- Email: [email protected]
Gynecologic malignancies in Ashkenazi families with the MSH2 A636P founder mutation
Research
www. AJOG.org
ONCOLOGY
Gynecologic malignancies in Ashkenazi families with the MSH2 A636P founder mutation Ofer Lavie, MD; Stephen B. Gruber, MD, MPH, PhD; Flavio Lejbkowicz, PhD; Sara Dishon, RN, MPA; Gad Rennert, MD, PhD OBJECTIVE: A founder mutation A636P in the MSH2 gene was found to be related to hereditary nonpolyposis colorectal cancer in Ashkenazi Jews. Although the incidence of colorectal cancer in carriers is relatively well established, the frequency of other tumors is less clear. STUDY DESIGN: We studied a consecutive series of 19 carrier families
that were cared for by the Clalit Health Studies National Familial Cancer Consultation Service, most of whom were identified through a populationbased case-control study of colorectal cancer in northern Israel. RESULTS: Gynecologic cancers, 88% of which (28 cases) were endo-
metrial cancers, were diagnosed in 78.9% of the carrier families and in
26.2% of the women who were at risk, with a mean age at diagnosis of 51.2 years. Forty-six percent of the women with endometrial cancer reported at least 1 other primary tumor. CONCLUSION: Genetic counseling and testing for the MSH2 A636P
mutation is indicated for Ashkenazi Jewish women with an endometrial cancer, especially if the cancer is detected before the age of 70 years in women with a personal or family history of colorectal cancer. Key words: Ashkenazi Jews, colorectal cancer, endometrial cancer, HNFCC, MSH2 A636P founder mutation
Cite this article as: Lavie O, Gruber SB, Lejbkowicz F, et al. Gynecologic malignancies in Ashkenazi families with the MSH2 A636P founder mutation. Am J Obstet Gynecol 2008;199:148.e1-148.e3.
T
he MSH2 A636P mutation is a founder mutation in the Ashkenazi population that causes Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]) and has a prevalence of approximately 0.4%-0.7%.1,2 The mutation probably arose between 11 and 22 generations ago.3 Carriers of this mutation have been identified generally through the detection of colorectal cancer in families with clinical criteria that From the Division of Gynecology & Oncology (Dr Lavie), the Department of Community Medicine and Epidemiology and CHS National Cancer Control Center (Drs Lejbkowicz and Rennert and Ms Dishon), Carmel Medical Center and B. Rappaport Faculty of Medicine, Technion, Haifa, Israel; and the Departments of Internal Medicine and Epidemiology, University of Michigan, Ann Arbor, MI (Dr Gruber). Received Aug. 4, 2007; revised Oct. 31, 2007; accepted Feb. 8, 2008. Reprints: Gad Rennert, MD, PhD, CHS National Cancer Control Center, Carmel Medical Center, 7 Michal St, Haifa 34362, Israel. [email protected]. 0002-9378/$34.00 © 2008 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2008.02.018
148.e1
are suggestive of Lynch syndrome. In addition to malignancies of the lower gastrointestinal tract, other malignancies are overrepresented among carriers,4-8 and the suggestion has been made that women with mismatch repair gene mutations have an even higher lifetime risk of endometrial cancer than of colon cancer.9 In a hospital-based series, the MSH6 A636P mutation was identified in 2 of 197 women with endometrial cancer and in 0 of 83 women with ovarian cancer.1 Including carriers who were ascertained through high-risk families, 25 apparently unrelated Ashkenazi Jewish families have been found to harbor this mutation. Although this mutation accounts for only 1% of all colorectal cancer in Ashkenazi Jewish families and 2%-3% of colorectal cancer diagnosed at age ⬍60 years and up to 7% in younger cases, it accounts for approximately onethird of HNPCC in Ashkenazi Jewish families that fulfill the Amsterdam criteria because of its high penetrance.1,10,11 We studied a consecutive series of families in which individuals were identified with the MSH2 A636P mutation in 1 familial cancer service in Israel for the frequency of reported gynecologic malignancies.
