Abstract
IntroductionBreast carcinoma is the most common cancer in women, but its incidence is not increased in Lynch syndrome (LS) and studies on DNA mismatch repair deficiency (MMR) in LS-associated breast cancers have arrived at conflicting results. This study aimed to settle the question as to whether breast carcinoma belongs to the LS tumor spectrum.MethodsMMR status and epigenetic profiles were determined for all available breast carcinomas identified among 200 LS families from a nation-wide registry (23 tumors from mutation carriers and 18 from non-carriers). Sporadic breast carcinomas (n = 49) and other cancers (n = 105) from MMR gene mutation carriers were studied for comparison.ResultsThe proportion of breast carcinomas that were MMR-deficient based on absent MMR protein, presence of microsatellite instability, or both was significantly (P = 0.00016) higher among breast carcinomas from mutation carriers (13/20, 65%) compared to non-carriers (0/14, 0%). While the average age at breast carcinoma diagnosis was similar in carriers (56 years) and non-carriers (54 years), it was lower for MMR-deficient versus proficient tumors in mutation carriers (53 years versus 61 years, P = 0.027). Among mutation carriers, absent MMR protein was less frequent in breast carcinoma (65%) than in any of seven other tumor types studied (75% to 100%). Tumor suppressor promoter methylation patterns were organ-specific and similar between breast carcinomas from mutation carriers and non-carriers.ConclusionsBreast carcinoma from MMR gene mutation carriers resembles common breast carcinoma in many respects (for example, general clinicopathological and epigenetic profiles). MMR status makes a distinction: over half are MMR-deficient typical of LS spectrum tumors, while the remaining subset which is MMR-proficient may develop differently. The results are important for appropriate surveillance in mutation carriers and may be relevant for LS diagnosis in selected cases.
Highlights
Breast carcinoma is the most common cancer in women, but its incidence is not increased in Lynch syndrome (LS) and studies on DNA mismatch repair deficiency (MMR) in LS-associated breast cancers have arrived at conflicting results
The percentage of MMR-deficient breast carcinomas was lower among human mutS homolog 6 (MSH6) mutation carriers (2/6, 33% by IHC and 0/7 by microsatellite instability (MSI) analysis) compared to carriers of human mutS homolog 2 (MSH2) (3/3, 100% and 3/5, 60%, respectively) or human mutL homolog 1 (MLH1) mutation (8/11, 73% and 5/11, 45%, respectively)
The breast carcinomas we studied from MMR gene mutation carriers were predominantly ductal, estrogen receptor (ER)- and progesterone receptor (PR)-positive and human epidermal growth factor receptor 2 (HER2)-negative, resembling breast carcinomas from noncarriers (Table 1) and those from the unselected Finnish population [33,41]
Summary
Breast carcinoma is the most common cancer in women, but its incidence is not increased in Lynch syndrome (LS) and studies on DNA mismatch repair deficiency (MMR) in LS-associated breast cancers have arrived at conflicting results. Germline mutation in one of four genes with DNA mismatch repair (MMR) function, MLH1, MSH2, MSH6, and PMS2, causes susceptibility to cancers of multiple organs known as Lynch syndrome (LS) [1]. Among all cancers, those of the colon and rectum, endometrium, Breast cancer is the most common cancer among women worldwide [4]. Those of the colon and rectum, endometrium, Breast cancer is the most common cancer among women worldwide [4] It is presently not included in the LS tumor spectrum because its incidence has not been found to be elevated in LS patients, whether carriers of MLH1 or MSH2 mutation [5,6,7,8] or MSH6 mutation [9]. Among Brazilian families meeting the most stringent clinical (Amsterdam I) criteria for LS [12] but with no mutation data available, breast cancer was the most frequent extracolonic cancer in women, even exceeding the frequency of endometrial cancer [13]
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