Circumcision

  

Circumcision knife from the Congo;
wood, iron; late 19th/early 20th century[1]

Male circumcision is the surgical removal of the foreskin from the human penis.[1][2][3][4]

The oldest documented evidence for circumcision comes from ancient Egypt.[1][5] The Egyptian Book of the Dead describes the sun god Ra as having circumcised himself.[1][6][7]

British and American doctors began recommending circumcision in the late 19th century, primarily as a deterrent to masturbation.[1][8][9] 

Prior to the 20th century, masturbation was believed to be the cause of a wide range of physical and mental illnesses including epilepsy, paralysis, impotence, gonorrhea, tuberculosis, feeble-mindedness, and insanity.[1][10][11]

Approximately one-third of males worldwide are circumcised, most often for non-medical reasons.[1][5][13] 

Prevalence of circumcision by country.[1]

A 2010 review of literature worldwide found circumcisions performed by medical practitioners to have a median complication rate of 1.5% for newborns and 6% for older children, with few cases of severe complications.[1][13][14][15]

A 2013 systematic review found that circumcision did not appear to affect sexual desire, pain with intercourse, premature ejaculation, time to ejaculation, erectile dysfunction or difficulties with orgasm.[1][16]

Circumcision surgery with hemostats and scissors.[1]

The procedure is most often elected for religious or cultural reasons,[1][5] but may be indicated as a treatment option for pathological phimosis (inability to retract the foreskin over the glans penis)  and chronic urinary tract infections (UTIs).[1][2][12][13][30][32][33] 

Circumcision is associated with a reduced prevalence of oncogenic types of Human papillomavirus (HPV) infection.[35]

• The procedure is associated with increased clearance of the papillomavirus by the body,[26][27] which may account for the finding of reduced prevalence.[27] 

• There is no statistically significant relationship between being circumcised and the presence of genital warts.[1][19][19][20][21]

Important risk factors for penile cancer include phimosis and HPV infection, both of which are mitigated by circumcision.[1][13][25][34][35][36]

Yeast infections are the most common penile infection and are rarely identified in samples taken from circumcised males.[1][31]

***

The World Health Organization (WHO) and the Joint United Nations Program on HIV/AIDS (UNAIDS) state that male circumcision is an efficacious intervention for HIV prevention, but should be carried out by well-trained medical professionals and under conditions of informed consent.[1][5][17][18][21]

• The joint WHO/UNAIDS recommendation also notes that circumcision only provides partial protection from HIV and should not replace known methods of HIV prevention (ex: condoms).[1][5][17]  

• As HIV/AIDS is an incurable disease that is expensive to manage, significant effort has been spent studying the cost-effectiveness of circumcision to reduce its spread in parts of Africa that have a relatively high infection rate and low circumcision prevalence.[1][22] 

• In Rwanda, circumcision has been found to be cost-effective across a wide range of age groups from newborn to adult,[1][19] with the greatest savings achieved when the procedure is performed in the newborn period due to the lower cost per procedure and greater time-frame for HIV infection protection.[1][20] 

• Circumcision for the prevention of HIV transmission in adults has also been found to be cost-effective in South Africa, Kenya and Uganda, with cost savings estimated in the billions of US dollars over 20 years.[1][22][23] 

***

In 2014, the Centers for Disease Control and Prevention released, "Draft CDC Recommendations for Providers Counseling Male Patients and Parents Regarding Male Circumcision and the Prevention of HIV Infection, STIs, and Other Health Outcomes." 

These draft guidelines suggested that the benefits of male circumcision outweigh the risks. 
The following is their summary of beneficial versus adverse effects:[24]

Health benefits of elective male circumcision in adults and adolescents:

• Male circumcision reduces the risk of acquiring HIV infection through penile-vaginal sex by 50-60%, as demonstrated in three well-conducted clinical trials among adult men living in sub-Saharan Africa.
• In clinical trials involving heterosexual males living in sub-Saharan Africa, male circumcision reduces the risk of some sexually transmitted infections.
• HSV-2 (herpes simplex virus type 2): circumcised men were approximately 30%-45% less likely to acquire HSV-2 infection than were uncircumcised men.
• HPV (human papillomavirus): circumcised men were approximately 30% less likely to be infected with high-risk strains of HPV associated with cancers than were uncircumcised men.

