Cancers Other Than Breast and Ovarian Cancer

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Table 1 groups studies, by type, that have examined the association of cancers other than breast and ovarian/FT cancers with BRCA1/2 mutations, or in families with breast and/or ovarian cancer. Inclusion in the table was restricted to claims of statistically significant findings.

Colorectal Cancer

Early linkage studies and family-based studies in which there was no genotyping of colorectal cancer cases observed significant associations between BRCA1/2 mutations

Table 1 Genotype/Phenotype Correlation Studies, Listed by Type (see text), Associating BRCA1/2 Mutations with Cancer Risks

Studies (by type)

Gene type

Actual or Gall actual/ bladder Other potential No. of Colon/ Kidney/ bile Fallopian Squamous cancers carriers families rectal Stomach bladder Pancreas Liver duct Uterine Pertonium tube Cervix Prostate Lymphoma cell skin Leukemia Melanoma combined

Linkage

The Breast Cancer Linkage Consortium, 1999

Inferred genotype

Johannsson, 1999

(104) Johannsson, 1999

Sigurdsson, 1997

(105) Johannsson, 1999

Moslehi, 2000 (29)

BRCA1

BRCA1

BRCA2

BRCA1/2

29/596 5

16 20

4.1R NS NS

NS NS

X NS NS

NS NS

NS NS NS

X NS

NS NS

NS NS

NS NS

Genotyped proband

BRCA1

Genotyped proband

BRCA1

Brose, 2002 (55)

381$/102cf

147

2.0

6.9

NS

2.8

120 NS

NS

NS

Thompson, 2002

2245

699

2.0

NS

NS

2.3

4.1 NS 2.6

3.7 NS

NS

NS

NS cfNS/?2.3

(106)

Struewing, 1997

BRCA1/2

120/5218 AJ

NS

NS

NS

NS

NS

4.2

NS

NS

BRCA1

(28) Association

Kirchhoff, 2004B

(107) Edwards, 2003

(108) Ozcelik, 1997

(109) Kirchhoff, 2004A

(112) Hubert, 1999

(110) Vazina, 2000

(111) Levine, 2003

(103) Kirchhoff, 2004A (112)

BRCA1

BRCA1I2

6/586 AJ

5/263

4/39 AJ

8/251 AJ

3/87

5/174

NS 23.0

Note: Inclusion in the table was restricted to studies showing statistically significant findings, or significant null results.

Abbreviations'. AJ, Ashkenazi Jews; BC, breast cancer; CR, carriers' relatives; FT, fallopian tube; n, noncarriers' relatives; NS, not significant; PPC, primary peritoneal carcinoma; R, rectal only; X, not reported.

and colorectal cancers. Using linkage kindreds, Ford et al. (51) estimated the RR for colon cancer in BRCA1 carriers as 4.1. Johannsson et al. (104) used the Swedish Cancer Registry to derive an RR based on cancer in family members of mutation carriers (29 BRCA1 index cases and 20 BRCA2 index cases). Among female relatives of BRCA1 mutation carriers, they estimated the RR of colon cancer to be 4.1, but there was no excess risk found among male relatives. Based on kindreds derived from 649 unselected ovarian cancer index cases, Risch et al. (77) observed an elevated risk of colon cancer for BRCA2 mutation carriers with an RR of 2.5; no significant increase in risk was found for BRCA1 mutation carriers. Studies by Brose et al. (55), with subjects drawn from risk evaluation clinics, and by Thompson and Easton (106), with participants drawn from 699 kindreds across 30 centers in Western Europe and North America, both estimated a twofold RR for colon cancer among carriers of BRCA1 mutations. These family-based studies were "indirect" in that genotyping was not performed on colon cancer cases themselves, and histologic confirmation of reported family history information was also generally not provided. This leaves open the possibility for reporting bias in cases compared to controls. Chen-Shtoyerman et al. (113), in a study of 225 unselected Ashkenazi Jewish colorectal cancer patients, found the frequency of BRCA1/2 founder mutations in this group to be close to the average for the general Ashkenazi population, suggesting no increase in the risk of colorectal cancer to mutation carriers. Kirchhoff et al. (112) found no increased RR for colon cancer in BRCA1/2 mutation carriers, based on the frequency of the founder mutations in 586 Ashkenazi colon cancer patients unselected for family history, with an unaffected Ashkenazi control group of 5012 individuals. Similarly, Niell et al. (114) found no association between BRCA mutations and colorectal cancer in 1002 case patients compared to 1038 control subjects. These later studies suggest that if there is a risk for colorectal neoplasia in BRCA mutation carriers, it is very modest at best.

