探討修飾BRCA1/2突變患者罹癌風險的基因及環境因子

Abstract

在遺傳諮詢的探討上，對於帶有BRCA基因變異之患者，其家族遺傳率及個案自身的乳癌發病風險皆為癌症遺傳諮詢上重要的課題。乳癌為我國女性好發癌症排名第一位，相較於歐美國家，國人乳癌的好發年齡也有較早發的趨勢。臨床上所見，帶有BRCA基因變異的個案在疾病的外顯率上卻不盡相同，同一家族中有小於40歲以前的早發個案卻也有高達74歲高齡不曾有乳癌罹病史的健康個案。根據以上臨床所見之實證，故推斷除了BRCA基因的變異所增加的罹癌風險，應仍有許多未知的修飾因子可左右乳癌發病的風險。本實驗收納了帶有BRCA基因遺傳之個案共149位，BRCA1變異82位；BRCA2變異者67位，修飾因子探討分為(1)基因修飾子：95位個案抽取了血液DNA送至中研院利用Axiom Genome-Wide TWB 2.0 Array Plate進行單核苷酸多態性(single nucleotide polymorphism, SNP)分析，並將結果比對國外已發表之乳癌風險之SNP權重並證實rs4593472、rs11242675、rs204247、rs4415084、rs6837016及rs9693444共計6個SNPs等位基因變異與個案間具有調控罹癌風險之統計意義。(2)環境修飾因子的腸道菌相：收取了105位個案的糞便檢體進行腸道菌相之分析，在105位個案中再就發病年齡最極端之早晚發族群做進一步的分析與討論，其中在早於40歲以前發病的早發族群，共計27位個案，腸道菌相中可見Eggerthella lenta及Bifidobacterium sp.菌種具有相對豐富度的結果；另在晚於60歲發病或未發病之個案，共計8位，在腸道菌相中則可見Akkermansia sp.的相對豐富度。(3)環境修飾因子的賀爾蒙暴露史：回收了78份問卷針對個案之初經年齡、經期規則性、生產史及哺乳史與賀爾蒙較相關之變因，進行相對風險及勝算比的討論，在結果的呈現上卻未有顯著的調控效力。 綜整以上，各修飾因子的調控尚需要更清楚的釐清，在臨床病人的諮詢及預防醫學的理念上才能更確實的協助個案以及個案的親屬們在面對高風險乳癌帶因者的診斷下，擁有更多的預防性處置。

In cancer genetic counseling for the carriers of BRCA gene mutation, the heritability of the mutation run in the family and the individual’s own risk of breast cancer are both important studies. Breast cancer is the most common cancer among females in Taiwan. Compared with occidental countries, the age of onset for breast cancer in Taiwanese tends to be earlier. In clinical finding, cases with BRCA gene mutations had different penetrance of the breast cancer. In the same family, there are not only early-onset cases, which onset at the age before 40 years old, but also a healthy case, which had no history of breast cancer up to 74 years old. Based on the clinical evidence, we inferred that in addition to the mutation of the BRCA gene, there should exist many unknown modifiers which affect the risk of breast cancer. In our study, a total of 149 participants with the mutation of BRCA gene were included, 82 cases with BRCA1 mutations and 67 cases with BRCA2 mutations. To discuss how others modifiers affect the penetrance of breast cancer, we divided them into three parts: 1. Genetic modifiers: 95 cases with their blood DNA were collected and sent to the National Center for Genomic Medicine for the SNPs analysis were performed by the Axiom Genome-Wide TWB 2.0 Array Plate. The results were compared to the published SNPs report of breast cancer, and 6 SNPs were weighted and confrimed to have statistically significant relationship between the breast cancer risk and our cases: rs4593472、rs11242675、rs204247、rs4415084、rs6837016 and rs9693444. 2. Gut microbiota of environmental modifiers: 105 cases with their fecal DNA were collected and performed the analysis based on the captured theory. Then, we will further analyze and discuss the cases with the most extremely early or late onset age in early-and-late onset groups. There were 27 cases in the early-onset group with onset age younger than 40 years old, and we found that Eggerthella lenta and Bifidobacterium sp. have the higher relative abundance in their intestinal flora. Additionally, 8 cases in the late-onset group with onset age elder than 60 years old, and we found that Akkermansia sp. has the higher relative abundance in their intestinal flora. 3. Hormone exposure history of environmental modifiers: 78 questionnaires were collected, and we calculated the relative risk and odds ratio of several variable including, the first menstrual age, menstrual regularity, pregnancy history, and breastfeeding history of the cases. However, there was no significant finding in the questionnaires. In summary, the regulation of the various modifiers needs to be clarified more clearly. To achieve the goal of preventive medicine, the cancer genetic counseling should not only pay attention to the affected but also the unaffected carrier in the pedigree. Give them not only clinical preventive treatment like breast ultrasound examination, blood test for cancer indicators but also some lifestyle habit. More clinical advice can make patients less worried. In addition, the ability to control cancer from the daily routine is the greatest boon for everyone.