American Journal of Obstetrics & Gynecology AUGUST 2008
M ATERIALS AND M ETHODS The Clalit Health Studies (CHS) National Familial Cancer Consultation Service is responsible for counseling families with a multitude of cancer cases. The Service evaluates and cares for families that are referred by treating physicians, by self-referral, or by families that are detected in population-based studies of cancer causes that are conducted at the National Cancer Control Center. Families of Ashkenazi descent with a family history that is suggestive of HNPCC were tested for the A636P mutation in the MSH2 gene. All participants of the population-based Molecular Epidemiology of Colorectal Cancer case-control study were also studied for this mutation. Once a mutation had been diagnosed in a family, an effort was made to expand the testing to as many affected and nonaffected family members as possible. DNA extraction from white blood cells was performed with the Puregene DNA isolation kit (Gentra Systems, Inc, Minneapolis, MN) according to the manufacturer’s recommendation. To genotype the samples for the hMSH2A636P mutation, we used the 5’ nuclease TaqMan allelic discrimination assay with the ABI-Prism 7900HT Sequence
Oncology
www.AJOG.org
Research
TABLE
Description of gynecologic cancers in MSH2-A636P positive families (CHS National Cancer Control Center, Israel) Family number
Source of case: clinic or population-based study
Women at risk age >30 y, no TAH (n)
Women with gynecologic cancers (n)
Case number
Type of cancer and age (y) at diagnosis
Medical record to confirm diagnosis
Multiple tumors
Mutation status
1729
Study
10
1
I:2
Uterus, 41
No
No
NT
2569
Clinic
8
3
III:2
Uterus, 63
Yes
No
Carrier
IV:3
Uterus, 44
Yes
Yes (colorectal cancer ⫻ 2)
Carrier
IV:1
Ovary, 38
Yes
No
Carrier
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
2743
Clinic
6
1
II:4
Uterus, 40
No
Yes (colorectal cancer)
NT
2978
Study
6
2
III:2
Uterus, 51
Yes
No
Carrier
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
II:1
Uterus, 56
No
No
NT
IV:2
Uterus, 43
Yes
No
Carrier
III:5
Uterus, 66
No
No
Carrier
III:1
Uterus, 74
Yes
Yes (colorectal cancer)
Carrier
................................................................................................................................................................................................................................................................................................................................................................................
2983
Study
12
4
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
IV:5
Uterus, ?
No
Yes (breast)
NT
3006
Study
1
1
IV:2
Uterus, 47
Yes
No
Carrier
3194
Clinic
7
3
III:5
Uterus, 53
Yes
Yes (lung ⫹ melanoma)
NT
II:3
Uterus, 79
Yes
No
NT
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
III:11
Uterus, 61
No
No
NT
II:2
Uterus, 75
No
Yes (kidney)
NT
................................................................................................................................................................................................................................................................................................................................................................................
3200
Study
14
1
3201
Study
4
0
3202
Study
3
0
3247
Clinic
1
0
3249
Study
6
1
III:2
Uterus, 53
No
Yes (colorectal cancer)
Carrier
3321
Study
8
1
III:2
Uterus, 66
No
Yes (colorectal cancer ⫹ kidney)
NT
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
3408
Study
13
4
II:7
Uterus, 60
No
No
NT
III:5
Uterus, 53
Yes
Yes (colorectal cancer)
NT
III:9
Uterus, 45
No
No
NT
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
III:8
Uterus, ?
No
No
NT
III:6
Uterus, 60
No
Yes (colorectal cancer)
NT
................................................................................................................................................................................................................................................................................................................................................................................
3429
Study
5
3
................................................................................................................................................................................................................................................................................................................................................................................
III:5
Uterus, ?
No
No
NT
IV:1
Cervix, 54
Yes
Yes (colorectal cancer)
Carrier
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
3430
Study
2
0
3431
Study
4
2
................................................................................................................................................................................................................................................................................................................................................................................
