Dr. Shulman is The Anna Ross Lapham Professor in Obstetrics and Gynecology and Chief, Division of Clinical Genetics, Feinberg School of Medicine of Northwestern University, Chicago, Illinois.

Lee P. Schulman, MD

Committee on Practice Bulletins-Gynecology and the Society of Gynecologic Oncology

	ACOG Practice Bulletin Number 147: Lynch Syndrome, November 2014. Obstet Gynecol. 2014;124:1042–54. Full text of ACOG Practice Bulletins is available to ACOG members at 

http://www.acog.org/Resources-And-Publications/Practice-Bulletins/Committee-on-Practice-Bulletins-Gynecology/Lynch-Syndrome

Lynch syndrome, previously known as hereditary nonpolyposis colorectal cancer, is an autosomal dominant inherited cancer susceptibility syndrome caused by defects in the mismatch repair system. This system depends on a family of genes that are conserved across most living organisms and is responsible for repairing single-base mismatches that occur during DNA replication. In addition to colorectal cancer, hallmark diseases of Lynch syndrome include endometrial and ovarian cancer. Other tumors within the spectrum of Lynch syndrome include gastric cancer, small bowel cancer, hepatobiliary cancer, renal pelvis and ureter cancer, as well as some types of breast cancer, certain brain tumors, and sebaceous skin tumors 

(1–4). By identifying individuals at risk of Lynch syndrome through assessment of personal and family medical histories and genetic counseling and testing, when indicated, physicians are able to offer screening and prevention strategies to reduce morbidity and mortality from this syndrome.

Notably, the molecular abnormalities present in Lynch syndrome-associated tumors cause specific changes in the tumor tissue that can be detected by laboratory testing and, thus, identify the syndrome even in the absence of an informative family medical history. Because two of the most common types of cancer in Lynch syndrome occur in the female reproductive tract, obstetricians, gynecologists, and gynecologic oncologists are in a unique position to identify women who are at substantial risk of Lynch syndrome. The purpose of this document is to educate and provide an overview of Lynch syndrome because early identification of mutation carriers allows prevention of most Lynch syndrome-associated malignancies (5, 6).

	Used with permission. Copyright the American College of Obstetricians and Gynecologists.

Commentary: Identification and surveillance will help carriers avoid cancer

	Dr. Shulman is The Anna Ross Lapham Professor in Obstetrics and Gynecology and Chief, Division of Clinical Genetics, Feinberg School of Medicine of Northwestern University, Chicago, Illinois.

	Until recently, cancer risk assessment has been driven mostly by an individual’s personal medical history, family history or environmental exposures, with obtaining records concerning the actual presence of a specific malignancy in a family member or the patient being needed to provide the most accurate assessment of risk for cancer development. Indeed, obtaining medical records of affected family members to confirm the presence or absence of a particular malignancy was, and continues to be, one of the most important steps in arriving at an accurate risk of cancer development. This assessment could then be used to initiate a change in surveillance or intervention, so as to reduce the likelihood of cancer or improve the likelihood of an early diagnosis that would be associated with a more favorable clinical outcome.

	The ongoing contributions of the Human Genome Project have provided the framework to better identify individuals at increased risk of developing certain malignancies as a result of inheriting cancer predisposition gene mutations. One such cancer-predisposing condition is Lynch syndrome, previously known as Hereditary Non-Polyposis Colorectal Cancer syndrome (HNPCC). Lynch syndrome is the most common cause of hereditary endometrial cancer and hereditary colorectal cancer (CRC), accounting for approximately 3% of all colon and endometrial cancers. It is also the second most common cause of inherited ovarian epithelial cancer, after hereditary breast and ovarian cancer syndrome (HBOC). The recent American College of Obstetricians and Gynecologists Practice Bulletin (No. 147) addresses issues germane to the obstetrician/gynecologist caring for women at increased risk of malignancies associated with Lynch syndrome as well as women who are found to be carriers of Lynch syndrome gene mutations.

	Lynch syndrome is a highly penetrant autosomal-dominant inherited cancer syndrome in which predisposition to malignancy results from an underlying defect in the cellular mismatch repair (MMR) system. The MMR proteins form a complex that detects and corrects replication errors. When the MMR system is compromised by a germline gene mutation there is an accelerated and expanded accumulation of somatic mutations, increasing the likelihood of carcinogenesis. Specifically Lynch syndrome is caused mutations in the following genes: 

that produce MMR proteins. About 80% of Lynch syndrome cases are caused by mutations in the 

 genes, with most of the remaining cases resulting from mutations in 

	In addition to colon, ovarian epithelial and endometrial malignancies, other cancers associated with Lynch syndrome include hepatobiliary, urinary, small bowel, brain/central nervous system, and sebaceous tumors. As noted, about 2% to 3% of all cases of endometrial and colon cancer, respectively, are attributable to Lynch syndrome and can be characterized by absent mismatch repair gene expression. This frequency of gene mutation increases to 5% to 13% in endometrial or colorectal cancers occurring in women diagnosed before age 50.

