Genetic Testing of BRCA 1 & 2 genes are used in the U.S. for clinical risk assessment of hereditary breast and ovarian cancers. However, these tests are currently used almost solely for research purpose and not in clinical practice in Japan. We describe the current situation of these genetic tests in Japan from the perspective of a commercial reference laboratory that has been trying to put these tests to practical use in clinical medicine, as in the U.S., in correlation with the established Japanese ethical guidelines for clinical genetic testing.
To elucidate the mutation rate and SNPs information of the BRCA1 and the BRCA2 genes in Japanese familial breast cancer, we developed a multi-center studying group of the genetic testing and performed the genetic testing by the stop codon assay and direct DNA sequencing analysis. We identified 11 pathogenic protein-truncating mutations and many SNPs in 65 individuals from 60 unrelated Japanese breast cancer families. Through the process of the project, we became aware of several critical points that should be incorporated in future studies. First, consideration for the ELSI of familial cancer, it is important to organize the studying group based on the ethical rules for implementing genetic testing for familial cancer. Second, the clinical validity and costeffectiveness for each method adopted for genetic testing should be evaluated. Finally, development of an accurate assay that can monitor the protein functions is necessary to distinguish between polymorphisms and missense mutations.
Among 113 Japanese breast cancer families, we have identified 15（13 ％）and 21（19 ％）deleterious germline mutations in BRCA1 and BRCA2 genes, respectively. Among patients with BRCA1 or BRCA2 mutation carrier, breast cancers occurred in significantly younger women with higher frequency of bilateral breast cancers as compared with non-carriers. The estimated cumulative lifetime risk of breast cancer for women who carry BRCA1 or BRCA2 mutations was nearly 80%. In BRCA1 breast cancers, a higher rate of histological grade III and a higher frequency of estrogen-receptor negativity were characterized as compared to sporadic cancers. On the contrary, there was no significant difference in cancers between BRCA2 mutation carriers and non-carriers. These clinicopathological factors found in Japanese BRCA1 or BRCA2 mutation carriers seem to be similar with those of Caucasian mutation carriers.
We performed presymptomatic BRCA gene testing to the three family members including of twins in a familial breast cancer family diagnosed pathogenetic mutation in BRCA2 gene. All members were over the twenty years. We explained familial breast cancer and BRCA gene testing and got autonomic consent before gene testing. Two women were carriers and one was not, and dizygotic twins were made clear by genetically. We told high risk for breast cancer and diet or breast cancer screening for breast cancer prevention to carriers and the same risk of breast cancer as general population to non-carrier in familial tumor counseling.
A survey of familial breast cancer was conducted among postoperative breast cancer patients. The questionnaire was sent to 135 subjects who underwent the breast cancer surgery in our department between 1999 and 2004, and responses were received from 86 of 135 (response rate 63.7%). The questionnaire includes: 1. Do you know the characteristics of familial breast cancer? If there were a possibility of this kind of disease, 2. Would you want to receive genetic testing? 3. Would you want to undergo prophylactic mastectomy or oophorectomy? [Result]: Fifty percent of patients who responded to the investigation knew about “Familial breast cancer”, and there is a 73.3% of 86 samples would have liked to receive genetic testing. Most of the patients preferred regular follow-up and nobody wanted to undergo prophylactic mastectomy, while 5.8% were willing to have prophylactic oophorectomy and 8.2% chemoprevention with the anti-estrogen medicines. Most of the questionnaire responses showed uneasiness towards genetic diagnosis. True information offered by the patients, an investigation system and follow-up system are necessary for the research and treatment of familial breast cancer.
The extension symposium of the 11th Annual Meeting of the Japanese Society for Familial Tumors（JSFT） was held in Fukushima City on June 25, 2005. The theme of the symposium was‘ Considering cancer heredity’, and six speakers gave the participants a series of lectures about hereditary colorectal cancer, familial breast cancer, and multiple endocrine neoplasia as well as patient support systems for these diseases. Using this opportunity, I, as co-chairperson, summarized the symposium and described my personal view about the future direction of the JSTF.
A large number of clinical trials have beenperformed using sulindac, a non-steroidal antiinflammatorydrug （NSAID）. Sulindac reduces thesize and number of large bowel polyps. However, itcannot be used for this indication in clinical settings as yet, because of the frequent occurrence of seriousgastrointestinal side effects. There are a number ofcases in which aggressive tumors developed despite areduction in the size of polyps. In addition toNSAIDs, clinical trials have been performed usingvitamins and dietary components. These show minimalside effects, but their efficacy is still insufficient forclinical use, and further studies are anticipated.
We describe the use of laparoscopic total colectomy by the prolapsing technique for surgical treatment of familial adenomatous polyposis（FAP）in a 34-year-old woman. First, the entire colon was laparoscopically ablated and removed via a small incision in the abdominal wall. Then, an ileal J-pouch was formed extracorporeally. Next, the distal rectum was gradually everted and transanally pulled outside the body. It was then transected under direct vision with a TA-stapler, pushed back through the anus into the pelvic cavity, and anastomosed with the ileal J-pouch using the laparoscopic double stapling technique. The postoperative course of the patient has been favorable for 18 months. The frequency of defecation is 6 times per day or less, and she has no fecal incontinence. These minimally invasive surgical procedures appear to be promising as a radical treatment for patients with FAP.