II:4
Uterus, 76
Yes
No (colorectal cancer)
Carrier
................................................................................................................................................................................................................................................................................................................................................................................
III:2
Uterus, 51
Yes
No
Carrier
III:1
Uterus, 58
No
Yes (colorectal cancer ⫻ 2)
Carrier
................................................................................................................................................................................................................................................................................................................................................................................
3432
Study
5
2
................................................................................................................................................................................................................................................................................................................................................................................
IV:3
Uterus, ⬍50
No
No
NT
III:1
Uterus, 69
Yes
Yes (colorectal cancer ⫻ 2)
Carrier
II:4
Ovary, 80
No
No
NT
III:7
Cervix, 49
Yes
No
Noncarrier
................................................................................................................................................................................................................................................................................................................................................................................
3661
Clinic
7
3
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
NT, blood not available for testing (mostly deceased); TAH, total abdominal hysterectomy. Lavie. Gynecologic malignancies in Ashkenazi families with the MSH2 A636P founder mutation. Am J Obstet Gynecol 2008.
AUGUST 2008 American Journal of Obstetrics & Gynecology
148.e2
Research
Oncology
Detection System (Applied Biosystems, Foster City, CA) apparatus. Primers and probes were generated by the assay-bydesign custom oligonucleotide reagent service (Applied Biosystems). All tested family members, from the study or the service sources, signed an informed consent form approved by the Carmel Medical Center. All cases of gynecologic cancers as reported by the proband or other family members were taken into account. An effort was made to ascertain the reported case through the study of medical records, when possible.
R ESULTS Altogether, 19 families were identified with at least 1 family member who carries the MSH2 A636P mutation: 14 families from the Molecular Epidemiology of Colorectal Cancer study and 5 families from a high-risk clinic (Table). Of these, 15 families (78.9%) expressed at least 1 gynecologic cancer in a family member. Of 122 adult women in these at-risk families (age ⱖ30 years, no hysterectomy, regardless of carrier status), 32 women (26.2%) were diagnosed with gynecologic cancers, compared with 24 women who were diagnosed with colorectal cancer. Endometrial cancer was the most prominent tumor to be diagnosed in this group (88% of all gynecologic cancers), with a mean age at diagnosis of 51.2 years. Multiple primary tumors were found commonly in the women with endometrial cancer; 13 of 28 women with endometrial cancer (46.4%) reported at least 1 other primary tumor. This was most commonly colorectal cancer (10/13 women); kidney (2 women), lung (1 woman), breast (1 woman), and melanoma (1 woman) were also identified.
C OMMENT In our series of families in which the MSH2 A636P mutation has been identified, endometrial cancer was found to be highly prevalent (22% of the women at risk, compared with a lifetime probability of ⬍1% in the general population). Endometrial cancer is considered a ma-
148.e3