Adverse events and risks associated with elective male circumcision of adults: 

• For adult male circumcision performed by clinicians, the rate of adverse events is between 2% and 4%, with pain, bleeding, infection and unsatisfactory post-surgical appearance most commonly reported. While severe and/or long-term complications have been reported, they are so rare that they have not been precisely established.
• Adult men who undergo circumcision generally report minimal or no change in sexual satisfaction or function. 

Health benefits of neonatal male circumcision:

• The estimated annual rate of urinary tract infections (UTIs) in uncircumcised male infants is 0.70%. Male circumcision reduces the risk for infant UTIs by about 80%.
• In the U.S., the estimated lifetime risk of penile cancer for males is about 1 in 1,400 (0.07%) and that of prostate cancer is about 15%. Neonatal male circumcision reduces the risk of penile carcinoma by about 90% and may reduce the risk of prostate cancer by 15% compared to men who are uncircumcised. 

Adverse events and risks associated with neonatal male circumcision:

• Adverse events: For male circumcision performed by clinicians, the rate of reported adverse events is as follows:
• 0.4% in infants (age through 12 mo.)
• 9.1% in children (age 1-9 years)

***
Fin

References:

[1] http://en.wikipedia.org/wiki/Circumcision

[2] Lissauer T, Clayden G (October 2011). Illustrated Textbook of Paediatrics, Fourth edition. Elsevier. pp. 352–353. ISBN 978-0-7234-3565-5.

[3] Rudolph C, Rudolph A, Lister G, First L, Gershon A (18 March 2011). Rudolph's Pediatrics, 22nd Edition. McGraw-Hill Companies, Incorporated. p. 188. ISBN 978-0-07-149723-7.

[4] Sawyer S (November 2011). Pediatric Physical Examination & Health Assessment. Jones & Bartlett Publishers. pp. 555–556. ISBN 978-1-4496-7600-1.

[5] "Male circumcision: Global trends and determinants of prevalence, safety and acceptability" (PDF). World Health Organization. 2007.

[6] Alanis MC, Lucidi RS (May 2004). "Neonatal circumcision: a review of the world's oldest and most controversial operation". Obstet Gynecol Surv 59 (5): 379–95.doi:10.1097/00006254-200405000-00026. PMID 15097799.

[7] Gollaher (2001), ch. 1, The Jewish Tradition, pp. 1-30

[8] Matthew, H. C. G. (2004). Oxford dictionary of national biography : in association with the British Academy : from the earliest times to the year 2000. Oxford New York: Oxford University Press. ISBN 978-0-19-861411-1.

[9] Siegfried N, Muller M, Volmink J et al. (2003). Siegfried, Nandi, ed. "Male circumcision for prevention of heterosexual acquisition of HIV in men". Cochrane Database of Systematic Reviews (3): CD003362. doi:10.1002/14651858.CD003362.PMID 12917962.

[10] Boyle GJ, Hill G (2011). "Sub-Saharan African randomised clinical trials into male circumcision and HIV transmission: methodological, ethical and legal concerns". J Law Med19 (2): 316–34. PMID 22320006.

[11] Dowsett GW, Couch M (May 2007). "Male circumcision and HIV prevention: is there really enough of the right kind of evidence?". Reproductive Health Matters 15 (29): 33–44.doi:10.1016/S0968-8080(07)29302-4. PMID 17512372.

 [12] Hay W, Levin M (25 June 2012). Current Diagnosis and Treatment Pediatrics 21/E. McGraw Hill Professional. pp. 18–19. ISBN 978-0-07-177971-5.

[13] Weiss HA, Larke N, Halperin D, Schenker I; Larke; Halperin; Schenker (2010). "Complications of circumcision in male neonates, infants and children: a systematic review". BMC Urol 10: 2. doi:10.1186/1471-2490-10-2. PMC 2835667.PMID 20158883.

[14] American Academy of Pediatrics Task Force on Circumcision (2012). "Technical Report". Pediatrics 130 (3): e756–e785.doi:10.1542/peds.2012-1990. ISSN 0031-4005. PMID 22926175.

[15] "Circumcision: Position Paper on Neonatal Circumcision". American Academy of Family Physicians. 2007. 