Stomach (Gastric) Cancer

A study by Brose et al. (55) estimated a significantly increased risk of gastric cancer among BRCA1 mutation carriers (RR = 6.9), although no increase was noted in the Thompson and Easton Study (106). Risch et al. (77) derived a similar RR of stomach cancer for BRCA1 mutation-positive individuals, but a nonsignificant risk for BRCA2 mutation carriers. Johannsson et al. (104) stratified their study by gender, as well as by gene mutation, and found a significantly elevated risk of stomach cancer in female BRCA1 carriers (RR = 5.2) but not in male carriers. They noted that classification of some of the stomach cancers may have been erroneous. The BCLC study (36) estimated an RR of stomach cancer of 2.6 based on a comparison of the observed incidence in the cohort with SEER and International Agency for Research on Cancer (IARC) data. Histologic confirmation of history of cancer was attempted only in probands and first-degree relatives, and was successful in only 48% of such cases. Because direct genotyping association studies of gastric cancer in Ashkenazi Jews have not yet been performed to confirm this association, and because the unconfirmed diagnosis of gastric and ovarian cancers may be confounding variables, the association of BRCA mutations and gastric cancer remains speculative.

Pancreatic Cancer

Several studies have claimed an increased risk of pancreatic cancer largely with BRCA2 mutation carriers; indeed BRCA2 somatic mutations were first identified in a pancreatic tumor (16). Thompson and Easton observed an elevated risk of pancreatic cancer, RR = 2.3, in BRCA1 mutation carriers (106), a finding that was confirmed in a smaller, highly selected series (55), but in only one of two larger, unselected series of BRCA -mutated ovarian cancer probands (29,77). The BCLC study (36) also found a significant excess risk of pancreatic cancer in BRCA2 mutation carriers in the study group and estimated the RR of pancreatic cancer to be 3.5. A study by Hahn et al. (115) included 26 European, non-Ashkenazi families with two or more histologically confirmed cases of pancreatic cancer and found 12% of these families to be positive for BRCA2 mutations. Murphy et al. (116) ascertained 29 U.S. kindreds with three or more cases of pancreatic cancer where two were first-degree relatives. Five families (17%) were found to harbor BRCA2 mutations. A higher than expected number of Ashkenazi individuals with pancreatic cancer harbored BRCA2 mutations in a large association study (109); and two previous studies noted that a family history of pancreatic cancer was a predictor of an increased frequency of BRCA2 mutations (117,118). Finally, a study by Lal et al. (119) ascertained 102 subjects from among newly diagnosed, histologically verified pancreatic cancer patients. Of these individuals, 14 were Ashkenazi, three of whom had a BRCA2 and one had a BRCA1 mutation. Thus, while the risk of pancreatic cancer is clearly associated with BRCA2 mutations, its association with BRCA1 mutations is still under study.

Prostate Cancer

Early linkage studies suggested an RR of prostate cancer of 3.3 among the 33 multiplex kindreds studied (51). When broken down by BRCA1 versus BRCA2, the linkage consortium found no increased risk in BRCA1-linked kindreds (106), but in BRCA2 mutation carriers, a statistically significant increase in the risk for prostate cancer was noted (RR = 4.6) (36). The RR was higher for prostate cancer before the age of 65 years (RR = 7.3). Sigurdsson et al. (105) ascertained 53 mutation-positive first-degree male relatives of breast cancer probands in known Icelandic BRCA2 kindreds. Among these men, the estimated RR of prostate cancer was 4.6. Among mutation-positive second-degree male relatives, the corresponding RR was 2.5. The 383 men in another study by Johannsson et al. (104) were all from known Icelandic BRCA2-linked kindreds and had been diagnosed with cancer. Standardized morbidity rates estimated for prostate cancer were 2.4 after male breast cancer index cases were excluded. Struewing et al. (28) compared prostate cancer incidence among first-degree relatives of carriers versus noncarriers of BRCA1/2 Ashkenazi founder mutations. The RR of prostate cancer for relatives of carriers was 4.2. However, Risch et al. (77) found no significant differences in RR for prostate cancer in BRCA1 or BRCA2 carriers compared to noncarriers, a finding similar to that of Moslehi et al. (29). Association studies have not been in agreement about the excess risk of prostate cancer attributable to BRCA1/2. Hubert et al. (110) found no excess frequency of BRCA1/2 mutations among 83 Ashkenazi with prostate cancer, unselected for family history or age; however, Kirchhoff et al. (107) noted an increased risk of prostate cancer in a larger number of cases studied. The risk was not associated with an earlier age at onset, and was seen only in Ashkenazi BRCA2 but not BRCA1 mutation carriers. Thus, prostate cancer risk is increased in BRCA2 mutation carriers, but because of the absence of earlier onset, preventive health implications are modest.