www.AJOG.org jor component of the HNPCC or Lynch syndrome,4,7,12 but the penetrance for endometrial cancer for specific mutations is not known in carriers,6,9,12 although it is clear that endometrial cancer is very common in carriers of mutations in MSH6.13 Our data unequivocally demonstrate that the A636P mutation in MSH2 is expressed commonly as endometrial cancer, frequently accompanied by another primary colorectal cancer. Fourteen of the 19 reported families were identified through our populationbased colorectal cancer study (1 of them was found in the control arm with an unaffected proband), and only 5 families were identified through the clinical service, which strengthens the study estimates. As expected, the prevalence of endometrial cancer was slightly lower in families that were detected through the population-based study (21%) than those families that were detected through clinical service (24%). Nevertheless, still close to 80% of our ascertained study families included at least 1 woman with endometrial cancer. The common demonstration of double primary endometrial and colorectal cancers in families with the MSH2 A636P Ashkenazi mutation is in line with other reports of an increased rate of mutations in MLH1, MSH2, and MSH6 in cases with multiple primary tumors.8 Ashkenazi Jewish women who are detected with an endometrial cancer should be offered genetic counseling routinely that includes testing for the MSH2 A636P mutation. Ashkenazi women who are diagnosed with either endometrial cancer at ⬍70 years of age or with a family history of colorectal cancer are especially likely to carry a mutation, and site-specific testing for MSH2 A636P should be offered before a more comprehensive molecular diagnostic workup is pursued for other mismatch repair mutations. Risk-reducing measures for women with this mutation should be discussed and could involve a variety of interventions, from enhanced surveillance with transvaginal sonography and random sampling of the uterus
American Journal of Obstetrics & Gynecology AUGUST 2008
to diagnostic hysteroscopy and prophyf lactic hysterectomy. REFERENCES 1. Foulkes WD, Thiffault I, Gruber SB, et al. The founder mutation MSH2*1906G¡C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population. Am J Hum Genet 2002;71:1395-412. 2. Zauber NP, Sabbath-Solitare M, Marotta S, et al. Clinical and genetic findings in an Ashkenazi Jewish population with colorectal neoplasms. Cancer 2005;104:719-29. 3. Sun S, Greenwood CM, Thiffault I, Hamel N, Chong G, Foulkes WD. The HNPCC associated MSH2*1906G¡C founder mutation probably originated between 1440 CE and 1715 CE in the Ashkenazi Jewish population. J Med Genet 2005;42:766-8. 4. Lynch HT, Casey MJ, Shaw TG, Lynch JF. Hereditary factors in gynecologic cancer. Oncologist 1998;3:319-38. 5. Bermejo JL, Eng C, Hemminki K. Cancer characteristics in Swedish families fulfilling criteria for hereditary nonpolyposis colorectal cancer. Gastroenterology 2005;129:1889-99. 6. Quehenberger F, Vasen HF, van Houwelingen HC. Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment. J Med Genet 2005;42:491-6. 7. Oliveira Ferreira F, Napoli Ferreira CC, Rossi BM, et al. Frequency of extra-colonic tumors in hereditary nonpolyposis colorectal cancer (HNPCC) and familial colorectal cancer (FCC) Brazilian families: an analysis by a Brazilian Hereditary Colorectal Cancer Institutional Registry. Fam Cancer 2004;3:41-7. 8. Cederquist K, Emanuelsson M, Goransson I, et al. Mutation analysis of the MLH1, MSH2 and MSH6 genes in patients with double primary cancers of the colorectum and the endometrium: a population-based study in northern Sweden. Int J Cancer 2004;109:370-6. 9. Bianchi F, Rosati S, Belvederesi L, et al. MSH2 splice site mutation and endometrial cancer. Int J Gynecol Cancer 2006;16: 1419-23. 10. Fidder HH, Figer A, Geva R, et al. Genetic analyses in consecutive Israeli Jewish colorectal cancer patients. Am J Gastroenterol 2005; 100:1376-80. 11. Guillem JG, Moore HG, Palmer C, et al. A636P testing in Ashkenazi Jews. Fam Cancer 2004;3:223-7. 12. Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatchrepair genes. Int J Cancer 1999;81:214-8. 13. Planck M, Koul A, Fernebro E, et al. hMLH1, hMSH2 and hMSH6 mutations in hereditary non-polyposis colorectal cancer families from southern Sweden. Int J Cancer 1999; 83:197-202.
