The Emperor of All Maladies: A Biography of Cancer (106 page)

450
In 2008, both Vogelstein’s group and the Cancer Genome Atlas:
Roger McLendon et al., “Comprehensive Genomic Characterization Defines Human Glioblastoma Genes and Core Pathways,”
Nature
455, no. 7216 (2008): 1061–68. Also see D. Williams Parsons et al., “An Integrated Genomic Analysis of Human Glioblastoma Multiforme,”
Science
321, no. 5897 (2008): 1807–12; and Roger McLendon et al., “Comprehensive Genomic Characterization.”

452
Only a few cancers are notable exceptions:
C. G. Mullighan et al., “Genome-Wide Analysis of Genetic Alterations in Acute Lymphoblastic Leukemia,”
Nature
446, no. 7137 (2007): 758–64.

452
“In the end,” as Vogelstein put it:
Bert Vogelstein, comments on lecture at Massachusetts General Hospital, 2009; also see Vogelstein and Kinzler, “Cancer Genes and the Pathways They Control.”

453
Other mutations are not passive players:
The distinction between passenger and driver mutations has generated an enormous debate in cancer genetics. Many scientists suspect that the initial analysis of the breast cancer genome may have overestimated the number of driver mutations. Currently, this remains an open question in cancer genetics. See, for instance, Getz et al., Rubin et al., and Forrest et al.,
Science
317, no 5844: 1500, comments on Sjöblom article above.

453
In a recent series of studies, Vogelstein’s team:
See, for example, Rebecca J. Leary, “Integrated Analysis of Homozygous Deletions, Focal Amplifications, and Sequence Alterations in Breast and Colorectal Cancers,”
Proceedings of the National Academy of Sciences of the United States of America
105, no. 42 (2008): 16224–29; Siân Jones et al., “Core Signaling Pathways in Human Pancreatic Cancer Revealed by Global Genomic Analyses,”
Science
321, no. 5897 (2008): 1801–6.

454
“Cancer,” as one scientist recently put it:
Emmanuel Petricoin, quoted in Dan Jones, “Pathways to Cancer Therapy,”
Nature Reviews Drug Discovery
7 (2008): 875–76.

455
In a piece published in the
New York Times: “To Fight Cancer, Know the Enemy,”
New York Times
, August 5, 2009.

456
In 2000, the so-called Million Women Study:
Valerie Beral et al., “Breast Cancer and Hormone-Replacement Therapy in the Million Women Study,”
Lancet
362, no. 9382 (2003): 419–27.

456
The second controversy also has its antecedents:
See, for instance, F. J. Roe and M. C. Lancaster et al., “Natural, Metallic and Other Substances, as Carcinogens,”
British Medical Bulletin
20 (1964): 127–33; and Jan Dich et al., “Pesticides and Cancer,”
Cancer Causes & Control
8, no. 3 (1997): 420–43.

457
In 2005, the Harvard epidemiologist David Hunter:
Yen-Ching Chen and David J. Hunter, “Molecular Epidemiology of Cancer,”
CA: A Cancer Journal for Clinicians
55 (2005): 45–54.

457
In the mid-1990s, building on the prior decade’s advances:
Yoshio Miki et al., “A Strong Candidate for the Breast and Ovarian Cancer Susceptibility Gene
BRCA1,
”
Science
266, no. 5182 (1994): 66–71; R. Wooster et al., “Localization of a Breast Cancer Susceptibility Gene, BRCA2, to Chromosome 13q12–13,”
Science
265, no. 5181 (1994): 2088–90; J. M. Hall et al., “Linkage of Early-Onset Familial Breast Cancer to Chromosome 17q21,”
Science
250, no. 4988 (1990): 1684–89; Michael R. Stratton et al., “Familial Male Breast Cancer Is Not Linked to the
BRCA1
Locus on Chromosome 17q,”
Nature Genetics
7, no. 1 (1994): 103–7.

457
An Israeli woman:
Breast cancer patient O. B-L. (name withheld), interview with author, December 2008.

458
In the mid-1990s, John Dick:
Tsvee Lapidot et al., “A Cell Initiating Human Acute Myeloid Leukaemia After Transplantation into SCID Mice,”
Nature
367, no. 6464 (1994): 645–58.

459
Indeed, as the fraction of those affected by cancer creeps:
“One in three” is from the recent evaluation by the National Cancer Institute. See http://www.cancer.gov/newscenter/tip-sheet-cancer-health-disparities. The number “one in two” comes from the NCI seer statistics, http://seer.cancer.gov/statfacts/html/all.html, but includes all cancer sites, summarized in Matthew Hayat et al., “Cancer Statistics, Trends and Multiple Primary Cancer Analyses,”
Oncologist
12 (2007): 20–37.

ATOSSA’S WAR

461
We aged a hundred years:
Anna Akhmatova, “In Memoriam, July 19, 1914,” in
The Complete Poems of Anna Akhmatova
, vol. 1 (Chicago: Zephyr Press, 1990), 449.

461
It is time, it is time for me too to depart:
Aleksandr Solzhenitsyn,
Cancer Ward
(New York: Farrar, Straus and Giroux, 1974), 476.

461
On May 17, 1973:
“A Memorial Tribute in Honor of Dr. Sidney Farber, 1903–1973,” Thursday, May 17, 1973. Gift of Thomas Farber to the author.

464
It is impossible to enumerate:
Atossa’s case and her survival numbers are speculative, but based on several sources. See, for instance, “Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials,”
Lancet
, 365, no. 9472: 1687–1717.

465
In 1997, the NCI director, Richard Klausner:
See Barnett S. Kramer and Richard D. Klausner, “Grappling with Cancer—Defeatism Versus the Reality of Progress,”
New England Journal of Medicine
337, no. 13 (1997): 931–35.

