Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 1.1.3
• Status (Pediatric): Incomplete (Consensus scoring is Incomplete)
• GENE/GENE PANEL: MLH1, MSH2, MSH6, PMS2, EPCAM
• Condition: Lynch Syndrome
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• MLH1 ⇔ 0012249 (colorectal cancer, hereditary nonpolyposis, type 2): Assertion Pending
• MSH2 ⇔ 0007356 (lynch syndrome 1): Assertion Pending
• MSH6 ⇔ 0013710 (colorectal cancer, hereditary nonpolyposis, type 5): Assertion Pending
• PMS2 ⇔ 0013699 (colorectal cancer, hereditary nonpolyposis, type 4): Assertion Pending
• EPCAM ⇔ 0013196 (colorectal cancer, hereditary nonpolyposis, type 8): Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Gene Condition Pairs: MLH1 ⇔ 0012249 (OMIM:609310) MSH2 ⇔ 0007356 (OMIM:120435) MSH6 ⇔ 0013710 (OMIM:614350) PMS2 ⇔ 0013699 (OMIM:614337) EPCAM ⇔ 0013196 (OMIM:613244)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Colorectal cancer / Surveillance	2	3A	3A	2	10AA
Endometrial Cancer / Surveillance	2	3A	1A	2	8AA
Endometrial Cancer / Risk Reducing Surgery	2	3A	3B	1	9AB

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Currently in the US, roughly 1,154,000 people are living with CRC while 600,000 women are living with endometrial cancer. LS is the most common heritable CRC and accounts for 1-5% of all CRC cases and 2% of all endometrial cancer cases. [1, 2, 3, 4, 5, 6]

Clinical Features

LS is characterized by an increased risk of CRC and other cancers including endometrial, ovarian, and gastric. Cancers typically develop at an early age and individuals may develop multiple cancers. The majority (>90%) of LS-associated CRC tumors show microsatellite instability indicating the malfunction or loss of mismatch repair gene products. [1, 2, 3, 5, 6, 7, 8]

Natural History

The average age at diagnosis is 44-61 years for CRC, 48-62 years for endometrial cancer, 42 years for ovarian cancer, and later for other LS-associated cancers. The most common LS-associated cancer is CRC, which is not associated with polyposis and typically arises from a single colorectal lesion, advances more rapidly from adenoma to carcinoma than sporadic CRC, and is most common on the right side of the colon. The lifetime risk of cancer varies with the gene mutated and sex, with males having a higher risk of developing CRC compared to females. Recurrence of CRC is common. However, patients with LS-associated CRC and endometrial cancer have improved survival compared to patients with sporadic tumors. [2, 3, 6, 7, 8]

2. How effective are interventions for preventing harm?

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed ACT sheets to help clinical decision-making when one or more pathogenic variants in LS genes are identified as secondary findings and for people with a family history of colon cancer:
Secondary Findings ACT sheet: https://www.acmg.net/PDFLibrary/Lynch-Syndrome.pdf
Family History ACT Sheet: https://www.acmg.net/PDFLibrary/Colon-Cancer.pdf

Prophylactic hysterectomy and salpingo-oophorectomy have been shown to reduce the risk to develop endometrial and ovarian cancer associated with LS, and should be discussed as an option to mutation carriers once child-bearing is complete and after age 35-40. A retrospective study showed an absence of gynecological cancers among women who underwent prophylactic hysterectomy and/or bilateral salpingo-oophorectomy, compared to 33% and 5% incidence of endometrial and ovarian cancer, respectively, among women who did not have surgery. (Tier 2) [2, 5, 6, 7, 8, 9]

Regular aspirin significantly reduces LS cancer incidence. Evidence from a randomized controlled trial indicated regular aspirin reduced the incidence of CRC and other LS-associated cancers by 60%. (Tier 2) [2, 5, 6, 10]

Health professionals should be aware of potential psychosocial problems associated with genetic testing and surveillance, and patients experiencing psychological distress should be offered referral to a clinical psychologist. (Tier 2) [5]

Surveillance

Regular colonoscopic surveillance has been shown to lead to significant reduction of LS CRC incidence, detection of CRC cases at an earlier stage, and reduction in CRC-associated mortality. Individuals with LS should undergo colonoscopy every 1-3 years starting at age 20-25 years. Five out of six studies found a significantly reduced incidence rate of CRC with surveillance (OR estimates ranged from 0.11 to 0.35), while the sixth study reporting an OR of 0.93 was not significant. Two out of four studies have shown a significant reduction in CRC-related mortality with surveillance (OR estimates range from 0.04 to 0.17), while three of the four studies reported no mortality in the study arm with surveillance. (Tier 1) [7, 11]

Transvaginal ultrasound with endometrial biopsy may detect cancers and premalignant lesions of the endometrium, though interval endometrial carcinomas still occur and no subsequent improvement in survival has been demonstrated. (Tier 1) [7]

Individuals with LS should undergo esophagogastroduodenoscopy to screen for gastric cancer, though the age to start screening and the frequencies varies across recommendations, from age 30-25 to age 50 and from twice a year to every 2-3 years, respectively. However, there was no evidence provided that this surveillance reduces mortality. (Tier 2) [6, 8, 12, 13]

