Breast Cancer and Melanoma in the Same Pedigree
1. Professor of Clinical Surgery, New Jersey Medical School, University of Medicine and Dentistry, Newark, New Jersey. Attending Surgeon, Department of Surgery, St. Barnabas Medical Center, Livingston, New Jersey. firstname.lastname@example.org
This report is to document the occurrence of breast cancer and melanoma within either the same pedigree or the same patient and to make others aware of this association. A series of 52 patient pedigrees is presented from one clinical practice in which both breast cancer and melanoma were found over a 30-month period. It is suggested that formal pedigrees be obtained in addition to routine medical history questionnaires when either breast cancer or melanoma are encountered. It is further suggested that patients with either malignancy be screened for the other.
Few publications have been written about those mutations that may be predisposing to both breast cancer and melanoma [1-8]. Similarly, there are relatively few observations that breast cancer and melanoma occur within the same pedigree [9, 10, 11, 12]. Additional observations have been made of melanoma and breast cancer occurring within the same patient [13, 14, 15, 16, 17].
The p16 gene is an autosomal dominant tumor suppressor gene that is associated with 20-40 percent of inherited melanoma cases. It has been estimated that 10 percent of all melanomas are hereditary. Melanoma families are found to also have links to pancreatic cancer but not necessarily breast cancer . The BRCA1 gene accounts for 45 percent of hereditary breast cancer but is not associated with an increased risk for melanoma . The BRCA2 gene, on the other hand, has been associated not only with an increased risk for breast cancer but also with increased risk for melanoma [6, 11]. The Li-Fraumeni syndrome, associated with mutations in the p53 gene, has also been associated with both breast cancer and melanoma.
Author MHS has observed the occurrence of breast cancer and melanoma in the same pedigree and not infrequently in the same patient. Thus the presentation of such a group of patients is thought to be important.
Materials and Methods
In the course of obtaining family histories of malignancy the co-existence of breast cancer and melanoma was repetitive enough that a prospective investigation was started. Over two and one-half years, 52 such pedigrees were recorded. A pedigree was not obtained from all patients.
Patients completed a medical history form inquiring about a family history of breast cancer, ovarian cancer or any other cancer in a blood relative. They were then questioned verbally specifically as to whether any of the following malignancies were present: colon, prostate, leukemia, lymphoma, salivary gland or melanoma. If any were identified, a formal pedigree was obtained. It was not possible to verify the accuracy of the malignancies reported by the patients.
Patient medical records were abstracted and entered into FileMaker® Pro 8, analyzed, and presented in Tables 1 and 2 (Filemaker Inc., 5201 Patrick Henry Drive, Santa Clara, California 95054).
Fifty-two patients with breast cancer and melanoma in an individual or their pedigree were identified. Of the 52 patients studied 24 patients had breast cancer themselves and 15 patients had a history of melanoma themselves. Five of the studied patients had a personal history of both a breast cancer and a melanoma. Table 1 reflects the distribution of breast cancer and melanoma within the 52 patients and their relatives. Table 2 offers a representation of the cancers other than breast or melanoma within the pedigree.
Four patients had testing for the BRCA1 and BRCA2 genes. One patient was positive for a BRCA1 mutation.
The identification of 52 distinct melanoma and breast cancer pedigrees within a 30-month time frame in a single clinical practice, suggests that the association of breast cancer and melanoma may be far more common than is usually recognized. Each patient received a personal interview with author MHS to confirm the accuracy of malignancy diagnoses. Genetic testing was discussed when appropriate with patients; however, age, religion, insurance coverage, denial, and other considerations precluded testing of the majority. The medical literature has approached the genetic relationship and clinical associations of breast cancer and melanoma from a number of different approaches. They are:
1. Breast cancer patients subsequently developing a melanoma
Mutations in the BRCA2 gene have been observed in breast-ovarian cancer families such that the relative risk for melanoma was 2.6 [9, 11]. A number of studies devoted to identifying second cancers in women who have had breast cancer have noted an excess of melanoma [20-26]. Goggins et al. specifically noted a 42 percent increased risk of melanoma in breast cancer patients following radiation . Similarly, Satram-Hoang et al.  observed an increase in melanoma as a second cancer in men who have had breast cancer.
Weitzen et al.  noted an excess risk for melanoma in women with breast cancer. No excess risk for breast cancer was noted in the melanoma patients. Data from the Connecticut Tumor Registry found an increased occurrence of melanoma and breast cancer in the same patient .
2. Melanoma patients subsequently developing breast cancer
Utilizing a large Utah population and genealogic database, Larson et al.  studied the incidence of non-melanoma malignancies in relatives of patients having had a melanoma and found an increased risk for breast cancer as well as other cancers.
Borg et al.  reported a series of 52 melanoma families and noted an increase in breast cancer. A report from the Massachusetts General Hospital  identified 22 patients with melanoma who either had a preceding breast cancer or developed one after developing the melanoma.
Rio et al.  concluded that there was not a statistical increase in breast cancer following melanoma. Schmid-Wendtner et al.  and Bhatia et al.  at the City of Hope National Medical Center both found no increase in breast cancer in melanoma patients.
3. References specifically devoted to genetic alterations
Ghiorzo et al.  notes that the CDKN2A gene is often mutated in many tumor types including but not limited to breast cancer and melanoma. Prowse et al.  suggest that mutations affecting p16 INK4A/p14ARF or both may predispose to breast cancer in melanoma prone kindreds but are not a common event in other families in which breast cancer is predominant. Debniak et al.  however, found no causative mutations in the CDKN2A/ARF genes in families with an aggregation of melanoma and breast cancer.
Walsh et al.  found that the mutational spectra of BRCA1 and BRCA2 include many high-penetrance, individually rare, genomic rearrangements. Gast et al.  state that melanomas in general are characterized by a high frequency of somatic mutations in the B-RAF and N-RAS genes. Such mutations are not common in breast cancers. Hemminki et al.  comment that breast cancer genes and melanoma genes interact such that with melanoma in the father and breast cancer in the mother there is an increased relative risk of breast cancer and melanoma in the offspring.
Jing et al.  studying sporadic breast cancer patients concluded that hypermethylation of BRCA1, p16 and 14-3-3s is present in all histologic types, stages and grades in sporadic breast cancer and can be detected in serum DNA. Monnerat et al.  screened individuals who had both breast cancer and melanoma for germline mutations. They found that 23 percent of such individuals with a positive family history for either breast cancer or melanoma had a germline mutation as contrasted with only 4 percent of such individuals without a family history of either.
Author MHS has previously documented [37, 38, 39] that patients are poor historians and it is important to document formal pedigrees. It is likely, given the date presented herein, that the frequency of an association between breast cancer and melanoma must be far more common than has been publicized. Additional prospective studies are warranted to confirm the extent of this association, but unfortunately such studies either retrospectively or prospectively are not possible on this patient population because the records are not electronic and author MHS has retired from clinical practice. Our goal is to enhance awareness of this association so that individuals with both breast cancer and melanoma in their pedigree will be screened carefully for the other malignancy and their blood relatives alerted to this occurrence.
Acknowledgements: Author MHS wishes to acknowledge the encouragement of dermatologists Dr. Roger Brodkin of the St. Barnabas Medical Center, Livingston, New Jersey and Dr. David Polsky of New York University Medical Center, New York City in pursuing this report.
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