[16]Ko MC, Liu CK, Lee WK, Jeng HS, Chiang HS, Li CY (April 2007). "Age-specific prevalence rates of phimosis and circumcision in Taiwanese boys". Journal of the Formosan Medical Association=Taiwan Yi Zhi 106 (4): 302–7. doi:10.1016/S0929-6646(09)60256-4. PMID 17475607.

[17]  "WHO and UNAIDS announce recommendations from expert consultation on male circumcision for HIV prevention". World Health Organization. March 2007.

[18] "New Data on Male Circumcision and HIV Prevention: Policy and Programme Implications" (PDF). World Health Organization. March 28, 2007.

[19] Albero G, Castellsagué X, Giuliano AR, Bosch FX (February 2012). "Male Circumcision and Genital Human Papillomavirus: A Systematic Review and Meta-Analysis".Sex Transm Dis 39 (2): 104–113. doi:10.1097/OLQ.0b013e3182387abd.PMID 22249298.

[20] Kim H, Li PS, Goldstein M, Howard H; Li, Philip S; Goldstein, Marc (November 2010). "Male circumcision: Africa and beyond?". Current Opinion in Urology 20 (6): 515–9.doi:10.1097/MOU.0b013e32833f1b21. PMID 20844437.

[21] Siegfried N, Muller M, Deeks JJ, Volmink J; Muller; Deeks; Volmink (2009). Siegfried, Nandi, ed. "Male circumcision for prevention of heterosexual acquisition of HIV in men". Cochrane Database of Systematic Reviews (2): CD003362.doi:10.1002/14651858.CD003362.pub2. PMID 19370585.

[22] Doyle S, Kahn J, Hosang N, Carroll P (2010). "The Impact of Male Circumcision on HIV Transmission". Journal of Urology 183 (1): 21–26. doi:10.1016/j.juro.2009.09.030.PMID 19913816.

[23]  Hankins C, Forsythe S, Njeuhmeli E (Mar 2012). Sansom, Stephanie L, ed. "Voluntary medical male circumcision: an introduction to the cost, impact, and challenges of accelerated scaling up". Arch Pediatr Adolesc Med 8 (11): e1001127.doi:10.1371/journal.pmed.1001127. PMC 3226452. PMID 22140362
[24] http://www.regulations.gov/#!documentDetail;D=CDC-2014-0012-0003

[25] Larke et al. "Male circumcision and human papillomavirus infection in men: a systematic review and meta-analysis" (2011), Albero et al. "Male Circumcision and Genital Human Papillomavirus: A Systematic Review and Meta-Analysis" (2012), Rehmeyer "Male Circumcision and Human Papillomavirus Studies Reviewed by Infection Stage and Virus Type" (2011).

[26] Larke N, Thomas SL, Dos Santos Silva I, Weiss HA (November 2011). "Male circumcision and human papillomavirus infection in men: a systematic review and meta-analysis". J. Infect. Dis. 204 (9): 1375–90. doi:10.1093/infdis/jir523. PMID 21965090.

[27] Rehmeyer C, CJ (2011). "Male Circumcision and Human Papillomavirus Studies Reviewed by Infection Stage and Virus Type". J Am Osteopath Assoc 111 (3 suppl 2): S11–S18. PMID 21415373.

[28]Templeton DJ, Millett GA, Grulich AE; Millett; Grulich (February 2010). "Male circumcision to reduce the risk of HIV and sexually transmitted infections among men who have sex with men". Current Opinion in Infectious Diseases 23 (1): 45–52.doi:10.1097/QCO.0b013e328334e54d. PMID 19935420.

[29] Millett GA, Flores SA, Marks G, Reed JB, Herbst JH (October 2008). "Circumcision status and risk of HIV and sexually transmitted infections among men who have sex with men: a meta-analysis". JAMA 300 (14): 1674–84. doi:10.1001/jama.300.14.1674.PMID 18840841.

[30] Becker K (January 2011). "Lichen sclerosus in boys". Dtsch Arztebl Int 108 (4): 53–8.doi:10.3238/arztebl.2011.053. PMC 3036008. PMID 21307992.

[31] Aridogan IA, Izol V, Ilkit M (August 2011). "Superficial fungal infections of the male genitalia: a review". Crit. Rev. Microbiol. 37 (3): 237–44.