	Women with Lynch syndrome exhibit typical characteristics of genetic cancer predisposition syndromes, including considerably increased risk of cancer development, earlier age of onset compared to the general population, higher rate of multiple primary cancers, and the potential absence of certain environmental risk factors. The lifetime risk of endometrial cancer in women with Lynch syndrome is 20% to 60% compared to 2% to 3% in the general population. The lifetime risk of CRC in those carrying a Lynch syndrome gene mutation is also 20% to 60%, compared to 4% to 5% in the general population. For ovarian epithelial cancer, lifetime risk in women with Lynch syndrome is approximately 10% compared to 1.5% in the general population. In contrast, 

 mutation a 15 to 20% risk of ovarian cancer. The mean age of CRC diagnosis in individuals with Lynch syndrome is 44 to 61 years compared to 69 years among sporadic cases. The specific gene mutation impacts the risk of cancer development with a lifetime risk of CRC in individuals with 

 gene mutations of 30% to 74% compared to 10% to 22% among individuals with 

 mutations and 15% to 20% among those with 

	Before the advent of genetic testing, criteria were established to identify individuals at risk of inheriting Lynch syndrome gene mutations. The initial criteria (Amsterdam I) did not include extracolonic malignancies; Amsterdam II and Bethesda criteria were subsequently developed that included extracolonic malignancies. However, these criteria while highly specific have low sensitivity in identifying individuals at risk of Lynch syndrome malignancies. In addition, these guidelines do not identify which patients with endometrial tumors should undergo further evaluation, an omission that has been addressed in the more current Bethesda (II) criteria that incorporate endometrial cancer as a sentinel malignancy (Table).

	Most individuals at risk of a cancer predisposition syndrome as result of cancer development or family history are typically provided genetic counseling and offered genetic testing that evaluates the individual for a germline gene mutation. While the diagnosis of Lynch syndrome is made by detecting a germline mutation in one of the MMR complex genes, a direct analysis of these mutations is not the usual diagnostic process in Lynch syndrome because such testing involves sequencing and screening for large rearrangements of the relevant mismatch repair genes, a complex and costly process fraught with problematic clinical outcomes. Germline DNA tests will not identify a causative mutation in 10% to 15% of cases of endometrial cancer with loss of either 

gene expression and in 35% to 40% of cases of endometrial cancers with loss of either 

gene expression. Accordingly, while the detection of a deleterious mutation is a conclusive finding associated with Lynch syndrome, the failure to detect a deleterious mutation does not necessarily exclude Lynch syndrome. As such, initiation of testing for Lynch syndrome usually begins with testing tumors using immunohistochemistry (IHC) or microsatellite instability testing (MSI), unlike HBOC and other cancer predisposition syndromes.

	Immunohistochemistry is used to evaluate tumors for the expression of the four mismatch repair genes by detecting the presence of their protein products. A relatively inexpensive test that is widely available, IHC can also identify which of the four mismatch gene proteins are absent, which helps to guide further genetic testing. Finding all four MMR proteins considerably reduces the likelihood of Lynch syndrome, but does not entirely eliminate that possibility. In cases characterized by the absence of the MLH1 protein, testing for methylation of the 

promoter is needed, with or without the absence of the PMS2 protein. This is because 15% to 20% of cases of colorectal cancer and 20% to 30% of cases of endometrial cancer will have silencing of 

promoter. To determine if these abnormalities are due to a non-inherited methylation of the 

promoter versus germline DNA mutation in 

(both of which cause Lynch syndrome), a laboratory can directly assess the potential Lynch syndrome-associated tumor for methylation of the 

promoter. When the MLH1 protein is absent and there 

promoter, then Lynch syndrome is excluded. But when the MLH1 protein is absent and there is 

promoter, then the patient is at risk of Lynch syndrome and testing of germline DNA is required for confirmation.

	In cases in which personal or family history is strongly supportive of Lynch syndrome, tumors can be further evaluated by MSI. Such testing requires tumor tissue and normal tissue to determine if there has been insertion or deletion of nucleotides to informative microsatellites, indicative of a mutation in that specific gene and facilitating confirmatory germline testing. If no microsatellite instability is detected, Lynch syndrome can be essentially ruled out regardless of family history or cancer presentation.

