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Management of reproductive health in Cowden syndrome complicated by endometrial polyps and breast cancer.

ABSTRACT: BACKGROUND:Cowden syndrome is an autosomal-dominant condition associated with mutations in the tumor suppressor gene PTEN. Gynecologic malignancies are common with a 5-10% risk of endometrial cancer and 25-50% risk of breast cancer. CASE:A 37-year-old woman with a history of breast cancer, other neoplasms, and multiple skin lesions was diagnosed with Cowden syndrome after a germline PTEN mutation was identified. The endometrium had high glucose uptake on positron emission tomography scan and was irregularly thickened on ultrasonography; biopsy revealed endometrial polyps and simple hyperplasia. Fifteen months later, hysteroscopy again confirmed numerous benign endometrial polyps. CONCLUSION:Recurrent, multiple endometrial polyps portend a high risk of endometrial cancer in women with Cowden syndrome. Monitoring for malignancy and consideration of hysterectomy after childbearing is completed is warranted.

SUBMITTER: Kalin A

PROVIDER: S-EPMC3799979 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Management of reproductive health in Cowden syndrome complicated by endometrial polyps and breast cancer.

Kalin Asli A Merideth Melissa A MA Regier Debra S DS Blumenthal Gideon M GM Dennis Phillip A PA Stratton Pamela P

Obstetrics and gynecology 20130201 2 Pt 2 Suppl 1

<h4>Background</h4>Cowden syndrome is an autosomal-dominant condition associated with mutations in the tumor suppressor gene PTEN. Gynecologic malignancies are common with a 5-10% risk of endometrial cancer and 25-50% risk of breast cancer.<h4>Case</h4>A 37-year-old woman with a history of breast cancer, other neoplasms, and multiple skin lesions was diagnosed with Cowden syndrome after a germline PTEN mutation was identified. The endometrium had high glucose uptake on positron emission tomograp ...[more]

PMID: 23344409

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Project description:BackgroundCowden syndrome is a rare autosomal-dominant disease with a high risk of malignant tumors of the breast, commonly caused by germline mutations in the PTEN gene. Most breast cancers related to Cowden syndrome showed typically a slow-growing and favorable clinical course. Here, we report a progressive case of triple-negative breast cancer in a patient who was diagnosed with Cowden syndrome.Case presentationA 35-year-old female with breast cancer was referred to our hospital. Histopathological examination of the tumor showed that it was triple-negative breast cancer with high proliferation marker. Preoperative positron emission tomography-computed tomography showed abnormal uptake in the left cerebellar hemisphere in addition to the right breast and axillary lymph node. Brain T2-weighted magnetic resonance imaging revealed hyperintense bands in the left cerebellar hemisphere lesion, which demonstrated a "tiger-stripe" appearance. The patient's mother had died of endometrial cancer. Subsequently, she underwent genetic testing, leading to a diagnosis of Cowden syndrome with a pathogenic variant c.823_840del.18 at exon 8 in PTEN. She was treated with neoadjuvant chemotherapy of eribulin and cyclophosphamide followed by adriamycin and cyclophosphamide. However, her tumors increased after these treatments. She was immediately surgically treated and received adjuvant chemotherapy of capecitabine. Unfortunately, the cancer recurred in the lung nine months after surgery. We then administered paclitaxel and bevacizumab therapy, but the disease rapidly progressed. Consequently, the patient died due to breast cancer about three months after recurrence.ConclusionWe report an aggressive case of cancer with Cowden syndrome which was resistant to standard chemotherapy. Alteration of the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin pathway due to inactivating PTEN protein may be associated with chemoresistance and serves as a candidate for therapeutic intervention in PTEN-related cancers.