[32] Jagannath VA, Fedorowicz Z, Sud V, Verma AK, Hajebrahimi S (2012). Fedorowicz, Zbys, ed. "Routine neonatal circumcision for the prevention of urinary tract infections in infancy". Cochrane Database of Systematic Reviews 11: CD009129.doi:10.1002/14651858.CD009129.pub2. PMID 23152269.

[33] Jagannath VA, Fedorowicz Z, Sud V, Verma AK, Hajebrahimi S (2011). Fedorowicz, Zbys, ed. "Routine neonatal circumcision for the prevention of urinary tract infections in infancy (Protocol)". Cochrane Database of Systematic Reviews (5): CD009129.doi:10.1002/14651858.CD009129.

[34] Hayashi Y, Kojima Y, Mizuno K, Kohri K (2011). "Prepuce: phimosis, paraphimosis, and circumcision". ScientificWorldJournal 11: 289–301. doi:10.1100/tsw.2011.31.PMID 21298220.

[35] Larke NL, Thomas SL, Dos Santos Silva I, Weiss HA (August 2011). "Male circumcision and penile cancer: a systematic review and meta-analysis". Cancer Causes Control 22 (8): 1097–110. doi:10.1007/s10552-011-9785-9. PMC 3139859.PMID 21695385.

[36] "Can penile cancer be prevented?". Learn About Cancer: Penile Cancer: Detailed Guide. American Cancer Society. 

Additional Resources:

http://www.webmd.com/sexual-conditions/guide/circumcision

http://www.scientificamerican.com/article/male-circumcision-benefits-outweigh-risks-cdc-says/?WT.mc_id=SA_HLTH_20141209

http://www.theguardian.com/us-news/2014/dec/02/guidelines-male-circumcision
American Academy of Pediatrics Task Force on Circumcision (2012). "Technical Report". Pediatrics 130 (3): e756–e785.doi:10.1542/peds.2012-1990. ISSN 0031-4005. PMID 22926175.

Image Credits:

"Mangbetu Beschneidungsmesser Museum Rietberg RAC 15" by Photograph: Andreas Praefcke - Own work (own photograph). Licensed under Public Domain via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:Mangbetu_Beschneidungsmesser_Museum_Rietberg_RAC_15.jpg#mediaviewer/File:Mangbetu_Beschneidungsmesser_Museum_Rietberg_RAC_15.jpg

"Global Map of Male Circumcision Prevalence at Country Level" by Emilfaro - The World Health Organization report of 14 December 2007. Male circumcision: global trends and determinants of prevalence, safety and acceptability. This report is the result of collaborative work between the London School of Hygiene and Tropical Medicine, the World Health Organization and the Joint United Nations Programme on HIV/AIDS (UNAIDS). Based on:13. Demographic and health surveys. MEASURE DHS, 2006 (http://www.measuredhs.com, accessed 21 September 2006).53. Drain PK et al. Male circumcision, religion and infectious diseases: an ecologic analysis of 118 developing countries. BMC Infect Dis, 2006, 6(1):172.54. Williams BG et al. The potential impact of male circumcision on HIV in sub-Saharan Africa. PLoS Med, 2006, 3(7):262.55. International religious freedom report for 2004. U.S. Department of State (http://www.state.gov/g/drl/rls/irf/2004/index.htm, accessed 21 September 2006).. Licensed under Public Domain via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:Global_Map_of_Male_Circumcision_Prevalence_at_Country_Level.png#mediaviewer/File:Global_Map_of_Male_Circumcision_Prevalence_at_Country_Level.png

"Circumcision illustration" by MrArifnajafov - File:Sünnət_circumcision_əməliyyatı.gif. Licensed under CC BY-SA 1.0 via Wikipedia - http://en.wikipedia.org/wiki/File:Circumcision_illustration.jpg#mediaviewer/File:Circumcision_illustration.jpg

The BRCA1 Gene

DNA damage resulting in multiple broken chromosomes.[38]

BRCA1 is a human *tumor suppressor gene[1][2][3]; its protein, BRCA1 is involved in the repair of DNA double-strand breaks.[1][4][5][6][7][8] 

*A tumor suppressor gene is a gene that protects a cell from one step on the path to cancer. When this gene mutates to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.[36][37]