www. AJOG.org
ONCOLOGY
Gynecologic malignancies in Ashkenazi families with the MSH2 A636P founder mutation Ofer Lavie, MD; Stephen B. Gruber, MD, MPH, PhD; Flavio Lejbkowicz, PhD; Sara Dishon, RN, MPA; Gad Rennert, MD, PhD OBJECTIVE: A founder mutation A636P in the MSH2 gene was found to be related to hereditary nonpolyposis colorectal cancer in Ashkenazi Jews. Although the incidence of colorectal cancer in carriers is relatively well established, the frequency of other tumors is less clear. STUDY DESIGN: We studied a consecutive series of 19 carrier families
that were cared for by the Clalit Health Studies National Familial Cancer Consultation Service, most of whom were identified through a populationbased case-control study of colorectal cancer in northern Israel. RESULTS: Gynecologic cancers, 88% of which (28 cases) were endo-
metrial cancers, were diagnosed in 78.9% of the carrier families and in
26.2% of the women who were at risk, with a mean age at diagnosis of 51.2 years. Forty-six percent of the women with endometrial cancer reported at least 1 other primary tumor. CONCLUSION: Genetic counseling and testing for the MSH2 A636P
mutation is indicated for Ashkenazi Jewish women with an endometrial cancer, especially if the cancer is detected before the age of 70 years in women with a personal or family history of colorectal cancer. Key words: Ashkenazi Jews, colorectal cancer, endometrial cancer, HNFCC, MSH2 A636P founder mutation
Cite this article as: Lavie O, Gruber SB, Lejbkowicz F, et al. Gynecologic malignancies in Ashkenazi families with the MSH2 A636P founder mutation. Am J Obstet Gynecol 2008;199:148.e1-148.e3.
T
he MSH2 A636P mutation is a founder mutation in the Ashkenazi population that causes Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]) and has a prevalence of approximately 0.4%-0.7%.1,2 The mutation probably arose between 11 and 22 generations ago.3 Carriers of this mutation have been identified generally through the detection of colorectal cancer in families with clinical criteria that From the Division of Gynecology & Oncology (Dr Lavie), the Department of Community Medicine and Epidemiology and CHS National Cancer Control Center (Drs Lejbkowicz and Rennert and Ms Dishon), Carmel Medical Center and B. Rappaport Faculty of Medicine, Technion, Haifa, Israel; and the Departments of Internal Medicine and Epidemiology, University of Michigan, Ann Arbor, MI (Dr Gruber). Received Aug. 4, 2007; revised Oct. 31, 2007; accepted Feb. 8, 2008. Reprints: Gad Rennert, MD, PhD, CHS National Cancer Control Center, Carmel Medical Center, 7 Michal St, Haifa 34362, Israel. [email protected]. 0002-9378/$34.00 © 2008 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2008.02.018
148.e1
are suggestive of Lynch syndrome. In addition to malignancies of the lower gastrointestinal tract, other malignancies are overrepresented among carriers,4-8 and the suggestion has been made that women with mismatch repair gene mutations have an even higher lifetime risk of endometrial cancer than of colon cancer.9 In a hospital-based series, the MSH6 A636P mutation was identified in 2 of 197 women with endometrial cancer and in 0 of 83 women with ovarian cancer.1 Including carriers who were ascertained through high-risk families, 25 apparently unrelated Ashkenazi Jewish families have been found to harbor this mutation. Although this mutation accounts for only 1% of all colorectal cancer in Ashkenazi Jewish families and 2%-3% of colorectal cancer diagnosed at age ⬍60 years and up to 7% in younger cases, it accounts for approximately onethird of HNPCC in Ashkenazi Jewish families that fulfill the Amsterdam criteria because of its high penetrance.1,10,11 We studied a consecutive series of families in which individuals were identified with the MSH2 A636P mutation in 1 familial cancer service in Israel for the frequency of reported gynecologic malignancies.