Project description:Cowden syndrome (CS), a Mendelian autosomal-dominant disorder, predisposes to breast, thyroid and other cancers. Germline mutations in phosphatase and tensin homolog (PTEN) have been recently reported in 23% of a large series of classic CS. Here, we validated our small (n = 10) pilot study in a large patient series that germline variations in succinate dehydrogenase genes (SDHx) occur in 8% (49/608) of PTEN mutation-negative CS and CS-like (CSL) individuals (SDH(var+)). None of these SDHx variants was found in 700 population controls (P < 0.0001). We then found that SDHx variants also occur in 6% (26/444) of PTEN mutation-positive (PTEN(mut+)) CS/CSL individuals (PTEN(mut+)/SDH(var+)). Of 22 PTEN(mut+)/SDH(var+) females, 17 had breast cancers compared with 34/105 PTEN(mut+) (P < 0.001) or 27/47 SDH(var+) patients (P = 0.06). Notably, individuals with SDH(var+) alone had the highest thyroid cancer prevalence (24/47) compared with PTEN(mut+) patients (27/105, P = 0.002) or PTEN(mut+)/SDH(var+) carriers (6/22, P = 0.038). Patient-derived SDH(var+) lymphoblastoid cells had elevated cellular reactive oxygen species, highest in PTEN(mut+)/SDH(var+) cells, correlating with apoptosis resistance. SDH(var+) cells showed stabilized and hyperactivated hypoxia inducible factor (HIF)1? signaling. Most interestingly, we also observed the loss of steady-state p53 in the majority of SDH(var+) cells. This loss of p53 was regulated by MDM2-independent NADH quinone oxidoreductase 1-mediated protein degradation, likely due to the imbalance of flavin adenine dinucleotide/nicotinamide adenine dinucleotide in SDH(var+) cells. Our data suggest the potential regulation of HIF1?, p53 and PTEN signaling by mitochondrial metabolism in CS/CSL tumorigenesis. Together, our findings suggest the importance of considering SDHx as candidate predisposing and modifier genes for CS/CSL-related malignancy risks, and a mechanism which suggests ways of therapeutic reversal or prevention.

Project description:ContextGermline loss-of-function phosphatase and tensin homolog gene (PTEN) mutations cause 80% of Cowden syndrome, a rare autosomal-dominant disorder (1 in 200,000 live births), characterized by high risks of breast, thyroid, and other cancers. A large heterogeneous group of individuals with Cowden-like syndrome, who have various combinations of Cowden syndrome features but who do not meet Cowden syndrome diagnostic criteria, have PTEN mutations less than 10% of the time, making molecular diagnosis, prediction, genetic counseling, and risk management challenging. Other mechanisms of loss of function such as hypermethylation, which should result in underexpression of PTEN or of KILLIN, a novel tumor suppressor transcribed in the opposite direction, may account for the remainder of Cowden syndrome and Cowden-like syndrome.ObjectiveTo determine whether germline methylation is found in Cowden syndrome or Cowden-like syndrome in individuals lacking germline PTEN mutations.Design, setting, and participantsNucleic acids from prospective nested series of 123 patients with Cowden syndrome or Cowden-like syndrome and 50 unaffected individuals without PTEN variants were analyzed for germline methylation and expression of PTEN and KILLIN at the Cleveland Clinic, August 2008-June 2010. Prevalence of component cancers between groups was compared using the Fisher exact test.Main outcome measuresFrequency of germline methylation in PTEN mutation-negative Cowden syndrome and Cowden syndrome-like individuals. Prevalence of component cancers in methylation-positive and PTEN mutation-positive individuals.ResultsOf 123 patients with Cowden syndrome or Cowden-like syndrome, 45 (37%; 95% confidence interval [CI], 29%-45%) showed hypermethylation upstream of PTEN but no transcriptional repression. The germline methylation was found to transcriptionally down-regulate KILLIN by 250-fold (95% CI, 45-14 286; P = .007) and exclusively disrupted TP53 activation of KILLIN by 30% (95% CI, 7%-45%; P = .008). Demethylation treatment increased only KILLIN expression 4.88-fold (95% CI, 1.4-18.1; P = .05). Individuals with KILLIN -promoter methylation had a 3-fold increased prevalence of breast cancer (35/42 vs 24/64; P < .0001) and a greater than 2-fold increase of kidney cancer (4/45 vs 6/155; P = .004) over individuals with germline PTEN mutations.ConclusionsGermline KILLIN methylation is common among patients with Cowden syndrome or Cowden-like syndrome and is associated with increased risks of breast and renal cancer over PTEN mutation-positive individuals. These observations need to be replicated.

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Management of reproductive health in Cowden syndrome complicated by endometrial polyps and breast cancer.

Publications

Management of reproductive health in Cowden syndrome complicated by endometrial polyps and breast cancer.

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