The human BRCA1 gene is located on the
long (q) arm of chromosome 17 at region
2 band 1, from base pair 41,196,312 to
base pair 41,277,500.[1][9] 

The DNA double-strand repair mechanism that BRCA1 participates in is homologous recombination.[1] 

During homologous recombination, repair proteins utilize either the homologous intact sequence from a sister chromatid, or that from the same chromosome as a template, depending on cell cycle phase.[1][10][11][12] 

The following statistics (current as of today) are from  The National Cancer Institute's website:[13]

Breast cancer: About 12% of women in the general population will develop breast cancer sometime during their lives.[14]  By contrast, according to the most recent estimates, 55 - 65% of women who inherit a harmful BRCA1 mutation and around 45% of women who inherit a harmful BRCA2 mutation will develop breast cancer by age 70 years.[15][16] 

Ovarian cancer: About 1.4% of women in the general population will develop ovarian cancer sometime during their lives.[14]  By contrast, according to the most recent estimates, 39% of women who inherit a harmful BRCA1 mutation [15][16] and 11 to 17 percent of women who inherit a harmful BRCA2 mutation will develop ovarian cancer by age 70 years.[15][16]

***

*A germ line is the sex cells (ova/egg and sperm) that are used by sexually reproducing organisms to pass on genes from generation to generation. Ova/egg and sperm cells are called germ cells, in contrast to the other cells of the body that are called somatic cells.[34] 

Although about 1 million oocytes are present at birth in the human ovary, only about 500 of these ovulate, and the rest are wasted.[1] 

Women with a *germ line BRCA1 mutation appear to have a diminished oocyte reserve and decreased fertility compared to normally aging women.[1][20][21][22]

All germ line BRCA1 mutations identified to date have been inherited, suggesting the possibility of a large ‘founder effect’ in which a certain mutation is common to a well-defined population group and can, in theory, be traced back to a common ancestor.[1]

An example of a 'founder effect' is seen among Ashkenazi Jews.[1]  

Three mutations in BRCA1 have been reported to account for the majority of Ashkenazi Jewish patients with inherited BRCA1-related breast and/or ovarian cancer: 185delAG, 188del11 and 5382insC in the BRCA1 gene.[17][18][19] (There are similar examples within at least 22 other populations.)

***

For patients with BRCA1 and BRCA2 mutations, methods to diagnose the likelihood of getting cancer were covered by patents owned or controlled by Myriad Genetics.[1][23][24] 

Myriad's business model of offering the diagnostic test exclusively, led to controversy over high prices and the inability to get second opinions from other diagnostic labs, which in turn led to the landmark Association for Molecular Pathology v. Myriad Genetics lawsuit.[1][25][26][27][28][29][30]

In June of 2013, the US Supreme Court ruled unanimously that:[1][31][35]

"A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated." 

Thus, invalidating Myriad's patents on the BRCA1 and BRCA2 genes. However, the Court also held that manipulation of a gene to create something not found in nature could still be eligible for patent protection.[1][31]  

Association for Molecular Pathology v. Myriad Genetics, Inc.[35]
Supreme Court of the United States
Argued April 15, 2013 Decided June 13, 2013
Full case name	Association for Molecular Pathology, et al. v. Myriad Genetics, Inc., et al.
Docket nos.	12-398
Citations	569 U.S. ___ (more)
Prior history	The District Court for the Southern District of New Yorkfound that patents were ineligible. 702 F.Supp. 2d 181, 192–211 (SDNY 2010). On appeal, the Federal Circuitreversed the decision and found 2-1 in favor of Myriad (689 F.3d 1303).
Holding
Naturally occurring DNA sequences, even when isolated from the body, cannot be patented, but artificially created DNA is patent eligible because it is not naturally occurring.
Court membership
Chief Justice John G. Roberts Associate Justices Antonin Scalia · Anthony Kennedy Clarence Thomas · Ruth Bader Ginsburg Stephen Breyer · Samuel Alito Sonia Sotomayor · Elena Kagan
Case opinions
Majority	Thomas, joined by Roberts, Kennedy, Ginsburg, Breyer, Alito, Sotomayor, Kagan, Scalia (in part)
Concurrence	Scalia (all but part I-A)
Laws applied
U.S. Const. Article I, Section 8, Clause 8, 35 U.S.C. § 101