American Journal of Obstetrics & Gynecology AUGUST 2008
M ATERIALS AND M ETHODS The Clalit Health Studies (CHS) National Familial Cancer Consultation Service is responsible for counseling families with a multitude of cancer cases. The Service evaluates and cares for families that are referred by treating physicians, by self-referral, or by families that are detected in population-based studies of cancer causes that are conducted at the National Cancer Control Center. Families of Ashkenazi descent with a family history that is suggestive of HNPCC were tested for the A636P mutation in the MSH2 gene. All participants of the population-based Molecular Epidemiology of Colorectal Cancer case-control study were also studied for this mutation. Once a mutation had been diagnosed in a family, an effort was made to expand the testing to as many affected and nonaffected family members as possible. DNA extraction from white blood cells was performed with the Puregene DNA isolation kit (Gentra Systems, Inc, Minneapolis, MN) according to the manufacturer’s recommendation. To genotype the samples for the hMSH2A636P mutation, we used the 5’ nuclease TaqMan allelic discrimination assay with the ABI-Prism 7900HT Sequence
Oncology
www.AJOG.org
Research
TABLE
Description of gynecologic cancers in MSH2-A636P positive families (CHS National Cancer Control Center, Israel) Family number
Source of case: clinic or population-based study
Women at risk age >30 y, no TAH (n)
Women with gynecologic cancers (n)
Case number
Type of cancer and age (y) at diagnosis
Medical record to confirm diagnosis
Multiple tumors
Mutation status
1729
Study
10
1
I:2
Uterus, 41
No
No
NT
2569
Clinic
8
3
III:2
Uterus, 63
Yes
No
Carrier
IV:3
Uterus, 44
Yes
Yes (colorectal cancer ⫻ 2)
Carrier
IV:1
Ovary, 38
Yes
No
Carrier
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
2743
Clinic
6
1
II:4
Uterus, 40
No
Yes (colorectal cancer)
NT
2978
Study
6
2
III:2
Uterus, 51
Yes
No
Carrier
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
II:1
Uterus, 56
No
No
NT
IV:2
Uterus, 43
Yes
No
Carrier
III:5
Uterus, 66
No
No
Carrier
III:1
Uterus, 74
Yes
Yes (colorectal cancer)
Carrier
................................................................................................................................................................................................................................................................................................................................................................................
2983
Study
12
4
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
IV:5
Uterus, ?
No
Yes (breast)
NT
3006
Study
1
1
IV:2
Uterus, 47
Yes
No
Carrier
3194
Clinic
7
3
III:5
Uterus, 53
Yes
Yes (lung ⫹ melanoma)
NT
II:3
Uterus, 79
Yes
No
NT
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
III:11
Uterus, 61
No
No
NT
II:2
Uterus, 75
No
Yes (kidney)
NT
................................................................................................................................................................................................................................................................................................................................................................................
3200
Study
14
1
3201
Study
4
0
3202
Study
3
0
3247
Clinic
1
0
3249
Study
6
1
III:2
Uterus, 53
No
Yes (colorectal cancer)
Carrier
3321
Study
8
1
III:2
Uterus, 66
No
Yes (colorectal cancer ⫹ kidney)
NT
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
3408
Study
13
4
II:7
Uterus, 60
No
No
NT
III:5
Uterus, 53
Yes
Yes (colorectal cancer)
NT
III:9
Uterus, 45
No
No
NT
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
III:8
Uterus, ?
No
No
NT
III:6
Uterus, 60
No
Yes (colorectal cancer)
NT
................................................................................................................................................................................................................................................................................................................................................................................
3429
Study
5
3
................................................................................................................................................................................................................................................................................................................................................................................
III:5
Uterus, ?
No
No
NT
IV:1
Cervix, 54
Yes
Yes (colorectal cancer)
Carrier
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
3430
Study
2
0
3431
Study
4
2
................................................................................................................................................................................................................................................................................................................................................................................
II:4
Uterus, 76
Yes
No (colorectal cancer)
Carrier
................................................................................................................................................................................................................................................................................................................................................................................
III:2
Uterus, 51
Yes
No
Carrier
III:1
Uterus, 58
No
Yes (colorectal cancer ⫻ 2)
Carrier
................................................................................................................................................................................................................................................................................................................................................................................
3432
Study
5
2
................................................................................................................................................................................................................................................................................................................................................................................
