2月13日,，發(fā)表在《臨床腫瘤學(xué)雜志》(Journal of Clinical Oncology)上的一項(xiàng)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(fēng)險(xiǎn)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(jié)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(cuò)配修復(fù)(MMR)基因突變引起的對(duì)結(jié)直腸癌及某些其他癌癥(如子宮內(nèi)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(yàn)血液時(shí)發(fā)現(xiàn)的這種常染色體顯性遺傳疾病是由4個(gè)DNA錯(cuò)配修復(fù)(MMR)基因(MLH1,、MSH2、MSH6或PMS2)中的一個(gè)突變引起的,。估計(jì)人群中攜帶頻率為1/360~1/3,010,，數(shù)值取決于計(jì)算中納入所有4個(gè)特異性突變，還是納入少于4個(gè)特異性突變,。已知這種綜合征可使多種類型癌癥的風(fēng)險(xiǎn)增高,，包括結(jié)腸癌,。通常建議患者在較低年齡開始進(jìn)行結(jié)腸鏡檢查,，并以較一般人群更高的頻率重復(fù)檢查,。但無突變的家庭成員無癌癥風(fēng)險(xiǎn)增高，也不需要進(jìn)行較一般人群更密集的篩查,，原因尚未完全闡明,。
研究者對(duì)1997-2010年間結(jié)腸癌家庭注冊(cè)數(shù)據(jù)庫中的446例突變攜帶者和1,029非攜帶者親屬進(jìn)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(shí)，不同亞組的平均年齡介于40~50歲之間,。注冊(cè)數(shù)據(jù)庫包括來自美國(guó),、加拿大、澳大利亞和新西蘭的受試者,。
結(jié)果顯示,，經(jīng)過中位數(shù)為5年的隨訪發(fā)現(xiàn)，突變攜帶者結(jié)腸癌,、子宮內(nèi)膜癌,、卵巢癌、腎癌,、胃癌和膀胱癌的風(fēng)險(xiǎn)分別為一般人群的20,、31、19,、11和10倍,。乳腺癌和胰腺癌的風(fēng)險(xiǎn)分別增加了4倍和11倍。對(duì)于每種癌癥類型,，突變攜帶者的風(fēng)險(xiǎn)增加均具有高度統(tǒng)計(jì)學(xué)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(rèn)為，對(duì)于MMR基因突變攜帶者的某些特殊部位癌癥風(fēng)險(xiǎn),，應(yīng)進(jìn)行恰當(dāng)?shù)呐R床管理,，如篩查性結(jié)腸鏡檢、預(yù)防性全子宮切除和雙側(cè)輸卵管卵巢切除可能降低結(jié)直腸癌,、子宮內(nèi)膜癌和卵巢癌風(fēng)險(xiǎn),。（生物谷Bioon.com）
doi:10.1200/JCO.2011.39.5590
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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.
