tumors, especially in childhood, should be alert to this syndrome. For patients with Li-Fraumeni syndrome, what should be done to prevent cancer? For women, breast screening every six months to a year, and annual mammograms as well as MRIs starting at age 20. For other tumor prevention, colonoscopy every 2-5 years starting at age 25 and screening for relevant tumors in conjunction with family history. In addition, Cowden syndrome is also worth mentioning. This syndrome is associated with mutations in the PTEN gene, and patients have a 25-50% lifetime probability of developing breast cancer, in addition to other tumors: thyroid cancer (10%), endometrial cancer (5-10%), colorectal cancer of the mismatched tumor subtype that we just mentioned in the section on hereditary colorectal cancer, and renal cell carcinoma. Patients with this Cowden syndrome have typical pathological mucocutaneouslesions on the skin. 9. Besides colorectal cancer and breast cancer, what other hereditary tumors are there? MEN is the abbreviation of "multiple endocrine neoplasms", and there are two types of MEN syndromes, MEN1 and MEN2. If you encounter a patient with medullary thyroid cancer in your clinic, you need to be alert for MEN2 syndrome. About 20% of patients with medullary thyroid cancer have MEN2 syndrome, which is divided into MEN2A and MEN2B, both of which have a 100% chance of developing medullary thyroid cancer (!). In addition to medullary carcinoma, there are two other tumors associated with MEN2A: pheochromocytoma and primary parathyroid hyperplasia, and two tumors associated with MEN2B: pheochromocytoma and mucinous neuroma. the gene associated with MEN2 syndrome is RET gene activation, and for clear carriers, the thyroid needs to be removed before age 6, and pheochromocytoma and parathyroid function need to be followed up. In addition to this MEN2, there is also the MEN1 syndrome, which is primarily a condition in which patients have an elevated probability of developing parathyroid tumors, pituitary tumors, and carcinoid tumors.