生命科學與醫學獎
2018

2018年度邵逸夫生命科學與醫學獎頒予瑪莉-克萊爾・金 (Mary-Claire King)，以表彰她繪製第一個乳腺癌基因的基因圖。瑪莉-克萊爾・金利用數學模型預測和證明乳腺癌可以由單個基因引起。她繪製的基因圖促成了乳腺癌基因的克隆，因而挽救了許多人的生命。瑪莉-克萊爾・金是美國西雅圖的華盛頓大學醫學系和基因組科學系美國癌症協會講座教授。

金的職業生涯大部分時間都專注在癌症流行病學上。她非凡的洞察力促使她投入研究遺傳與乳腺癌的關係。眾所周知，同一癌症在不同群組中的發病率會存在差異。其他科學家對這事實並不特別關注，但金推測這個現象必定和基因有關，若利用遺傳學技術研究，有可能成功發現它。雖然有很多癌症研究人員對她的想法持懷疑態度，她卻堅持自己的想法。乳腺癌是一種常見而又複雜的疾病，普遍認為是由多種遺傳和環境因素相互作用而產生。但瑪莉-克萊爾認為觀察到的現象，暗示一部份的乳腺癌，可能是遺傳引起的。因此早在利用基因組工具進行人類基因分析之前，從1974年開始，她就對超過1500個有多位成員曾患乳腺癌的家庭進行針對性測試。她利用數學方法推測出這些家庭中大約有4%的成員具有這個疾病基因，從而解釋病例集群的現象。她還利用來自受影響和未受影響的年輕人和老年人的數據，預測出帶有突變基因的婦女到了70歲時患乳腺癌的風險約為80%，而沒有受影響等位基因的婦女，風險則只有8%。 同一領域的科學家對她的數學模型持相當懷疑的態度，因此她著手經由找出乳腺癌基因在染色體的定位，從而證明乳腺癌基因是確實存在的。她以一群發病率異常高的家庭作為研究對象，並於1990年利用連鎖分析方法將乳腺癌基因定位於人類17號染色體(基因座q21)，並命名為BRCA1 。

Breast cancer is a common complex disease, and until Mary-Claire King’s work, the prevailing view was that such diseases arise from interactions among multiple genetic and environmental factors. But she was intrigued by hints that there might be inherited forms of breast cancer and beginning in 1974, long before there were genomic tools for human genetic analysis, she tested this head-on by studying more that 1500 families, each identified through one woman with breast cancer. Using a mathematical approach, she determined that clustering of breast cancer in these families occurred more frequently than expected by chance, and that this clustering could be best explained by the presence of mutations in an unknown gene that greatly increased risk in about 4 % of families. By studying patterns of breast and ovarian cancer in families, she predicted that among women carrying mutations in this hypothetical gene, the risk of breast cancer would be about 80% by age 70, ten times more than among women in the same families without any mutation in this hypothetical gene.

The field was skeptical about her mathematical model so she set out to prove that her hypothetical gene existed, by mapping it to an exact chromosomal location. Toward this end, King analyzed DNA from hundreds of women in 23 families very severely affected with breast cancer. In many of these families, breast cancer struck young women, often in both breasts, and in some families, breast cancer even occurred in men. Finding the home of the hypothetical gene was difficult for multiple reasons. First, most cases of breast cancer are not familial. Might the critical mutations be inherited from unaffected fathers as well as from mothers with the disease? Second, breast cancer is common, so common that both inherited and non-inherited cases could occur in the same families. Third, breast cancer might not strike all women who carry a high-risk gene; some might be fortunate. And fourth, different families might carry different high-risk genes. No one had previously tackled such complexities, and an attempt to unearth a breast cancer gene seemed woefully naïve.