To screen for cancers of the urinary tract, individuals with LS should undergo urinalysis on an annual basis beginning at age 25-35 years. (Tier 2) [6, 8]

Circumstances to Avoid

Smoking and high BMI are associated with an increased risk of adenomas and CRC in LS, thus patients are advised to stay within the normal weight range and refrain from cigarette smoking. (Tier 2) [5]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

LS has an estimated prevalence of 1/440 in the general population. (Tier 3) [3]

By definition, cases of Lynch Syndrome are due to a defect in one of the mismatch repair genes. (Tier 3) [2]

Penetrance

Cumulative risks of cancer in LS by age 70: colorectal =25-70% , endometrial =30-70%, gastric=1-9%, small bowel=1-4%, biliary tract=1-2%, pancreas=1-4%, urinary tract =2-8%, upper urinary tract=6%, bladder=2-16%, ovarian=6-14%, brain =3.5%, prostate=9-30%, breast=5-14%. Risk may vary by MMR gene. Carriers of EPCAM deletions have a similar risk of CRC but a lower risk of endometrial cancer (12% by age 70). (Tier 3) [5]

Relative Risk

Males have a roughly 2.1- to 2.3-fold risk of prostate cancer. (Tier 1) [14]

Expressivity

Information in variable expressivity was not available.

4. What is the Nature of the Intervention?

Nature of Intervention

Endoscopic surveillance can be burdensome for individuals. (Tier 2)
In addition, colonoscopy is associated with risks, including pain, nausea, bleeding, perforation, and death. (Tier 3) [1, 7]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

LS-associated CRC has a lower average age of onset and advances at a more rapid rate compared to sporadic CRC and an increased risk of endometrial cancer, making it likely that these patients would escape detection using surveillance recommendations for average risk populations as screening for CRC is recommended in older populations and endometrial cancer screening is not recommended for the general population at all. (Tier 4) [7]

Date of Search: 02.11.2015

Reference List

1. Johnson PM, Gallinger S, McLeod RS. Surveillance colonoscopy in individuals at risk for hereditary nonpolyposis colorectal cancer: an evidence-based review. Dis Colon Rectum. (2006) 49(1):80-93; discussion 94-5.

2. Balmana J, Balaguer F, Cervantes A, Arnold D. Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines. Ann Oncol. (2013) 24 Suppl 6:vi73-80.

3. W Kohlmann, SB Gruber. Lynch Syndrome. 2004 Feb 05 [Updated 2014 May 22]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1211

4. American Cancer Society. Other. (2014) Website: www.cancer.org

5. Vasen HF, Blanco I, Aktan-Collan K, Gopie JP, Alonso A, Aretz S, Bernstein I, Bertario L, Burn J, Capella G, Colas C, Engel C, Frayling IM, Genuardi M, Heinimann K, Hes FJ, Hodgson SV, Karagiannis JA, Lalloo F, Lindblom A, Mecklin JP, Moller P, Myrhoj T, Nagengast FM, Parc Y, Ponz de Leon M, Renkonen-Sinisalo L, Sampson JR, Stormorken A, Sijmons RH, Tejpar S, Thomas HJ, Rahner N, Wijnen JT, Jarvinen HJ, Moslein G. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut. (2013) 62(6):812-23.

6. Giardiello FM, Allen JI, Axilbund JE, Boland CR, Burke CA, Burt RW, Church JM, Dominitz JA, Johnson DA, Kaltenbach T, Levin TR, Lieberman DA, Robertson DJ, Syngal S, Rex DK. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer. Am J Gastroenterol. (2014) 109(8):1159-79.

7. Association of Comprehensive Cancer Centres. Hereditary colorectal cancer. Amsterdam, The Netherlands Association of Comprehensive Cancer Centres. Other. (2009) Website: https://www.guidelinecentral.com/summaries/hereditary-colorectal-cancer/

8. Colorectal Cancer Screening. National Comprehensive Cancer Network. Other. (2013) Website: http://www.nccn.org/professionals/physician_gls/PDF/colorectal_screening.pdf

9. Stoffel EM, Mangu PB, Gruber SB, Hamilton SR, Kalady MF, Lau MW, Lu KH, Roach N, Limburg PJ. Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. J Clin Oncol. (2015) 33(2):209-17.

10. Prevention of vascular and metabolic disease. Guidelines for preventive activities in general practice, 8th edition.East Melbourne (Australia). Other. (2012) Website: http://www.nmml.org.au/content/Document/RACGP%20Red%20Book.pdf

11. Barrow P, Khan M, Lalloo F, Evans DG, Hill J. Systematic review of the impact of registration and screening on colorectal cancer incidence and mortality in familial adenomatous polyposis and Lynch syndrome. Br J Surg. (2013) 100(13):1719-31.

12. Cairns SR, Scholefield JH, Steele RJ, Dunlop MG, Thomas HJ, Evans GD, Eaden JA, Rutter MD, Atkin WP, Saunders BP, Lucassen A, Jenkins P, Fairclough PD, Woodhouse CR. Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). Gut. (2010) 59(5):666-89.

13. Diagnosis and management of colorectal cancer. A national clinical guideline. SIGN. (2011) Website: http://www.sign.ac.uk/guidelines/fulltext/126/

14. Ryan S, Jenkins MA, Win AK. Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. (2014) 23(3):437-49.