IV:3
Uterus, ⬍50
No
No
NT
III:1
Uterus, 69
Yes
Yes (colorectal cancer ⫻ 2)
Carrier
II:4
Ovary, 80
No
No
NT
III:7
Cervix, 49
Yes
No
Noncarrier
................................................................................................................................................................................................................................................................................................................................................................................
3661
Clinic
7
3
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
NT, blood not available for testing (mostly deceased); TAH, total abdominal hysterectomy. Lavie. Gynecologic malignancies in Ashkenazi families with the MSH2 A636P founder mutation. Am J Obstet Gynecol 2008.
AUGUST 2008 American Journal of Obstetrics & Gynecology
148.e2
Research
Oncology
Detection System (Applied Biosystems, Foster City, CA) apparatus. Primers and probes were generated by the assay-bydesign custom oligonucleotide reagent service (Applied Biosystems). All tested family members, from the study or the service sources, signed an informed consent form approved by the Carmel Medical Center. All cases of gynecologic cancers as reported by the proband or other family members were taken into account. An effort was made to ascertain the reported case through the study of medical records, when possible.
R ESULTS Altogether, 19 families were identified with at least 1 family member who carries the MSH2 A636P mutation: 14 families from the Molecular Epidemiology of Colorectal Cancer study and 5 families from a high-risk clinic (Table). Of these, 15 families (78.9%) expressed at least 1 gynecologic cancer in a family member. Of 122 adult women in these at-risk families (age ⱖ30 years, no hysterectomy, regardless of carrier status), 32 women (26.2%) were diagnosed with gynecologic cancers, compared with 24 women who were diagnosed with colorectal cancer. Endometrial cancer was the most prominent tumor to be diagnosed in this group (88% of all gynecologic cancers), with a mean age at diagnosis of 51.2 years. Multiple primary tumors were found commonly in the women with endometrial cancer; 13 of 28 women with endometrial cancer (46.4%) reported at least 1 other primary tumor. This was most commonly colorectal cancer (10/13 women); kidney (2 women), lung (1 woman), breast (1 woman), and melanoma (1 woman) were also identified.
C OMMENT In our series of families in which the MSH2 A636P mutation has been identified, endometrial cancer was found to be highly prevalent (22% of the women at risk, compared with a lifetime probability of ⬍1% in the general population). Endometrial cancer is considered a ma-
148.e3
www.AJOG.org jor component of the HNPCC or Lynch syndrome,4,7,12 but the penetrance for endometrial cancer for specific mutations is not known in carriers,6,9,12 although it is clear that endometrial cancer is very common in carriers of mutations in MSH6.13 Our data unequivocally demonstrate that the A636P mutation in MSH2 is expressed commonly as endometrial cancer, frequently accompanied by another primary colorectal cancer. Fourteen of the 19 reported families were identified through our populationbased colorectal cancer study (1 of them was found in the control arm with an unaffected proband), and only 5 families were identified through the clinical service, which strengthens the study estimates. As expected, the prevalence of endometrial cancer was slightly lower in families that were detected through the population-based study (21%) than those families that were detected through clinical service (24%). Nevertheless, still close to 80% of our ascertained study families included at least 1 woman with endometrial cancer. The common demonstration of double primary endometrial and colorectal cancers in families with the MSH2 A636P Ashkenazi mutation is in line with other reports of an increased rate of mutations in MLH1, MSH2, and MSH6 in cases with multiple primary tumors.8 Ashkenazi Jewish women who are detected with an endometrial cancer should be offered genetic counseling routinely that includes testing for the MSH2 A636P mutation. Ashkenazi women who are diagnosed with either endometrial cancer at ⬍70 years of age or with a family history of colorectal cancer are especially likely to carry a mutation, and site-specific testing for MSH2 A636P should be offered before a more comprehensive molecular diagnostic workup is pursued for other mismatch repair mutations. Risk-reducing measures for women with this mutation should be discussed and could involve a variety of interventions, from enhanced surveillance with transvaginal sonography and random sampling of the uterus
American Journal of Obstetrics & Gynecology AUGUST 2008
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