[Fat Bear Science] My aunt has a tumor. Will it be passed on to me? You can’t miss out on genetic knowledge

Anxious...zZ

What the hell are you doing?

What should I do? My aunt got ovarian cancer when she was less than 40 years old. Will I inherit the disease?

Your aunt is your husband's sister, not your mother's sister, so she won't pass it on to you. And your aunt is the only one who got it, so it's definitely not hereditary. Others who got it had many people in their family get tumors.

If a relative has a tumor, will I inherit it? Will a tumor patient pass the tumor on to their children? We often encounter similar questions, so is tumor hereditary?

In this issue, Fat Bear invites Yi Lin, deputy director of the Oncology Laboratory of Chongqing Cancer Hospital, to talk about genetics.

Yi Lin, female, chief technician. Deputy director of the Oncology Laboratory of Chongqing Cancer Hospital. Currently serves as a standing member of the Precision Medicine and Molecular Diagnosis Committee of Chongqing Association of Integrated Traditional Chinese and Western Medicine, a director of Chongqing Society of Biochemistry and Molecular Biology, and a member of the Precision Medicine and Molecular Diagnosis Group of the Oncology Committee of Chongqing Medical Association.

Director Yi Lin said that the answer is yes. A large number of studies have shown that genetic factors play a very important role in the occurrence and development of tumors. Tumors are a multi-gene genetic susceptibility disease, and often there is a phenomenon of family aggregation. In simple terms, the occurrence and development of tumors are more or less related to genetic factors, among which genetic factors play a leading role in the occurrence of some tumors. In other words, some tumors are hereditary.

To give a typical example, Hollywood actress Angelina Jolie underwent preventive bilateral mastectomy because genetic testing revealed that she inherited a mutated cancer susceptibility gene, BRCA1, from her mother, with an 87% chance of developing breast cancer. Therefore, she chose preventive mastectomy. Although public opinion was in uproar at the time, she promoted cancer and genetic susceptibility to society, further arousing people's attention to genetic susceptibility to cancer.

At present, the most common solid tumors that have been studied clearly include hereditary breast cancer, ovarian cancer, hereditary non-polyposis colorectal cancer (Lynch syndrome), etc. The occurrence of such malignant tumors is often closely related to gene mutations. If the pathogenic mutation that causes the tumor occurs at the germ cell level, the risk of tumors in the offspring of the family who acquire the mutation will be higher than that of the normal population.

Hereditary breast cancer Ovarian cancer

In hereditary breast cancer and ovarian cancer, BRCA1/BRCA2 gene mutations are more likely to cause disease. About 40%-50% of hereditary breast cancer is caused by BRCA1/BRCA2 gene mutations. Literature reports that people who carry BRCA1 gene mutations have a 50%-85% and 15%-45% risk of developing breast cancer and ovarian cancer, respectively. People who carry BRCA2 gene mutations have a 50%-85% and 10%-20% risk of developing breast cancer and ovarian cancer, respectively. However, not all mutation carriers will develop cancer, but people who carry this mutation have a high susceptibility to cancer. In addition to BRCA1 and BRCA2, mutations in TP53, PTEN, STK11/LKB1, CDH1, CHEK2, ATM, MLH1, MSH2, etc. have been shown to be associated with hereditary breast cancer and/or ovarian cancer.

Risk management for BRCA1/2 mutation carriers:

Hereditary colorectal cancer

Lynch syndrome is the most common hereditary colorectal cancer syndrome in clinic, accounting for 2%-4% of all colorectal cancers. Lynch syndrome is caused by mutations in germline DNA mismatch repair genes (MMR), which mainly include MLH1, MSH2, MSH6 and PMS2. Carriers of germline mutations in these genes are prone to a variety of tumors, such as colorectal cancer, endometrial cancer, ovarian cancer, gastric cancer, small intestine cancer, hepatobiliary cancer, upper urinary tract cancer, brain cancer, skin cancer, etc. Lynch syndrome patients are prone to multiple primary tumors in their lifetime. 54%~61% of patients will develop a second primary tumor, and 15%~23% of patients will develop three or more primary tumors.