The Federal Court of Australia came to the opposite conclusion, upholding the validity of an Australian Myriad Genetics patent over the BRCA1 gene in February 2013.[1][32] The Federal Court also rejected an appeal in September 2014.[1][33]

The Myriad patents began to expire in 2014.[1]

***

Fin

Updates / Related

BRCA gene mutations and ovarian cancer: an interview with Dr Matulonis, Harvard Medical School / news-medical.net / August 3, 2015

References:

[1] http://en.wikipedia.org/wiki/BRCA1

[2] Duncan JA, Reeves JR, Cooke TG (October 1998). "BRCA1 and BRCA2 proteins: roles in health and disease". Molecular pathology : MP 51 (5): 237–47.doi:10.1136/mp.51.5.237. PMC 395646. PMID 10193517.

[3] Yoshida K, Miki Y (November 2004). "Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage". Cancer science 95 (11): 866–71. doi:10.1111/j.1349-7006.2004.tb02195.x. PMID 15546503.

[4] Check W (2006-09-01). "BRCA: What we know now". College of American Pathologists. Retrieved 2010-08-23.

[5] Friedenson B (August 2007). "The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers". BMC Cancer 7: 152–162. doi:10.1186/1471-2407-7-152. PMC 1959234. PMID 17683622.

[6] Friedenson B (2008-06-08). "Breast cancer genes protect against some leukemias and lymphomas" (video). SciVee.

[7]  "Breast and Ovarian Cancer Genetic Screening". Palo Alto Medical Foundation.Archived from the original on 4 October 2008. Retrieved 2008-10-11.

[8] Friedenson B (2007). "The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers". BMC Cancer 7: 152. doi:10.1186/1471-2407-7-152. PMC 1959234. PMID 17683622.

[9] National Center for Biotechnology Information, U.S. National Library of MedicineEntrezGene reference information for BRCA1 breast cancer 1, early onset (Homo sapiens)

[10] Kimball's Biologh Pages

[11] Friedenson B (November 2011). "A common environmental carcinogen unduly affects carriers of cancer mutations: carriers of genetic mutations in a specific protective response are more susceptible to an environmental carcinogen". Med. Hypotheses 77 (5): 791–7.doi:10.1016/j.mehy.2011.07.039. PMID 21839586.

[12] Ridpath JR, Nakamura A, Tano K, Luke AM, Sonoda E, Arakawa H, Buerstedde JM, Gillespie DA, Sale JE, Yamazoe M, Bishop DK, Takata M, Takeda S, Watanabe M, Swenberg JA, Nakamura J (December 2007). "Cells deficient in the FANC/BRCA pathway are hypersensitive to plasma levels of formaldehyde". Cancer Res. 67 (23): 11117–22.doi:10.1158/0008-5472.CAN-07-3028. PMID 18056434.

[13] http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA

[14] Howlader N, Noone AM, Krapcho M, et al. (eds.). (2013) SEER Cancer Statistics Review, 1975-2010. Bethesda, MD: National Cancer Institute. Retrieved June 24, 2013.
[15] Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies. American Journal of Human Genetics 2003; 72(5):1117–1130.[PubMed Abstract]
[16] Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. Journal of Clinical Oncology 2007; 25(11):1329–1333. [PubMed Abstract]

[17] Struewing JP, Abeliovich D, Peretz T, Avishai N, Kaback MM, Collins FS, Brody LC (1978). "Isolation of two human tumor epithelial cell lines from solid breast carcinomas".Journal of the National Cancer Institute 61 (2): 967–978. doi:10.1038/ng1095-198.PMID 7550349.

[18] Tonin P, Serova O, Lenoir G, Lynch H, Durocher F, Simard J, Morgan K, Narod S (1995). "BRCA1 mutations in Ashkenazi Jewish women". American Journal of Human Genetics 57 (1): 189. PMC 1801236. PMID 7611288.

[19] Narod SA, Foulkes WD (2004). "BRCA1 and BRCA2: 1994 and beyond". Nature Reviews Cancer 4 (9): 665–676. doi:10.1038/nrc1431. PMID 15343273.

