生命科学与医学奖
2018

2018年度邵逸夫生命科学与医学奖颁予玛莉-克莱尔・金 (Mary-Claire King)，以表彰她绘制第一个乳腺癌基因的基因图。玛莉-克莱尔・金利用数学模型预测和证明乳腺癌可以由单个基因引起。她绘制的基因图促成了乳腺癌基因的克隆，因而挽救了许多人的生命。玛莉-克莱尔・金是美国西雅图的华盛顿大学医学系和基因组科学系美国癌症协会讲座教授。

金的职业生涯大部分时间都专注在癌症流行病学上。她非凡的洞察力促使她投入研究遗传与乳腺癌的关系。众所周知，同一癌症在不同群组中的发病率会存在差异。其他科学家对这事实并不特别关注，但金推测这个现象必定和基因有关，若利用遗传学技术研究，有可能成功发现它。虽然有很多癌症研究人员对她的想法持怀疑态度，她却坚持自己的想法。乳腺癌是一种常见而又复杂的疾病，普遍认为是由多种遗传和环境因素相互作用而产生。但玛莉-克莱尔认为观察到的现象，暗示一部份的乳腺癌，可能是遗传引起的。因此早在利用基因组工具进行人类基因分析之前，从1974年开始，她就对超过1500个有多位成员曾患乳腺癌的家庭进行针对性测试。她利用数学方法推测出这些家庭中大约有4%的成员具有这个疾病基因，从而解释病例集群的现象。她还利用来自受影响和未受影响的年轻人和老年人的数据，预测出带有突变基因的妇女到了70岁时患乳腺癌的风险约为80%，而没有受影响等位基因的妇女，风险则只有8%。 同一领域的科学家对她的数学模型持相当怀疑的态度，因此她著手经由找出乳腺癌基因在染色体的定位，从而证明乳腺癌基因是确实存在的。她以一群发病率异常高的家庭作为研究对象，并於1990年利用连锁分析方法将乳腺癌基因定位於人类17号染色体(基因座q21)，并命名为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.