Colorectal cancer is generally considered to be the primary cancer of Lynch syndrome, and the risk of men is higher than that of women. In men, if a Lynch syndrome patient does not undergo subtotal or total colectomy when the first colorectal cancer is discovered, the chance of developing another primary colorectal cancer within 10 years is approximately 25% to 30%. Therefore, early diagnosis of Lynch syndrome plays a significant guiding role in the treatment of colorectal cancer patients themselves. However, in women, in Lynch syndrome families, the incidence of endometrial cancer is greater than or equal to colorectal cancer. Among these female cases, 50% of patients have endometrial cancer or ovarian cancer as their first malignant tumor.

In Lynch syndrome-related endometrial cancer, mismatch repair genes are the main highly penetrant susceptibility genes, of which MSH2 gene accounts for 50-60%, MLH1 for 24-40%, and MSH6 for 10-13%. Women with germline mutations in hMLH1 and hMSH2 genes have a lifetime risk of developing endometrial cancer of 40-60% and a risk of ovarian cancer of 9-12%. A study evaluating women carrying hMSH6 gene mutations pointed out that when women reach the age of 70, the cumulative incidence of endometrial cancer is 71%.

Lynch syndrome clinical risk management:

When screening for these hereditary tumors, patients are advised to go to a professional genetic counseling clinic for consultation. For women with hereditary gene mutations, the main way to reduce the impact of the disease is early diagnosis. In addition, a reasonable diet, moderate exercise, quitting smoking and drinking, psychological balance, and maintaining good living habits are also important factors in reducing the incidence of tumors.

These are the things you need to know...

Q1: If several of my relatives have cancer, does it mean it must be hereditary?

First of all, we need to make it clear that the "relatives" we refer to in genetic analysis are "blood relatives" who are related to each other by blood. For example, you are blood relatives to your aunt and cousin, but not to your uncle and cousin's wife. So does it mean that if several blood relatives have tumors, it is hereditary? It depends on the specific situation.

For example, in the family below, two of A's mother's four sisters had breast cancer and one had ovarian cancer, and they were diagnosed at a young age, which was consistent with the characteristics of hereditary breast/ovarian cancer syndrome (HBOC). With the assistance of a counselor, BRCA1/2 gene testing was performed. The test report showed that the BRCA1 gene of the three sick sisters had a pathogenic mutation, confirming that they did have hereditary breast/ovarian cancer syndrome.

For example, in this family, B's father, grandfather and a cousin all had lung cancer, and the father and uncle were diagnosed more than 20 years earlier than the grandfather. After careful questioning and communication, we learned that B's grandfather was a non-smoker, but after retirement he had the habit of sitting in a teahouse every day, and was exposed to secondhand smoke for a long time; his father was a non-smoker, but due to work, he was exposed to car exhaust and dust for a long time; it was unclear whether the cousin smoked or not, but he had been engaged in decoration and painting for a long time.

On the one hand, the current consensus is that environmental factors are the main cause of lung cancer; on the other hand, from the information we have learned, B's father, grandfather and cousin have been exposed to adverse environmental factors (second-hand smoke, exhaust, dust, etc.) for a long time. Grandfather started to be exposed after retirement, while father and cousin were exposed for a long time at work, which is consistent with the fact that father and cousin were diagnosed earlier than grandfather. In the end, we believe that the main cause of lung cancer in the three people in B's family is adverse environmental factors.

Q2: Can “female tumors” such as ovarian cancer, breast cancer, and endometrial cancer only be inherited from the mother?

Let’s first understand chromosomes, DNA and genes.

Chromosomes are substances in the cell nucleus that carry genetic information. They are cylindrical or rod-shaped under a microscope and are mainly composed of DNA and protein. They are easily stained by basic dyes, hence their name. There are 46 chromosomes, or 23 pairs, in human somatic cells.

DNA is the abbreviation of deoxyribonucleic acid, which is a type of biological macromolecule that carries genetic information. It is formed by connecting four deoxyribonucleotides and usually has a double helix structure.