[20] Oktay K, Kim JY, Barad D, Babayev SN (January 2010). "Association of BRCA1 mutations with occult primary ovarian insufficiency: a possible explanation for the link between infertility and breast/ovarian cancer risks". J. Clin. Oncol. 28 (2): 240–4.doi:10.1200/JCO.2009.24.2057. PMC 3040011. PMID 19996028.

[21] Rzepka-Górska I, Tarnowski B, Chudecka-Głaz A, Górski B, Zielińska D, Tołoczko-Grabarek A (November 2006). "Premature menopause in patients with BRCA1 gene mutation". Breast Cancer Res. Treat. 100 (1): 59–63. doi:10.1007/s10549-006-9220-1.PMID 16773440.

[22] Titus S, Li F, Stobezki R, Akula K, Unsal E, Jeong K, Dickler M, Robson M, Moy F, Goswami S, Oktay K (February 2013). "Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans". Sci Transl Med 5 (172): 172ra21.doi:10.1126/scitranslmed.3004925. PMID 23408054.

[23] US patent 5747282, Skolnick HS, Goldgar DE, Miki Y, Swenson J, Kamb A, Harshman KD, Shattuck-Eidens DM, Tavtigian SV, Wiseman RW, Futreal PA, "7Q-linked breast and ovarian cancer susceptibility gene", issued 1998-05-05, assigned to Myriad Genetics, Inc., The United States of America as represented by the Secretary of Health and Human Services, and University of Utah Research Foundation

[24] US patent 5837492, Tavtigian SV, Kamb A, Simard J, Couch F, Rommens JM, Weber BL, "Chromosome 13-linked breast cancer susceptibility gene", issued 1998-11-17, assigned to Myriad Genetics, Inc., Endo Recherche, Inc., HSC Research & Development Limited Partnership, Trustees of the University of Pennsylvaina

[25]  Myriad Investor Page—see "Myriad at a glance" accessed October 2012

[26] Schwartz J (2009-05-12). "Cancer Patients Challenge the Patenting of a Gene".Health. New York Times.

[27] Robert Cook-Deegan, MD et al (2010) Impact of Gene Patents and Licensing Practices on Access to Genetic Testing for Inherited Susceptibility to Cancer: Comparing Breast and Ovarian Cancers to Colon Cancers: Patents and Licensing for Breast, Ovarian and Colon Cancer Testing Genet Med.12(4 Suppl): S15–S38.

[28] Benowitz S (January 2003). "European groups oppose Myriad's latest patent on BRCA1".J. Natl. Cancer Inst. 95 (1): 8–9. doi:10.1093/jnci/95.1.8. PMID 12509391.

[29] Conley J, Vorhous D, Cook-Deegan J (2011-03-01). "How Will Myriad Respond to the Next Generation of BRCA Testing?". Robinson, Bradshaw, and Hinson. Retrieved2012-12-09.

[30]  "Genetics and Patenting". Human Genome Project Information. U.S. Department of Energy Genome Programs. 2010-07-07.

[31] Liptak, Adam (June 13, 2013). "Supreme Court Rules Human Genes May Not Be Patented". New York Times. 

[32] Corderoy, Amy (February 15, 2013). "Landmark patent ruling over breast cancer gene BRCA1". Sydney Morning Herald. Retrieved June 14, 2013.

[33]  "Australian federal court rules isolated genetic material can be patented". The Guardian. 5 September 2014. Retrieved 14 September 2014.

[34] http://ghr.nlm.nih.gov/glossary=germline

[35] http://en.wikipedia.org/wiki/Association_for_Molecular_Pathology_v._Myriad_Genetics
[36] http://en.wikipedia.org/wiki/Tumor_suppressor_gene
[37] Weinberg, Robert A (2014). "The Biology of Cancer." Garland Science, page 231.

[38] http://en.wikipedia.org/wiki/DNA_repair

Image Credits:

"BRCA1 en" by Kuebi = Armin Kübelbeck - self-made with Inkscape. Derived from SVG-Masterfile.. Licensed under CC BY-SA 3.0 via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:BRCA1_en.png#mediaviewer/File:BRCA1_en.png

"Brokechromo". Licensed under CC BY-SA 3.0 via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:Brokechromo.jpg#mediaviewer/File:Brokechromo.jpg