	Detection of Lynch syndrome should initiate a change in health surveillance and the offering of targeted chemoprevention and surgical risk-reducing procedures. Initiation of such interventions will be specific to each patient and will be impacted by personal health history, including age, general health, and ability to initiate and continue specific pharmaceutical interventions.

	Combination oral contraceptives (COCs), systemic progestin therapies, and the copper and higher-dose levonorgestrel intrauterine devices have been shown to reduce the risk of developing endometrial cancer in the general population, while COCs have been associated with a reduced risk for ovarian epithelial cancer in high- and low-risk populations. COCs also have been associated with a reduced risk of colorectal cancer.

	Prophylactic hysterectomy and bilateral salpingo-oophorectomy should be discussed with women with Lynch syndrome who have completed childbearing as a risk-reducing option for endometrial and ovarian cancers. Counseling should affirm that surgery will reduce but not eliminate the risk of ovarian/peritoneal cancer. Postoperative vasomotor symptoms can be reduced with oral and non-oral low-dose estrogen-only postmenopausal hormonal therapy regimens in women with no contraindications to the use of estrogen.

	Despite the lack of proven cost-effective screening algorithms for endometrial or ovarian cancers, the earlier onset of endometrial cancer in women with Lynch syndrome has led to the recommendation for endometrial biopsy starting at age 30 to 35, to be repeated every 1 to 2 years, along with maintenance of a menstrual calendar to detect irregular menstrual bleeding. Screening for CRC by colonoscopy should begin at ages 20 to 25 or 2 to 5 years prior to the earliest age of CRC detection in a relative, whichever is earlier. There is also no proven approach to effective screening for women at increased risk of ovarian epithelial cancer. Approaches that have been used to screen 

positive women for ovarian cancer may not be applicable to women with Lynch syndrome because of the different genomic etiology of the malignancy. Indeed, neither ultrasound nor CA-125 has been shown to be of use in the early detection of ovarian cancer in women with Lynch syndrome.

	Our improved ability to identify women at risk of Lynch syndrome and other cancer predisposing syndromes allows for the initiation of effective surveillance and the offering of chemotherapeutic and surgical preventative measures to reduce the likelihood of cancer development or to allow for early detection that may improve clinical outcomes by preventing late-stage malignancies. While advances in the detection of Lynch syndrome genes have allowed us to prevent cancers and reduce mortality in at-risk women, it is important to recognize that such measures are not applicable to the vast majority of women who will develop endometrial, ovarian, and colorectal cancers. The search for genomic and molecular characteristics that can be used to develop effective screening and diagnostic algorithms must continue so that the advances associated with Lynch syndrome can be extended to the community at large.

	1. Watson P, Vasen HF, Mecklin JP, Bernstein I, Aarnio M, Jarvinen HJ, et al. The risk of extra-colonic, extraendometrial cancer in the Lynch syndrome. Int J Cancer 2008;123:444–9. (Level II-2)

	2. Win AK, Lindor NM, Young JP, Macrae FA, Young GP, Williamson E, et al. Risks of primary extracolonic cancers following colorectal cancer in Lynch syndrome. J Natl Cancer Inst 2012;104:1363–72. (Level II-2)

	3. Win AK, Lindor NM, Winship I, Tucker KM, Buchanan DD, Young JP, et al. Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst 2013;105:274–9. (Level II-2)

	4. Win AK, Lindor NM, Jenkins MA. Risk of breast cancer in Lynch syndrome: a systematic review. Breast Cancer Res 2013;15:R27. (Level II-2)

	5. Jarvinen HJ, Aarnio M, Mustonen H, Aktan-Collan K, Aaltonen LA, Peltomaki P, et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 2000;118:829–34. (Level II-2)

	6. Schmeler KM, Lynch HT, Chen LM, Munsell MF, Soliman PT, Clark MB, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med 2006;354:261–9. (Level II-2)

	1. Lynch syndrome. Practice Bulletin No. 147. American College of Obstetricians and Gynecologists. 

	2. Palomaki GE, McClain MR, Melillo S, et al. EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. 

	3. Cohen SA, Leininger A. The genetic basis of Lynch syndrome and its implications for clinical practice and risk management. 

	4. Shulman LP, Kiley JW. Combination Oral Contraception: The metamorphosis from birth control to pregnancy prevention with noncontraceptive benefits.

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