Uterine Cancer

Recent large studies have not shown an increased risk of uterine cancer in women with BRCA mutations who do not take tamoxifen (120). However, a rare subtype of uterine serous papillary cancer (USPC), resembling serous papillary carcinoma of the ovary or the peritoneum, may be associated with BRCA mutations. USPC is more aggressive than endometrial uterine cancer, is generally diagnosed in late stages, usually has a poor prognosis, and responds to treatment modalities employed in ovarian cancer (121). A study by Biron-Shental et al. (122) found that 6 of 22 patients (27%) with USPC had BRCA1 or BRCA2 mutations; four of the six had prior histories of breast or ovarian cancer. The authors of these three studies have suggested, based on these data, that USPC may be part of the spectrum of HBOC syndrome.

No increase in uterine cancers was noted in the linkage consortium analysis of BRCA2 mutation-carrying kindreds (36). Moslehi et al. (29) estimated that for first-degree relatives of ovarian cancer cases with BRCA mutations, the RR for uterine cancer was 6.5 at the age of 75 years; however, this was based only on four cases of reported cancer in relatives of BRCA1 mutation carriers. Risch et al. (77), based on a population-based series of 649 ovarian cancer cases, estimated the RR of uterine cancer to first-degree relatives of carriers to be not significantly elevated when compared to the relatives of noncarriers. Thompson and Easton (106) in a study of 699 kindreds and 2245 BRCA1 mutation carriers, estimated the RR of uterine cancer to carriers of BRCA1 mutations to be 2.65. However, in this study, as well as the previous studies, the BRCA genotype was inferred in relatives and/or the reported family histories of uterine cancers were not confirmed. Indeed, Thompson et al. indicate that some of the reported cases of uterine cancer may have been ovarian cancers. In a consecutive series of 199 Ashkenazi patients with endometrial carcinoma tested for the presence of BRCA1/2 mutations, only three (1.5%) were found to have BRCA1/2 mutations, which is below the ~2.5% frequency in the Ashkenazi population at large (123). None of these were of serous papillary subtype. The issue of uterine cancer risk in BRCA mutation carriers takes on significance because of the question regarding whether hysterectomy (removal of the uterus) as well as oophorectomy (removal of ovaries and FTs) represents the optimal risk-reducing surgical intervention in BRCA mutation carriers. Since large series have thus far not demonstrated an increased risk for uterine cancer in BRCA mutation carriers (120), oophorectomy and removal of the FTs remains an acceptable option to hysterectomy and oophorectomy. A separate issue in this clinical decision relates to possible risks associated with residual FT-derived tissue. Such foci, along with the larger amount of peritoneal tissue, remain potential sources for hereditary gynecologic malignancies in patients following risk-reducing surgeries.

Malignant Melanoma

An increased risk of cutaneous malignant melanoma associated with having an affected family member was quantified (OR = 2.69) in a study by Holman and Armstrong (124). It has been estimated that 8% to 12% of cases are attributable to inherited factors (11). There is a known association of malignant melanoma with a mutation in CDKN2 on chromosome 9 that codes for p16, another important regulator of the cell division cycle (125). Several studies have demonstrated an association of BRCA mutations and malignant melanoma. In 3728 individuals in 173 breast-ovarian cancer families with BRCA2 mutations, the BCLC (36) estimated a statistically significant RR for malignant melanoma of 2.58. However, a study by van Asperen et al. (126) noted no significant excess risk of malignant melanoma associated with BRCA mutations in first-degree relatives of mutation carriers in 139 BRCA2 families; and Johannesdottir et al. (33) concluded that BRCA2 accounts for a significant fraction of breast and ovarian cancer, but only a small proportion of other cancers, including malignant melanoma.

Risk of Contralateral Breast Cancer

The 10-year risks of contralateral breast cancer following the diagnosis of breast cancer in women who did not have an oophorectomy or take tamoxifen were 43.4% for BRCA1 carriers and 34.6% for BRCA2 carriers, confirming the estimates made from linkage studies (127). This risk can be reduced substantially by hormonal chemoprevention and/ or oophorectomy. Indeed, the widespread clinical acceptance of these procedures will impact on future prospective estimates of contralateral breast cancer risk in BRCA mutation carriers.

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