2月13日,，發(fā)表在《臨床腫瘤學雜志》(Journal of Clinical Oncology)上的一項前瞻性研究顯示，一種遺傳性疾病——林奇綜合征患者易患多種類型癌癥,，尤其是乳腺癌和胰腺癌風險均顯著增加,。
林奇綜合征是一種常染色體顯性遺傳病，約占所有結直腸癌的5％～15％,，既可見于癌癥患者,也可見于尚無癌癥者,。該綜合征定義為由錯配修復(MMR)基因突變引起的對結直腸癌及某些其他癌癥(如子宮內膜癌、胃癌)的遺傳易感性。這些MMR基因突變以常染色體顯性方式遺傳,主要包括MLH1,、MSH2、MSH6及PMS2基因突變,前二者較多見,。
在化驗血液時發(fā)現(xiàn)的這種常染色體顯性遺傳疾病是由4個DNA錯配修復(MMR)基因(MLH1,、MSH2、MSH6或PMS2)中的一個突變引起的,。估計人群中攜帶頻率為1/360~1/3,010,，數值取決于計算中納入所有4個特異性突變，還是納入少于4個特異性突變,。已知這種綜合征可使多種類型癌癥的風險增高,，包括結腸癌。通常建議患者在較低年齡開始進行結腸鏡檢查,，并以較一般人群更高的頻率重復檢查,。但無突變的家庭成員無癌癥風險增高，也不需要進行較一般人群更密集的篩查,，原因尚未完全闡明,。
研究者對1997-2010年間結腸癌家庭注冊數據庫中的446例突變攜帶者和1,029非攜帶者親屬進行了隨訪。幾乎所有研究受試者(96%)為白人,，女性比例略高于一半,。入選時，不同亞組的平均年齡介于40~50歲之間,。注冊數據庫包括來自美國,、加拿大、澳大利亞和新西蘭的受試者,。
結果顯示,，經過中位數為5年的隨訪發(fā)現(xiàn)，突變攜帶者結腸癌,、子宮內膜癌,、卵巢癌、腎癌,、胃癌和膀胱癌的風險分別為一般人群的20,、31、19,、11和10倍,。乳腺癌和胰腺癌的風險分別增加了4倍和11倍。對于每種癌癥類型,，突變攜帶者的風險增加均具有高度統(tǒng)計學意義,，P值介于0.009~<0.001之間。另外,，林奇綜合征患者通常在較一般人群更低的年齡被診斷出癌癥(J. Clin. Oncol),。
研究者認為,，對于MMR基因突變攜帶者的某些特殊部位癌癥風險，應進行恰當的臨床管理,，如篩查性結腸鏡檢,、預防性全子宮切除和雙側輸卵管卵巢切除可能降低結直腸癌、子宮內膜癌和卵巢癌風險,。（生物谷Bioon.com）
doi:10.1200/JCO.2011.39.5590
PMC:
PMID:
Colorectal and Other Cancer Risks for Carriers and Noncarriers From Families With a DNA Mismatch Repair Gene Mutation: A Prospective Cohort Study
Aung Ko Win, Joanne P. Young, Noralane M. Lindor, Katherine M. Tucker, Dennis J. Ahnen, Graeme P. Young, Daniel D. Buchanan, Mark Clendenning, Graham G. Giles, Ingrid Winship, Finlay A. Macrae, Jack Goldblatt, Melissa C. Southey, Julie Arnold, Stephen N. Thibodeau, Shanaka R. Gunawardena, Bharati Bapat, John A. Baron, Graham Casey, Steven Gallinger, Lo?c Le Marchand, Polly A. Newcomb, Robert W. Haile, John L. Hopper and Mark A. Jenkins
Purpose To determine whether cancer risks for carriers and noncarriers from families with a mismatch repair (MMR) gene mutation are increased above the risks of the general population.
Patients and Methods We prospectively followed a cohort of 446 unaffected carriers of an MMR gene mutation (MLH1, n = 161; MSH2, n = 222; MSH6, n = 47; and PMS2, n = 16) and 1,029 their unaffected relatives who did not carry a mutation every 5 years at recruitment centers of the Colon Cancer Family Registry. For comparison of cancer risk with the general population, we estimated country-, age-, and sex-specific standardized incidence ratios (SIRs) of cancer for carriers and noncarriers.
Results Over a median follow-up of 5 years, mutation carriers had an increased risk of colorectal cancer (CRC; SIR, 20.48; 95% CI, 11.71 to 33.27; P < .001), endometrial cancer (SIR, 30.62; 95% CI, 11.24 to 66.64; P < .001), ovarian cancer (SIR, 18.81; 95% CI, 3.88 to 54.95; P < .001), renal cancer (SIR, 11.22; 95% CI, 2.31 to 32.79; P < .001), pancreatic cancer (SIR, 10.68; 95% CI, 2.68 to 47.70; P = .001), gastric cancer (SIR, 9.78; 95% CI, 1.18 to 35.30; P = .009), urinary bladder cancer (SIR, 9.51; 95% CI, 1.15 to 34.37; P = .009), and female breast cancer (SIR, 3.95; 95% CI, 1.59 to 8.13; P = .001). We found no evidence of their noncarrier relatives having an increased risk of any cancer, including CRC (SIR, 1.02; 95% CI, 0.33 to 2.39; P = .97).
Conclusion We confirmed that carriers of an MMR gene mutation were at increased risk of a wide variety of cancers, including some cancers not previously recognized as being a result of MMR mutations, and found no evidence of an increased risk of cancer for their noncarrier relatives.