467
The new drug was none other than Gleevec:
See, for example, H. Joensuu, “Treatment of Inoperable Gastrointestinal Stromal Tumors (GIST) with Imatinib (Glivec, Gleevec),”
Medizinische Klinik
(Munich) 97, suppl. 1 (2002): 28–30; M. V. Chandu de Silva and Robin Reid, “Gastrointestinal Stromal Tumors (GIST): C-kit Mutations, CD117 Expression, Differential Diagnosis and Targeted Cancer Therapy with Imatinib,”
Pathology Oncology Research
9, no. 1 (2003): 13–19.

Acute lymphoblastic leukemia:
a variant of white blood cell cancer that affects the lymphoid lineage of blood cells.

Acute myeloid leukemia:
a variant of white blood cell cancer that affects the myeloid lineage of blood cells.

Apoptosis:
the regulated process of cell death that occurs in most cells, involving specific cascades of genes and proteins.

Carcinogen:
a cancer-causing or cancer-inciting agent.

Chimeric gene:
A gene created by the mixing together of two genes. A chimeric gene might be the product of a natural translocation, or might be engineered in the lab.

Chromosome:
a structure within a cell comprised of DNA and proteins that stores genetic information.

Cytotoxic:
Cell-killing. Usually refers to chemotherapy that works by killing cells, particularly rapidly dividing cells.

DNA:
Deoxyribonucleic acid, a chemical that carries genetic information in all cellular organisms. It is usually present in the cell as two paired, complementary strands. Each strand is a chemical chain made up of four chemical units—abbreviated A, C, T, and G. Genes are carried in the form of a genetic “code” in the strand and the sequence is converted (transcribed) into RNA (see p. 534) and then translated into proteins (see p.534).

Enzyme:
a protein that accelerates a biochemical reaction.

Gene:
a unit of inheritance, normally comprised of a stretch of DNA that codes for a protein or for an RNA chain (in special cases, genes might be carried in the RNA form).

Genetic engineering:
the capacity to manipulate genes in organisms to create new genes, or introduce genes into heterologous organisms (e.g., a human gene in a bacterial cell).

Genome:
the full complement of all genes within the organism.

Incidence
: In epidemiology, the number (or fraction) of patients who are diagnosed with a disease in a given period of time. It differs from prevalence because incidence reflects the rate of new diagnosis.

Kinase:
a protein enzyme that attaches phosphate groups to other proteins.

Metastatic:
cancer that has spread beyond its local site of origin.

Mitosis:
the division of one cell to form two cells that occurs in most adult tissues of the body (as opposed to meiosis, which generates germ cells in the ovary and the testes).

Mutation:
An alteration in the chemical structure of DNA. Mutations can be silent—i.e., the change might not affect any function of the organism—or can result in a change in the function or structure of an organism.

Neoplasm, neoplasia:
an alternative name for cancer.

Oncogene:
A cancer-causing or cancer-promoting gene. Activation or overexpression of a proto-oncogene (see below) promotes the transformation of a cell from normal to a cancer cell.

Prevalence:
in epidemiology, the number (or fraction) of affected patients in any given period of time.

Primary prevention:
prevention aimed at avoiding the development of a disease, typically by attacking the cause of the disease.

Prospective trial:
a trial in which a cohort of patients is followed forward in time (as opposed to retrospective, in which a cohort of patients is followed backward).

Protein:
A chemical comprised, at its core, of a chain of amino acids that is created when a gene is translated. Proteins carry out the bulk of cellular functions, including relaying signals, providing structural support, and accelerating biochemical reactions. Genes usually “work” by providing the blueprint for proteins (see DNA, p. 533). Proteins can be modified chemically by the addition of small chemicals such as phosphates or sugars or lipids.

Proto-oncogene:
A precursor to an oncogene. Typically, proto-oncogenes are normal cellular genes that, when activated by mutation or overexpression, promote cancer. Proto-oncogenes typically code for proteins that are associated with cell growth and differentiation. Examples of proto-oncogenes include
ras
and
myc
.

Randomized trial:
a trial in which treatment and control groups are randomly assigned.

Retrovirus:
an RNA virus that keeps its genes in the form of RNA and is capable, by virtue of an enzyme, reverse transcriptase, to convert its genes from the RNA form into a DNA form.

Reverse transcriptase:
An enzyme that converts a chain of RNA into a chain of DNA. Reverse transcription is a property of retroviruses.

RNA:
Ribonucleic acid, a chemical that performs several functions in the cells, including acting as an “intermediate” message for a gene to become a protein. Certain viruses also use RNA, not DNA, to maintain their genes (see Retrovirus, above).

Secondary prevention:
Prevention strategies that are aimed at early detection of a disease, typically by screening asymptomatic men and women. Typically, secondary prevention strategies attack early, pre-symptomatic stages of the disease.

Transfection:
the introduction of DNA into a cell.

Transgenic mice:
mice in which a genetic change has been artificially introduced.

Translocation (of a gene):
the physical reattachment of a gene from one chromosome to another.

Tumor suppressor gene (also called anti-oncogene):
A gene that, when inactivated fully, promotes the progression of a cell into a cancer cell. Tumor suppressors usually protect a cell from one step on the progression toward cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer. Typically, this occurs in combination with other genetic changes.

Two-hit hypothesis:
the notion that for tumor suppressor genes, both functionally intact copies of the gene must be inactivated in order for a cell to progress toward cancer.

Virus:
A microorganism that is incapable of reproducing by itself, but capable of creating progeny once it has infected a cell. Viruses come in diverse forms, including DNA viruses and RNA viruses. Viruses possess a core of either DNA or RNA, coated with proteins, and can be bound by an outer membrane made of lipids and proteins.

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