A gene is the smallest DNA fragment that has a certain biological function (such as encoding a protein).

So where do the 23 pairs of chromosomes in the human body come from? When the father and mother form sperm and egg cells, the number of chromosomes will be halved, that is, there are only 23 chromosomes in the sperm and egg cells. When they combine, they form a complete 23 pairs of chromosomes. So under normal circumstances, each pair of chromosomes in the human body comes from one father and one mother. At this point, everyone should understand that even some "female tumors" may have pathogenic mutations that are inherited from the father.

In addition, these "female tumors" do not only affect women. For example, the hereditary breast/ovarian cancer syndrome (HBOC) we mentioned earlier. Although men do not have ovaries and will not get ovarian cancer, men who carry BRCA1/2 pathogenic mutations have an increased risk of developing breast cancer (yes, although the risk is lower than that of women, men can also get breast cancer!), prostate cancer, pancreatic cancer and other tumors compared to the general male population.

Q3: If only one relative has a tumor, does that mean it is definitely not hereditary?

Having multiple blood relatives suffer from tumors is one of the important manifestations of hereditary tumors and one of the important reference indicators for evaluation, but it is not an absolute standard.

First, in addition to multiple blood relatives suffering from the disease, hereditary tumors also have other manifestations such as early onset age and multiple primary tumors in one person. Second, due to various reasons, the number of relatives is generally small nowadays, so sometimes it does not appear that "many relatives have tumors". Third, in addition to being acquired from parents, pathogenic mutations may also occur newly in an individual (yes, you read that right, newly.occurring).

Therefore, even if only one of your relatives has a tumor, don't be careless.

Q4: Why do we sometimes spend money and time on tumor susceptibility gene testing but don’t get the desired results?

First of all, we need to understand the significance of tumor susceptibility gene testing. Tumor susceptibility gene testing is of great significance in the clinical diagnosis and treatment of hereditary tumors. It can help us determine the genetic risk of an individual to develop a certain tumor, thereby helping us diagnose hereditary tumors and conduct individualized prevention and treatment. At the same time, we must also be aware that genetic testing itself has unavoidable limitations.

One is the limitation of our knowledge of tumor susceptibility genes. Although medicine is developing rapidly, we have not yet identified all genes related to hereditary tumors, so current genetic testing cannot cover all tumor susceptibility genes.

The second is the limitation of the technology itself. The various detection technologies currently used in the field of genetic testing have their own advantages and limitations. For example, PCR technology can only detect known sites, and sequencing technology has difficulty in detecting large fragment rearrangements.

The third is the limitation of the interpretation of the results. On the one hand, we are still unclear whether certain changes in DNA cause biological effects and how big the effects are. On the other hand, due to different bioinformatics capabilities and the influence of subjective factors such as experience and personal inclinations, different interpreters may make different interpretations of the raw data obtained from the test based on the existing evidence.

Based on the above factors, the situation of "spending money and time on tumor susceptibility gene testing but not getting the desired results" cannot be completely avoided at present, and it is not a "trap". According to the biological effects produced and the existing level of evidence, the detected DNA changes are generally divided into 5 categories: pathogenic mutations, suspected pathogenic mutations, mutations of unknown significance, suspected non-pathogenic mutations and non-pathogenic mutations.

"Mutations of unknown significance" is a serious conclusion reached by bioinformatics personnel after careful analysis of the DNA changes and review of a large amount of information. That is, it is currently impossible to judge whether the biological effect produced by the DNA changes themselves is pathogenic or non-pathogenic, and there is not enough literature evidence to prove whether it is pathogenic or non-pathogenic. With the development of medicine or the emergence of new evidence, it may be reclassified into other categories. When "Mutations of unknown significance" appear, don't let your imagination run wild. The consultant will analyze the specific situation and give health management suggestions.

Text/ Fat Bear Picture/ Online Reviewer/ Yi Lin

Original article, please do not reprint without authorization

Chongqing Cancer Prevention and Treatment Science Popularization Base/Member of China Medical Self-media Alliance

Chongqing Science and Technology Commission Science Popularization Funding Project